What is critical thinking? We all make mistakes even when we are intentially trying to think critically. I recently posted a comment on a blog criticizing big pharma and the FDA for their influence on science. The first rebuttal I received informed the world that I was a left winger with an anti-science attitude, and that I lacked critical thinking skills.
The statement was, "The biggest problem facing medical science comes from the Pharmaceutical industry and the FDA".
The rebuttal: "This is an excellent example of the anti-scientific thinking on the left. The science isn't the problem in the pharmaceutical industry or the FDA (capitalism and deregulation are the problems)."
Now let's break down the rebuttal in terms of critical thinking.
Question A: I'm a left winger.
The comment that I made was on a left wing blog. That is the bias that a critical thinker must avoid. I made no comment regarding my political viewpoints.
Question B: I'm anti-science.
Once it was assumed that I was a left winger it must be assumed that I am vehemently against all things that involve authority. However I made no negative comments regarding science. Rather I derided the influence big pharma and the FDA is having on the scientific process in medicine.
The last sentence, "The science isn't the problem in the pharmaceutical industry or the FDA" represents the real break down in critical thinking.
I say the science (X) is good. Big pharma (Y) and the FDA (Z) have a negative influence on science (X).
The rebuttal says that X isn't the problem in Y and Z. In parenthesis we see that capitalism (C) and deregulation (D) are the problems.
I claim that Y and Z have negatively influenced X.
The rebuttal claims that C and D have negatively influenced Y and Z.
It is assumed then (in the rebuttal) that X is merely a subset of Y and Z and thus cannot be influenced by them.
Science is never a subset of any other organization. It exists in the minds of men. It can be used by anyone who choses to try it. When big pharma goes through the FDA to put a drug on the market they are telling us that they used science to determine that the drug will alleviate some ailment that occurs in the human body. Quite often this is not the case. They manipulate data, which does not serve those engaged in the scientific process. Since the process involves many people putting together many pieces of the puzzle, anyone throwing in nonsense will create confusion along the path to the truth. They hire scientists but use their own ghost writers to write up the papers for the hired scientists to sign their names to. This is a shamefully anti-science practice meant to lend credence to the companies non-scientific marketing of their product.
I could go on but I'll stop there. The problem I encountered with my comment was that it appeared that I was attacking science. We want advances in medicine as much as the Cargo Cults want the cargo. We look to any organization who employs "science" to bring us our hopes and dreams in a neat little pill. The problem is that science is more than white lab coats and big words. You have to have the ability to cut through your biases and think critically about the issues at hand. What really matters? Nature will let you know if you set up your experiments properly. If you consider science a subset of the corporate process then you will have a hard time getting to the truth.
Wednesday, August 23, 2006
Tuesday, August 22, 2006
Visualize the Curves
This is a sigmoidal curve. It represents a system where something happens (y axis) as something is increased (x axis). In the case of the ELISA assay, we could be looking at an increase in absorbance as an antibody concentration is increased. Perhaps we're looking at the HIV ELISA. How can we describe the development of this assay?
Bob Gallo describes it without the useful graph. In 1984 they reported their assay as:
"100% of the AIDS sera were scored positive...84% of the lymphadenopathy patients were found to have serum antibodies to HTLV-III... 21% of healthy homosexual men with an increased risk of AIDS were also positive. No heterosexual controls... had antibodies to HTLV-III. The results strongly indicate that the antibodies to HTLV-III are diagnostic of AIDS or indicate significant risk of the disease, and suggest that HTLV-III is the primary cause of human AIDS."
The Gallo approach appears to be to test people using the ELISA assay. A signal equals HIV. So, if there serum produces a signal on the ELISA they have HIV which corralates with their illness (AIDS). That's not unreasonable, but what about the actual data? What is the cut off signal for a positive and negative signal? Midway up the sigmoidal curve? Let's add another curve to the chart the represents the negative patients blood serum.
The amount of protein in the sera can cause background signal. As you dilute the sera you will reduce the signal. On the sigmoidal curve chart we add a negative curve. It stays with the sigmoidal curve (moving from x and y equal zero) until that curve starts to rise. The negative curve stays close to the base line but gradually slopes up where it will again meet up with the sigmoidal curve. At this point in the x axis we are experiencing false negatives.
Using these two curves we can thus define the false negative and a false positive as points on the x axis. That means at some dilution of blood serum both HIV positive and HIV negative people will give the same signal. There will be a range in between these two point where negative and positive sera can be distinguished. The ideal concentration (dilution) will be where the positive signal has plateaued and the negative signal has not begun to rise. Since this is not the range where you will get false positives or false negatives it can be called the positive positive/positive negative range or ++/+- range. The x axis represents concentrations. They can thus be defined in the following manner
False negative: When positive control give no signal. --
False positive: When negative control gives a signal. -+
Positive positive: When positive control gives a signal ++
Positive negative: When negative control gives no signal +-
at concentrations A, B, C, D, E, F, and G
Positive control A-- B-- C++ D++ E++ F++ G++
Negative control A+- B+- C+- D+- E+- F-+ G-+
We can define our useful ELISA assay range as concentrations C, D and E.
The single data point ELISA followed up with a corralation to AIDS patients and a negative control group is not rigorous science. The assay development should begin by defining the positive and negative curves. Then you can think about changing a blocking buffer perhaps. Does it separate the ++/+- range further? Every tweak to the system must strive for that result. You are trying to get the ++ part to start as soon as possible along the x axis. That means you want to make the ELISA highly sensative to HIV antibodies. You want the false positive signal (-+) to start as late as possible. That means you want the assay to not be sensative to background proteins.
You will find yourself in meetings where Cargo Cult Scientists gather to discuss ELISAs. They will each have a repertoire of buzzwords for buffers, plate readers, plate washers, conjugated antibodies, substrates and graphing software. No one will talk about the curves. But it is the curves that explains how each change in buffers, plate readers and so on, will affect the system you are tying to set up.
Friday, August 18, 2006
Two Cans of Pears
Imagine a case of canned pears, unlabeled in aluminum cans. Pull out two cans. Label one with a brand name such as Delmonte and on the other put a generic looking sticker that says Pears. It is my firm belief that most people who try the pears and would pick the brand name pears as superior quality canned pears. Furthermore, if you were to hire a group of scientists to prove that the first can of pear is better than the next, they would successfuly complete the mission.
I also believe that science can be applied to anything. That would include the psychology of scientists. One way to test science would be to knowingly hire scientists to do something you know is wrong, such as analyzing two identical cans of pears with the goal of proving one superior to the other. When they get the results you wanted them to get, they have to get published. Once that is done you reveal the hoax and study the reactions of all who were involved. What you are studying is the process of pathological science. You could address motives, methods, the contributions of others, the response from the authorities and maybe even the response to the notion of being tested. No one likes to be tested when they are unaware that it is taking place. Yet everyday people go to work and make a contribution to their eventual evaluation. Shouldn't science be given an evaluation from time to time?
It is time to evaluate science on a grander scale than ever before. The reason is because science is operating on a grander scale than ever before. And lately things have gotten out of control. The drug money coming in has made some serious alterations to what was once considered science. Asking the drug companies to be honest about their drugs is like asking Delmonte to be honest about the quality of their canned pears.
The "Two Cans of Pears" scenario has a way around claims that one is superior to the other. You simply have to stop looking at the label and put a bar code on the can. Likewise, drugs need to have a non-marketing label. The motivations of drug companies must be taken out of the picture. The current model for clinical trials is often to have the drug company run the trials, analyze the data and report to the FDA. There needs to be a way to get the data points analyzed prior to any knowledge of what group they belong to. In other words, we need blind trials in the true sense of the word blind. The drugs need to be tested like a tin can that contains pears. Analyze what is inside and make your judgements. When it's done, take a look at the marketing label. Not before.
I also believe that science can be applied to anything. That would include the psychology of scientists. One way to test science would be to knowingly hire scientists to do something you know is wrong, such as analyzing two identical cans of pears with the goal of proving one superior to the other. When they get the results you wanted them to get, they have to get published. Once that is done you reveal the hoax and study the reactions of all who were involved. What you are studying is the process of pathological science. You could address motives, methods, the contributions of others, the response from the authorities and maybe even the response to the notion of being tested. No one likes to be tested when they are unaware that it is taking place. Yet everyday people go to work and make a contribution to their eventual evaluation. Shouldn't science be given an evaluation from time to time?
It is time to evaluate science on a grander scale than ever before. The reason is because science is operating on a grander scale than ever before. And lately things have gotten out of control. The drug money coming in has made some serious alterations to what was once considered science. Asking the drug companies to be honest about their drugs is like asking Delmonte to be honest about the quality of their canned pears.
The "Two Cans of Pears" scenario has a way around claims that one is superior to the other. You simply have to stop looking at the label and put a bar code on the can. Likewise, drugs need to have a non-marketing label. The motivations of drug companies must be taken out of the picture. The current model for clinical trials is often to have the drug company run the trials, analyze the data and report to the FDA. There needs to be a way to get the data points analyzed prior to any knowledge of what group they belong to. In other words, we need blind trials in the true sense of the word blind. The drugs need to be tested like a tin can that contains pears. Analyze what is inside and make your judgements. When it's done, take a look at the marketing label. Not before.
Wednesday, August 16, 2006
30 Million for a New Airport
The people of Florida have never read The Cargo Cult Scientist. They are debating whether or not to shell out another 30 million dollars to Scripps Research Institute. The Torrey Pines Institute for Molecular Studies wants $21 million in county money to put its headquarters in Boca Raton, creating 189 jobs. Scripps and IBM want $9 million to help establish the world's fastest supercomputer to battle avian flu, creating 42 jobs. That's 30 million to bring in 231 workers earning an average of around 56 thousand dollars per year.
Of course local governments want to attract business, create jobs and stimulate the economy. The question is whether or not Biotechnology is the industry to invest in.
Boca Raton Commissioner Burt Aaronson noted that in 2003, the county's $200 million-plus pledge to Scripps was supposed to spark a biotech bonanza. Scripps "was supposed to be the magnet, bringing everybody here," Aaronson said. "Evidently, they're not that magnet. They bring people here asking for more money."
ZING!!!
The same thing has happened all over the country. Biotechnology was supposed to be huge. In some areas it has been. Amgen and Genentech have generated jobs at a staggering pace. Overall however the industry has been a disaster. Maryland put up 20 million dollars to set up the Gallo Institute for Cargo Cult Alumnus Bob Gallo. Gallo had predicted 350 jobs and to be self supporting in a matter of a few years. Three years later he had 90 employees and was still dependent on tax payer money. All of his spin off companies were flops. In Seattle Paul Allen has developed a plan to bring Biotech to the South Lake Union area. So far no one has come. Even Lincoln Nebraska has started an organization to bring the industry to the cornfields.
It takes a lot of money for a company to succeed. The success of their products in human bodies is another story. What the local governments are asking for are Cargo Cult Airports hoping that the better the airport, the better the chances are of getting some cargo. It takes money even if you have a good drug. Very few biotech companies have any drug at all. They come with promises of a new and innovative technology that will change the way people look at drug development. They are all world leaders. They all promise big things. And they all come asking for money.
Florida is getting wise. The Biotechnology industry has become very good at obtaining funding. Everyone wants in on the success. But what brings success? Money? Money is suppose to go into the big idea that generates more money. However, it seems that the only money being made are by those who work for the companies who gobble up the capital. Florida is making a big step today. Scripps has been around a long time. Is it in their track record that they generate profits for the local economy? Is it worth the investment?
Of course local governments want to attract business, create jobs and stimulate the economy. The question is whether or not Biotechnology is the industry to invest in.
Boca Raton Commissioner Burt Aaronson noted that in 2003, the county's $200 million-plus pledge to Scripps was supposed to spark a biotech bonanza. Scripps "was supposed to be the magnet, bringing everybody here," Aaronson said. "Evidently, they're not that magnet. They bring people here asking for more money."
ZING!!!
The same thing has happened all over the country. Biotechnology was supposed to be huge. In some areas it has been. Amgen and Genentech have generated jobs at a staggering pace. Overall however the industry has been a disaster. Maryland put up 20 million dollars to set up the Gallo Institute for Cargo Cult Alumnus Bob Gallo. Gallo had predicted 350 jobs and to be self supporting in a matter of a few years. Three years later he had 90 employees and was still dependent on tax payer money. All of his spin off companies were flops. In Seattle Paul Allen has developed a plan to bring Biotech to the South Lake Union area. So far no one has come. Even Lincoln Nebraska has started an organization to bring the industry to the cornfields.
It takes a lot of money for a company to succeed. The success of their products in human bodies is another story. What the local governments are asking for are Cargo Cult Airports hoping that the better the airport, the better the chances are of getting some cargo. It takes money even if you have a good drug. Very few biotech companies have any drug at all. They come with promises of a new and innovative technology that will change the way people look at drug development. They are all world leaders. They all promise big things. And they all come asking for money.
Florida is getting wise. The Biotechnology industry has become very good at obtaining funding. Everyone wants in on the success. But what brings success? Money? Money is suppose to go into the big idea that generates more money. However, it seems that the only money being made are by those who work for the companies who gobble up the capital. Florida is making a big step today. Scripps has been around a long time. Is it in their track record that they generate profits for the local economy? Is it worth the investment?
Tuesday, August 15, 2006
John Darsee, Cargo Cult Alumnus
The case of John Darsee teaches us an important lesson here at the Cargo Cult Scientist. He was indeed a Cargo Cult Scientist in the area of heart damage. He worked at a top laboratory in a top institution, at Harvard Medical School, and he had published over 125 research articles, book chapters, shorter papers and abstracts. His boss at Harvard had authored more the 600 papers. These guys were accomplished at the one thing that will speed up any career in modern science, getting published.
Getting published requires skill in understanding what people want to hear and how to write about it. That doesn't mean that you have skills in scientific research, merely writing up what people want to hear. Those who accept or reject your paper will not be going into the lab to watch you work. Nor will they require any evidence that you actually did the work such as lab notebooks or any other form of raw data. The powers that be will read what you send in and use their superior knowledge of, well... reading papers, to determine if what you said is the honest truth or not. Furthermore, they will also know if you used all of the proper controls and formed the proper conclusions. Getting published means getting into the heads of these sorts and writing a paper that they can stand behind. It must then support their own theories, flatter their own body of work, and be authored and co-authored by respected individuals working at respected institutions and universities.
John Darsee and his boss Eugene Braunwald certainly had what it takes to get published. 109 of Darsees papers had 47 co-authors so there were plenty of people verifying the work. Yet Darsee managed to fool them all. He had fabricated data for many of his publications. In one startling case he proposed that a 17 year old subject had four children, ages 8, 7, 5, and 4. Eugene Braunwald didn't see it. The co-authors didn't do the math that would make the father 8 or 9 at the time of his first childs birth. The referees who read the paper didn't see it. The editor didn't see it. The readers of the article didn't see it either. Not until the notorious NIH duo Feder and Stewart got involved did anyone bother to bring up this puzzling set of data.
But not everyone was convinced that John Darsee was infallible. At Harvard three of Darsees laboratory colleagues started to wonder where he was getting all of the good data. They soon became convinced that he was outright making it up. They reported their suspicions up the chain of command forcing Darsee to finally show his superiors some raw data. Back in the lab he set out to obtain the final set of data to be presented. With co-workers looking on he began to mark down his data, Day 1, Day 2..., thus demonstrating his most effective method of obtaining positive data. You just make it up as you need it.
Three laboratory workers uncovered what 47 co-authors, scores of superiors and journal editors could not see. John Darsee was a fake. But he was a skilled paper writer and that is what made him a star early in life. The culture still exists. It is of course, The Cargo Culture, that we are interested in here on this blog. John Darsee is a high ranking member of the cult. He knew absolutely nothing about airplanes but he knew what the leaders wanted to hear. Not the sound of airplanes coming from the sky, but the sound of their own ideas being backed up by a bright young Cargo Cult Scientist. They sure did have a good run.
Where did the truth come from in this story? The laboratory. It's a tough place to be for Cargo Cult Scientists. If you want to make it in the ranks of the Cargo Cult, stay out of that lab.
Getting published requires skill in understanding what people want to hear and how to write about it. That doesn't mean that you have skills in scientific research, merely writing up what people want to hear. Those who accept or reject your paper will not be going into the lab to watch you work. Nor will they require any evidence that you actually did the work such as lab notebooks or any other form of raw data. The powers that be will read what you send in and use their superior knowledge of, well... reading papers, to determine if what you said is the honest truth or not. Furthermore, they will also know if you used all of the proper controls and formed the proper conclusions. Getting published means getting into the heads of these sorts and writing a paper that they can stand behind. It must then support their own theories, flatter their own body of work, and be authored and co-authored by respected individuals working at respected institutions and universities.
John Darsee and his boss Eugene Braunwald certainly had what it takes to get published. 109 of Darsees papers had 47 co-authors so there were plenty of people verifying the work. Yet Darsee managed to fool them all. He had fabricated data for many of his publications. In one startling case he proposed that a 17 year old subject had four children, ages 8, 7, 5, and 4. Eugene Braunwald didn't see it. The co-authors didn't do the math that would make the father 8 or 9 at the time of his first childs birth. The referees who read the paper didn't see it. The editor didn't see it. The readers of the article didn't see it either. Not until the notorious NIH duo Feder and Stewart got involved did anyone bother to bring up this puzzling set of data.
But not everyone was convinced that John Darsee was infallible. At Harvard three of Darsees laboratory colleagues started to wonder where he was getting all of the good data. They soon became convinced that he was outright making it up. They reported their suspicions up the chain of command forcing Darsee to finally show his superiors some raw data. Back in the lab he set out to obtain the final set of data to be presented. With co-workers looking on he began to mark down his data, Day 1, Day 2..., thus demonstrating his most effective method of obtaining positive data. You just make it up as you need it.
Three laboratory workers uncovered what 47 co-authors, scores of superiors and journal editors could not see. John Darsee was a fake. But he was a skilled paper writer and that is what made him a star early in life. The culture still exists. It is of course, The Cargo Culture, that we are interested in here on this blog. John Darsee is a high ranking member of the cult. He knew absolutely nothing about airplanes but he knew what the leaders wanted to hear. Not the sound of airplanes coming from the sky, but the sound of their own ideas being backed up by a bright young Cargo Cult Scientist. They sure did have a good run.
Where did the truth come from in this story? The laboratory. It's a tough place to be for Cargo Cult Scientists. If you want to make it in the ranks of the Cargo Cult, stay out of that lab.
Wednesday, August 09, 2006
We'll Do It Anyway
Science 9 July 2004:Vol. 305. no. 5681, pp. 158 - 159DOI: 10.1126/science.305.5681.158
News of the Week
OBESITY RESEARCH:Labs Fail to Reproduce Protein's Appetite-Suppressing Effects
by Trisha Gura
"In an unusual joint letter in Nature this week, more than 40 scientists announced that they cannot reproduce the central findings of a 2002 Nature paper that showed that a molecule called peptide YY3-36, when injected into rodents, dampens appetite for 12 hours or more."
AFX News: March 2, 2006
"...the Bothell, Wash.-based company said Merck terminated its agreement with XXXXX on March 1 after determining that earlier clinical data had shown PYY3-36 wasn't effective.
Regardless of Merck's decision, XXXXXX said it intends to pursue development of PYY3-36"
August 14, 2006
"XXXX announced today the initiation of a dose ranging study designed to evaluate the pharmacokinetic parameters, appetite, food intake and safety of various doses of XXXXXs proprietary PYY(3-36) nasal spray in obese subjects."
Here we go!!! Get ready for another study!!!
Aug. 14, 2006 PRNewswire-FirstCall/ XXXXX announced today the initiation of a dose ranging study designed to evaluate the pharmacokinetic parameters, appetite, food intake and safety of various doses of XXXXX's proprietary PYY(3-36) nasal spray in obese subjects
By the way, if it works 2 out of 20 studies, does it count? Since the FDA is not a close follower of the ways of science, they will allow it. The question is how well it will work this time and if it doesn't, what will comapany XXXX do? Remember, the decision to continue on with PYY was listed as number 4 on "The Five Dumbest Things on Wall Street This Week" by Colin Barr back in March of this year, 2006. We here at the Cargo Cult Scientist will stick it out to the bitter end. We will never give up until the airplanes either land or the cult gives up it's latest ceremony.
News of the Week
OBESITY RESEARCH:Labs Fail to Reproduce Protein's Appetite-Suppressing Effects
by Trisha Gura
"In an unusual joint letter in Nature this week, more than 40 scientists announced that they cannot reproduce the central findings of a 2002 Nature paper that showed that a molecule called peptide YY3-36, when injected into rodents, dampens appetite for 12 hours or more."
AFX News: March 2, 2006
"...the Bothell, Wash.-based company said Merck terminated its agreement with XXXXX on March 1 after determining that earlier clinical data had shown PYY3-36 wasn't effective.
Regardless of Merck's decision, XXXXXX said it intends to pursue development of PYY3-36"
August 14, 2006
"XXXX announced today the initiation of a dose ranging study designed to evaluate the pharmacokinetic parameters, appetite, food intake and safety of various doses of XXXXXs proprietary PYY(3-36) nasal spray in obese subjects."
Here we go!!! Get ready for another study!!!
Aug. 14, 2006 PRNewswire-FirstCall/ XXXXX announced today the initiation of a dose ranging study designed to evaluate the pharmacokinetic parameters, appetite, food intake and safety of various doses of XXXXX's proprietary PYY(3-36) nasal spray in obese subjects
By the way, if it works 2 out of 20 studies, does it count? Since the FDA is not a close follower of the ways of science, they will allow it. The question is how well it will work this time and if it doesn't, what will comapany XXXX do? Remember, the decision to continue on with PYY was listed as number 4 on "The Five Dumbest Things on Wall Street This Week" by Colin Barr back in March of this year, 2006. We here at the Cargo Cult Scientist will stick it out to the bitter end. We will never give up until the airplanes either land or the cult gives up it's latest ceremony.
Another Case
In my last post I presented the reader with an actual case of scientific misconduct. This kind of misconduct occurs everyday in industry and academia throughout the land. It is the kind of dishonesty where you get to select what data gets used. It happened to the doctor I spoke about who worked with Actonel data. It happened around me at a previous company involving siRNA and TNF alpha. I wanted to open up a discussion with other people who may be feeling guilty about the work they do. How many others put up with this sort of data mishandling? How many actually orchestrate it?
I believe I could come up with a case of similar misconduct from every position I've had except for one. That is to say, I think it's the most common form of Cargo Cult Science. People have lives to lead. They earn the money for those lives by working in science. If you run an experiment 10 times and only once do you get the desired results, you may disregard the other 9 experiments. You may choose to not report them. No one will find out most likely so you keep you mouth shut. The scientist who manufactures data most likely ran his or her experiments more than 10 times but never got the desired results.
Imagine however, if you truly could clone a stem cell. Imagine if you got the desired results because you were right about something. You know what? That still doesn't make you a scientist. You got lucky. Getting the desired results comes from standing on a large volume of information that lead you to design and conduct a proper experiment. Maybe you failed 900 times but each time you learned something. Each time you got closer to the truth. This is real science. Failing is good if you are prepared for it. If not you will be fabricating or selecting the data you want. Either way, you are a fraud.
This next case describes a way around selective data. It involved a protein purification. The goal was to purify a protein to make an antibody. Since there was no antibody available I used a few basic techniques. In the end I had 3 bands on my gel, which to some indicates that I have 3 proteins. What I did showed that there were at least 4. I would guess many more.
The 3 bands were all very close together indicating that there were three major sizes of protein purified. To further separate the bands I ran them on a higher percentage gel. They were still too close together. The cubicle scientist needed one of the bands to be the protein we were after. He merely wanted to be able to point to which band on the gel was the one. He wanted to show the gel and then a western blot of the same gel. The western blot would indicate which band was our protein but the bands were still too close together.
Out of the blue, a passing technician solved the problem. Our protein was glycosylated. Simply run a PNGF digestion, which would deglycosylate the protein, and run the gel and western again. This time the 3 bands showed up at the same location on the regular gel. On the western however the band shifted down well below the three major bands. This meant that none of the bands represented the protein we were after. Furthermore, there was no band on the gel where the western blot band was located. That means there was not enough of the protein to be visible on the gel.
Now the western blot varies in sensitivity. This particular western was very sensitive. As a young technician who had done at least 100 of these westerns by this time, I felt that the 3 bands were too big to give the kind of western results we were getting. The western would have showed a huge black blob up and down the western. Instead it gave a neat little band. What I learned from this was that many proteins migrate with others there size in a gel. A band is probably an aggregate of proteins close to each other in size. The amount of proteins it takes to make a visable band on a gel can be hundred and thousands of times more than you would need to get a nice sharp band on a western. Indeed I learned a lot from that experiment and how to look at these gels that so many use in there research. Each protein antibody combination differs when it comes to western blots. There is a cut off level where slight changes in concentration either way will give big differences in band intensity. At some point they'll remain the same over a range of concentrations. At some point they will give high background signals. Some combinations will detect the protein all throughout the lane but show a blob where most of the protein is.
I also learned that this experiment was not described by the cubicle scientst. He insisted that I give an answer as to the percentage of purity I had acheived in spite of the fact that we both had access to the whole set of data. I came up with less than one percent as my answer. He reported 20 percent. To back this up he showed the gel with 3 bands on it. He showed the western blots and said that it could not be determined which band was the protein of interest but the western proved that it was one of the three. They were just too close together to discern which one it was.
So he lied. He did not manufacture data but he did select what he needed. Furthermore, he left out the data that proved his conclusion to be wrong. I hung my head but I was powerless to change his report. I was out of the picture by now and just a lowly technician. Oddly enough, when the antibodies started showing up we found a few that were specific to the protein. It didn't matter that 99 percent of what I sent out was not the protein of interest. What little there was gave rise to specific antibodies to our protein. No harm not foul right? No one will ever know what happened.
I believe I could come up with a case of similar misconduct from every position I've had except for one. That is to say, I think it's the most common form of Cargo Cult Science. People have lives to lead. They earn the money for those lives by working in science. If you run an experiment 10 times and only once do you get the desired results, you may disregard the other 9 experiments. You may choose to not report them. No one will find out most likely so you keep you mouth shut. The scientist who manufactures data most likely ran his or her experiments more than 10 times but never got the desired results.
Imagine however, if you truly could clone a stem cell. Imagine if you got the desired results because you were right about something. You know what? That still doesn't make you a scientist. You got lucky. Getting the desired results comes from standing on a large volume of information that lead you to design and conduct a proper experiment. Maybe you failed 900 times but each time you learned something. Each time you got closer to the truth. This is real science. Failing is good if you are prepared for it. If not you will be fabricating or selecting the data you want. Either way, you are a fraud.
This next case describes a way around selective data. It involved a protein purification. The goal was to purify a protein to make an antibody. Since there was no antibody available I used a few basic techniques. In the end I had 3 bands on my gel, which to some indicates that I have 3 proteins. What I did showed that there were at least 4. I would guess many more.
The 3 bands were all very close together indicating that there were three major sizes of protein purified. To further separate the bands I ran them on a higher percentage gel. They were still too close together. The cubicle scientist needed one of the bands to be the protein we were after. He merely wanted to be able to point to which band on the gel was the one. He wanted to show the gel and then a western blot of the same gel. The western blot would indicate which band was our protein but the bands were still too close together.
Out of the blue, a passing technician solved the problem. Our protein was glycosylated. Simply run a PNGF digestion, which would deglycosylate the protein, and run the gel and western again. This time the 3 bands showed up at the same location on the regular gel. On the western however the band shifted down well below the three major bands. This meant that none of the bands represented the protein we were after. Furthermore, there was no band on the gel where the western blot band was located. That means there was not enough of the protein to be visible on the gel.
Now the western blot varies in sensitivity. This particular western was very sensitive. As a young technician who had done at least 100 of these westerns by this time, I felt that the 3 bands were too big to give the kind of western results we were getting. The western would have showed a huge black blob up and down the western. Instead it gave a neat little band. What I learned from this was that many proteins migrate with others there size in a gel. A band is probably an aggregate of proteins close to each other in size. The amount of proteins it takes to make a visable band on a gel can be hundred and thousands of times more than you would need to get a nice sharp band on a western. Indeed I learned a lot from that experiment and how to look at these gels that so many use in there research. Each protein antibody combination differs when it comes to western blots. There is a cut off level where slight changes in concentration either way will give big differences in band intensity. At some point they'll remain the same over a range of concentrations. At some point they will give high background signals. Some combinations will detect the protein all throughout the lane but show a blob where most of the protein is.
I also learned that this experiment was not described by the cubicle scientst. He insisted that I give an answer as to the percentage of purity I had acheived in spite of the fact that we both had access to the whole set of data. I came up with less than one percent as my answer. He reported 20 percent. To back this up he showed the gel with 3 bands on it. He showed the western blots and said that it could not be determined which band was the protein of interest but the western proved that it was one of the three. They were just too close together to discern which one it was.
So he lied. He did not manufacture data but he did select what he needed. Furthermore, he left out the data that proved his conclusion to be wrong. I hung my head but I was powerless to change his report. I was out of the picture by now and just a lowly technician. Oddly enough, when the antibodies started showing up we found a few that were specific to the protein. It didn't matter that 99 percent of what I sent out was not the protein of interest. What little there was gave rise to specific antibodies to our protein. No harm not foul right? No one will ever know what happened.
Tuesday, August 08, 2006
Actual Case
Let's take a look at a real Biotech research project. We'll break it down piece by piece in laymans terms. I want to make this as clear as possible. (Do scientists ever think this way?)
TNF alpha is a popular drug target. There are three monoclonal antibody drugs against TNF alpha already on the market. TNF alpha has a number of functions and most of them are not known. I won't discuss the science behind our understanding of TNF alpha. I will say that there are three drugs against TNF alpha. They are intended to alleviate rheumatoid arthritis and Crohns disease. The drugs reduce the effects of extra TNF alpha in the body by binding to it thus preventing it's usual interactions.
Another way of getting rid of TNF alpha is to use siRNA. DNA makes messenger RNA which makes proteins. If you take a small piece of the RNA however, it can result in the destruction of the messenger RNA by a newly discovered mechanism called RNA interferance. That's the story anyway and biotech is sticking to it. So if you want to start a biotech company you can choose TNF alpha as your drug target and siRNA as the way of zapping your target. It's that simple.
There appears to be only one company attempting this simple thing. They have over 200 mice sitting in formaldahyde waiting to be "scored" for arthritis. "Scoring" is an arbitrary method of measuring joint inflammation. The bigger the inflammation the higher the score. The goal then is to get as low a score as you can. You start with mice that have been bred to have high levels of arthritis or high scores. You use one of the antibodies as a positive control and a saline solution as a negative control. You also have a "scrambled" siRNA that has a nucleic acid sequence that is not linked to any known protein.
The mice, as I've stated, are still in formaldahyde. They have not been scored. The reason is due to an obvious lack of efficacy. Even the anti-TNF alpha control mice had developed arthritis. So big deal. It didn't work. The only place you will here about this is here on the Cargo Cult Scientist. I can't tell you what company did the experiment because I once worked there and I don't want any reprisals from them. But what they did with this experiment is wrong. The committed a cargo cult sin. They didn't report the results because they didn't get what they wanted.
In mainstream science they are struggling to define scientific fraud. Where is the line between fraud and sloppy practices? There are cases for example where a researcher will make up data. That is flat out fraud. There are cases where one out of ten experiments obtains the data that is desired. Using the favorable set of data and ignoring the rest is a lesser offense than manufacturing data. Yet to the Cargo Cult Scientist it is as bad. The only data that is useful is data the can be reproduced. If you sit in a board room or you are an editor of a journal you may not be aware of how many tries the researcher attempted before getting the data that supports his paper. This is a shame. If you are a lowly lab tech you probably know what is happening but you are powerless to stop it. It probably doesn't even matter in the big picture. Like the TNF alpha story I've just reported, most projects will fade away. The trick to being a Cargo Cult Scientist is to make sure that happens smoothly. As long as no one finds out about it you live to write another paper. Whether or not anyone uses that paper is another story. The chances are that no one will ever use siRNA to relieve the pressures of having excessive TNF alpha in their bodies. It won't matter however. There are plenty of drugs in the pipeline. Mostly they are me-too drugs. The research was me-too and the fade away will be a me-too method of resolving the scientific dilemma. Brush it under the rug and no one will know about it.
Perhaps this is why it's best to lab personel powerless.
TNF alpha is a popular drug target. There are three monoclonal antibody drugs against TNF alpha already on the market. TNF alpha has a number of functions and most of them are not known. I won't discuss the science behind our understanding of TNF alpha. I will say that there are three drugs against TNF alpha. They are intended to alleviate rheumatoid arthritis and Crohns disease. The drugs reduce the effects of extra TNF alpha in the body by binding to it thus preventing it's usual interactions.
Another way of getting rid of TNF alpha is to use siRNA. DNA makes messenger RNA which makes proteins. If you take a small piece of the RNA however, it can result in the destruction of the messenger RNA by a newly discovered mechanism called RNA interferance. That's the story anyway and biotech is sticking to it. So if you want to start a biotech company you can choose TNF alpha as your drug target and siRNA as the way of zapping your target. It's that simple.
There appears to be only one company attempting this simple thing. They have over 200 mice sitting in formaldahyde waiting to be "scored" for arthritis. "Scoring" is an arbitrary method of measuring joint inflammation. The bigger the inflammation the higher the score. The goal then is to get as low a score as you can. You start with mice that have been bred to have high levels of arthritis or high scores. You use one of the antibodies as a positive control and a saline solution as a negative control. You also have a "scrambled" siRNA that has a nucleic acid sequence that is not linked to any known protein.
The mice, as I've stated, are still in formaldahyde. They have not been scored. The reason is due to an obvious lack of efficacy. Even the anti-TNF alpha control mice had developed arthritis. So big deal. It didn't work. The only place you will here about this is here on the Cargo Cult Scientist. I can't tell you what company did the experiment because I once worked there and I don't want any reprisals from them. But what they did with this experiment is wrong. The committed a cargo cult sin. They didn't report the results because they didn't get what they wanted.
In mainstream science they are struggling to define scientific fraud. Where is the line between fraud and sloppy practices? There are cases for example where a researcher will make up data. That is flat out fraud. There are cases where one out of ten experiments obtains the data that is desired. Using the favorable set of data and ignoring the rest is a lesser offense than manufacturing data. Yet to the Cargo Cult Scientist it is as bad. The only data that is useful is data the can be reproduced. If you sit in a board room or you are an editor of a journal you may not be aware of how many tries the researcher attempted before getting the data that supports his paper. This is a shame. If you are a lowly lab tech you probably know what is happening but you are powerless to stop it. It probably doesn't even matter in the big picture. Like the TNF alpha story I've just reported, most projects will fade away. The trick to being a Cargo Cult Scientist is to make sure that happens smoothly. As long as no one finds out about it you live to write another paper. Whether or not anyone uses that paper is another story. The chances are that no one will ever use siRNA to relieve the pressures of having excessive TNF alpha in their bodies. It won't matter however. There are plenty of drugs in the pipeline. Mostly they are me-too drugs. The research was me-too and the fade away will be a me-too method of resolving the scientific dilemma. Brush it under the rug and no one will know about it.
Perhaps this is why it's best to lab personel powerless.
Sunday, August 06, 2006
Totalitarianism
Bob Schieffer, on Face the Nation this morning, said that the difference between a Totalinarian government and a Democratic government is that all of the news you get about a Totalinarian government comes from the government. In a Democratic society you have a free press to offset government spin.
What then do we make of the scientific press? Cell, Nature, Science and all of the other publications at times like to blur the lines between reporting science and being science. They often come across as the authority between what is fact and what is not. However, they have been duped time and time again with little recourse. They self police themselves and thus they are sciences self police force. If fraud or misconduct is caught a retraction is in order. How often does that happen however? Is there another source that can report contrary information that, while it is not a retraction, is an alternative explanation of the facts?
The current model of science represent a totalitarian system of governance. You have researchers, professors, principle investigators, reviewers, editors and so on. Who is the leader? How is science structured to keep bullshit from creeping into the fabric of its daily operations? A democratic society will wage war against liars and cheaters who want to use our resources for their own purposes. We must constantly update our laws. We must seek out scams that are draining our tax base. Science too needs leadership to prevent negative factors. It must begin with a free press that is allowed to speak out against what is considered bad science?
What if there were scientific articles written about Dr. Hwang's cloned stem cells? Articles on how we are simply taking his word for it? Articles asking the questions that the reviewers did not ask? Ariticles from people trying to reproduce this work? There is in fact a great oppportunity to create a more mainstream interest in science by discussing the claims made in Science, Nature and the rest of them. They of course will tell you that they police themselves. Furthermore, they are science and any commentary from other scources is simply chatter from the peanut gallery. Amateurs don't have the same rights as the professionals. But isn't this the same attitude of a totalinarian government? They run the show. Anyone not involved doesn't understand what they do and thus have no rights to discuss the details. It leaves the leaders too much room for corruption however.
Science needs more voices, more ideas freely floating around for all to discuss and think about. With the onslaught from the pharmaceutical companies and the financial pressure for certain outcomes, science is up against the wishes of a non-scientific powerhouse. They want science to say what they want to hear. But science isn't about individuals. It doesn't matter where you went to school or how much money you have. It's about getting to the truth. The way to do this is to open up the process to all people and to hear what they think. What does the research associate working at Pfizer think about his project? What results has he seen that perhaps didn't make it onto a report? What about researchers who have disagreed with a papers conclusions? Does he or she get a voice? There must be a place for these voices. Is it just going to be the blogging world, where no one reads anyone elses stuff 99% of the time? Who will fight against sciences totalitarian system and let others be heard?
What then do we make of the scientific press? Cell, Nature, Science and all of the other publications at times like to blur the lines between reporting science and being science. They often come across as the authority between what is fact and what is not. However, they have been duped time and time again with little recourse. They self police themselves and thus they are sciences self police force. If fraud or misconduct is caught a retraction is in order. How often does that happen however? Is there another source that can report contrary information that, while it is not a retraction, is an alternative explanation of the facts?
The current model of science represent a totalitarian system of governance. You have researchers, professors, principle investigators, reviewers, editors and so on. Who is the leader? How is science structured to keep bullshit from creeping into the fabric of its daily operations? A democratic society will wage war against liars and cheaters who want to use our resources for their own purposes. We must constantly update our laws. We must seek out scams that are draining our tax base. Science too needs leadership to prevent negative factors. It must begin with a free press that is allowed to speak out against what is considered bad science?
What if there were scientific articles written about Dr. Hwang's cloned stem cells? Articles on how we are simply taking his word for it? Articles asking the questions that the reviewers did not ask? Ariticles from people trying to reproduce this work? There is in fact a great oppportunity to create a more mainstream interest in science by discussing the claims made in Science, Nature and the rest of them. They of course will tell you that they police themselves. Furthermore, they are science and any commentary from other scources is simply chatter from the peanut gallery. Amateurs don't have the same rights as the professionals. But isn't this the same attitude of a totalinarian government? They run the show. Anyone not involved doesn't understand what they do and thus have no rights to discuss the details. It leaves the leaders too much room for corruption however.
Science needs more voices, more ideas freely floating around for all to discuss and think about. With the onslaught from the pharmaceutical companies and the financial pressure for certain outcomes, science is up against the wishes of a non-scientific powerhouse. They want science to say what they want to hear. But science isn't about individuals. It doesn't matter where you went to school or how much money you have. It's about getting to the truth. The way to do this is to open up the process to all people and to hear what they think. What does the research associate working at Pfizer think about his project? What results has he seen that perhaps didn't make it onto a report? What about researchers who have disagreed with a papers conclusions? Does he or she get a voice? There must be a place for these voices. Is it just going to be the blogging world, where no one reads anyone elses stuff 99% of the time? Who will fight against sciences totalitarian system and let others be heard?
Friday, August 04, 2006
Failures to Follow
I've mentioned that Cell Therapeutics spent over 878 million dollars put one drug on the market, which they sold for 70 million. They are left with one more candidate that will make or break the company. So far the drug has failed miserably in clinical trials. What other companies failed, how much did it cost and what was learned?
Cancervax was a one drug company. Their drug was a cancer cell that displayed over 20 antigens that would provide an immune response that would rain hellfire down on a tumor. That's what they said at least. It failed clinical trials and the company folded. The drug itself was 20 years in the making. How much money went into the notion that this would work? The answer to that would be hard to sum up. Let's just assume it's over 100 million dollars. The lessons learned are also not clear. This sort of thing happens all the time. This month in biotech:
PDL Biopharma Inc. Reports Results From Phase 3 Trial Of Terlipressin In Type 1 Hepatorenal Syndrome - Did Not Meet Its Primary Endpoint
NPS Pharmaceuticals faces a class action suit for making allegedly false statements about the prospects of osteoporosis drug PREOS.
Icagen Inc. said Friday it is cutting out approximately half of the patients involved in a late-stage study on the recommendation of an independent data monitoring committee. The announcement sent shares in a nosedive, dropping $3.26, or 77.1 percent
Takeda Pharmaceutical has informed BioNumerik Pharmaceuticals that it is considering terminating their alliance over Tavocept after the drug candidate failed to meet the primary endpoints of two phase III trials in cancer patients.
You get the idea. Many big ideas turn into dust and alot of money disappears. There are of course a few success stories. The Cargo Cult Scientist however is a study on things that don't work. It is meant to be an exercise in striving towards the positive, starting from the negative. The negative being things that don't work. What is so shocking about making drugs is how much money gets dumped into things that don't work. I began this post by asking who failed, how much did it cost and what was learned. The answer is that every month there is going to be a number of big projects that fail, costing millions and millions of dollars, and nothing is being learned from it.
The Cargo Cult Scientist has learned something about PREOS however. The active ingredient in PREOS is parathyroid hormone (PTH). Forteo is also a PTH drug that is on the market. There are still other PTH drugs trying to make it to the market as well. How will we know if they will make it or not? We at least know a drug containing PTH is not gaurenteed to work. Curious. It is highly possible that a new clinical trial could show PREOS to be effective. What seems to be not working here are clinical trials. This is the true Cargo Cult Airport. Clinical trial professionals are not very good at reproducing results. There is a need for reform but first we simply state the obvious, clinical trials are not run scientifically. How can we fix the situation and what is at stake? More later.
Cancervax was a one drug company. Their drug was a cancer cell that displayed over 20 antigens that would provide an immune response that would rain hellfire down on a tumor. That's what they said at least. It failed clinical trials and the company folded. The drug itself was 20 years in the making. How much money went into the notion that this would work? The answer to that would be hard to sum up. Let's just assume it's over 100 million dollars. The lessons learned are also not clear. This sort of thing happens all the time. This month in biotech:
PDL Biopharma Inc. Reports Results From Phase 3 Trial Of Terlipressin In Type 1 Hepatorenal Syndrome - Did Not Meet Its Primary Endpoint
NPS Pharmaceuticals faces a class action suit for making allegedly false statements about the prospects of osteoporosis drug PREOS.
Icagen Inc. said Friday it is cutting out approximately half of the patients involved in a late-stage study on the recommendation of an independent data monitoring committee. The announcement sent shares in a nosedive, dropping $3.26, or 77.1 percent
Takeda Pharmaceutical has informed BioNumerik Pharmaceuticals that it is considering terminating their alliance over Tavocept after the drug candidate failed to meet the primary endpoints of two phase III trials in cancer patients.
You get the idea. Many big ideas turn into dust and alot of money disappears. There are of course a few success stories. The Cargo Cult Scientist however is a study on things that don't work. It is meant to be an exercise in striving towards the positive, starting from the negative. The negative being things that don't work. What is so shocking about making drugs is how much money gets dumped into things that don't work. I began this post by asking who failed, how much did it cost and what was learned. The answer is that every month there is going to be a number of big projects that fail, costing millions and millions of dollars, and nothing is being learned from it.
The Cargo Cult Scientist has learned something about PREOS however. The active ingredient in PREOS is parathyroid hormone (PTH). Forteo is also a PTH drug that is on the market. There are still other PTH drugs trying to make it to the market as well. How will we know if they will make it or not? We at least know a drug containing PTH is not gaurenteed to work. Curious. It is highly possible that a new clinical trial could show PREOS to be effective. What seems to be not working here are clinical trials. This is the true Cargo Cult Airport. Clinical trial professionals are not very good at reproducing results. There is a need for reform but first we simply state the obvious, clinical trials are not run scientifically. How can we fix the situation and what is at stake? More later.
Thursday, August 03, 2006
The Doctor is Out
There is a doctor in England who received a 250 thousand dollar grant from Procter and Gamble. He claims that the company had denied him access to key data and then tried to ghostwrite his analysis of it. The doctor and one of his superiors were to evaluate the effectiveness of P&G's osteoporosis drug, Actonel. Their analysis was suppose to further demonstrate how Actonel affects women's bones and their susceptibility to fractures. The doctors superior (and cohort in this research) had already reviewed blood and urine samples from two previous P&G clinical trials of Actonel. The doctor was supposed to evaluate a third trial, with the aim of providing a final analysis of all three.
The doctor and his staff reviewed data from thousands of blood and urine samples from women with osteoporosis. They were blinded as to who had taken Actonel and who had been given the placebo. This is of course the fun part of science. Get you facts straight then open the envelope to see which group is which. Did the drug work. Procter and Gamble however didn't want the doctor to go that far. They had a ghostwriter who would take his information and use what was needed to publish a paper with a positive spin. They would be using his name on the publication but not necessarily his conclusions. The doctor repeatedly asked for the codes so he could properly interpret the results. They refused.
Ironically, P&G continued to pursue their plan to write up a manuscript using the doctors analysis which they expected him to present at the American Society of Bone and Mineral Research. The ghost writer would "help write up the Actonel manuscripts for publication" and the doctors name would be listed as an author. Noting that he and his superior could be guilty of scientific misconduct if they let their names be listed as authors without having seen the underlying data P&G came up with a compromise. They would let him perform his own analysis of his data but they would let him review what the company had worked out.
He went to their headquarters and saw what they were working on. On one critical graph on fracture rates, he noticed that 40% of the data was missing. He believed that inclusion of that 40% of data would have disproved P&Gs key message about their drugs effectiveness against bone fractures. As a scientist, the doctor could not allow this. After many months of trying to get P&G and the university to do the right thing, he decided to go public with his story. He was suspended from the University.
The doctor and his staff reviewed data from thousands of blood and urine samples from women with osteoporosis. They were blinded as to who had taken Actonel and who had been given the placebo. This is of course the fun part of science. Get you facts straight then open the envelope to see which group is which. Did the drug work. Procter and Gamble however didn't want the doctor to go that far. They had a ghostwriter who would take his information and use what was needed to publish a paper with a positive spin. They would be using his name on the publication but not necessarily his conclusions. The doctor repeatedly asked for the codes so he could properly interpret the results. They refused.
Ironically, P&G continued to pursue their plan to write up a manuscript using the doctors analysis which they expected him to present at the American Society of Bone and Mineral Research. The ghost writer would "help write up the Actonel manuscripts for publication" and the doctors name would be listed as an author. Noting that he and his superior could be guilty of scientific misconduct if they let their names be listed as authors without having seen the underlying data P&G came up with a compromise. They would let him perform his own analysis of his data but they would let him review what the company had worked out.
He went to their headquarters and saw what they were working on. On one critical graph on fracture rates, he noticed that 40% of the data was missing. He believed that inclusion of that 40% of data would have disproved P&Gs key message about their drugs effectiveness against bone fractures. As a scientist, the doctor could not allow this. After many months of trying to get P&G and the university to do the right thing, he decided to go public with his story. He was suspended from the University.
Wednesday, August 02, 2006
Why'd We Study So Hard?
If you've ever wondered how things could stray so far from reality you need only read Dilbert to gain some perspective. Dilbert was created by a disgruntled engineer who worked at Lucent Technologies. Frustrated with the way things were he lashed out with a comic strip depicting his daily work life. You laugh but you know it comes from real life experiences. It is the clash between scientists/engineers and corporate people. Many scientist/engineers know the pain of studying for a differential equations test and a physics test that'll be given on Monday and a statistics test on Tuesday. You walk past the frat house at 3 p.m. on your way to the physical chemistry test on Thursday and the frat brothers are already drinking beers in anticipation of a big weekend.
You think that they'll be sorry. Then you get a job and you reallize that those guys are running around with suits and ties and making decisions on your research budget. They cancel your request for a 30 thousand dollar a year research associate and they give themselves a 35 thousand dollar a year raise. They deny your request to give your current associate a 2 thousand dollar a year raise. The associate gets mad and sues the company. The same executives shell out 10 thousand dollars to defend against the lawsuit.
Worst of all however is the decisions that effect your scientific inquiry or your engineering designs. If you work in Biotechnology for example, you have a drug pipeline. Whatever project you are working on, the goal is to advance the drug towards the market. Here is what one blogger had to say about her job in the clinical affairs department of a large pharmaceutical company. "I've witnessed my industry manipulate, distort, subvert, suppress, and otherwise mangle facts in pursuit of increasing their consumption of the nation's wealth." You do not get credit for stopping a project that is going nowhere. You're job is to advance the project, not stop it. Executives make those decisions.
They are not teaching you how to mangle facts when you are studying for the big tests in college. Science, math and engineering are disciplines that have been advanced by people who have ignored their own hopes and dreams in order to see the world as it is. We learned about forces in nature and a little bit about how to discover such forces. The executives learned about people. They learned about being the best in a group. It has a lot to do with image. It's about looking good and speaking with authority, whether you have any or not. The current business model puts those skills at the top of the food chain. The geeky stuff that comes from science is only sexy when it's a break through. A vaccine for polio or the discovery of PCR will get you noticed. Verifying that the latest siRNA treatment is a bust will get you in the dog house.
So why do we study the hard stuff and work with the hard stuff? I believe that some people are simply wired that way. Some people can sit in meetings and talk about things that lead to nowhere and be satisfied that they've done work. Others aren't satisfied until the talking has ended and it's tiime to test out the theories. The latter prefers more doing than talking. There is a sense of satisfaction that comes from working as a scientist or engineer. It comes from thinking, applying, and seeing results. That's why we study so hard. Nature is tricky and you can't bullshit your way around it. If you're wrong, nature will find a way to let you know. A drug that doesn't work or a bridge that collapses are a couple of ways. You really have to let go of the notion that you will be rewarded financially. You have to be the kind of person who would pursue the cure for cancer even if you knew you would never receive the notoriety for it. Rather than dreaming of a big house and fancy new car, you dream of the day when you do that mouse experiment and you see with your own eyes that the tumors did not grow. You don't want to sit in a board room and here about it from someone else. You want to be there. The only way to get that rush is to work as a scientist with a white lab coat.
You think that they'll be sorry. Then you get a job and you reallize that those guys are running around with suits and ties and making decisions on your research budget. They cancel your request for a 30 thousand dollar a year research associate and they give themselves a 35 thousand dollar a year raise. They deny your request to give your current associate a 2 thousand dollar a year raise. The associate gets mad and sues the company. The same executives shell out 10 thousand dollars to defend against the lawsuit.
Worst of all however is the decisions that effect your scientific inquiry or your engineering designs. If you work in Biotechnology for example, you have a drug pipeline. Whatever project you are working on, the goal is to advance the drug towards the market. Here is what one blogger had to say about her job in the clinical affairs department of a large pharmaceutical company. "I've witnessed my industry manipulate, distort, subvert, suppress, and otherwise mangle facts in pursuit of increasing their consumption of the nation's wealth." You do not get credit for stopping a project that is going nowhere. You're job is to advance the project, not stop it. Executives make those decisions.
They are not teaching you how to mangle facts when you are studying for the big tests in college. Science, math and engineering are disciplines that have been advanced by people who have ignored their own hopes and dreams in order to see the world as it is. We learned about forces in nature and a little bit about how to discover such forces. The executives learned about people. They learned about being the best in a group. It has a lot to do with image. It's about looking good and speaking with authority, whether you have any or not. The current business model puts those skills at the top of the food chain. The geeky stuff that comes from science is only sexy when it's a break through. A vaccine for polio or the discovery of PCR will get you noticed. Verifying that the latest siRNA treatment is a bust will get you in the dog house.
So why do we study the hard stuff and work with the hard stuff? I believe that some people are simply wired that way. Some people can sit in meetings and talk about things that lead to nowhere and be satisfied that they've done work. Others aren't satisfied until the talking has ended and it's tiime to test out the theories. The latter prefers more doing than talking. There is a sense of satisfaction that comes from working as a scientist or engineer. It comes from thinking, applying, and seeing results. That's why we study so hard. Nature is tricky and you can't bullshit your way around it. If you're wrong, nature will find a way to let you know. A drug that doesn't work or a bridge that collapses are a couple of ways. You really have to let go of the notion that you will be rewarded financially. You have to be the kind of person who would pursue the cure for cancer even if you knew you would never receive the notoriety for it. Rather than dreaming of a big house and fancy new car, you dream of the day when you do that mouse experiment and you see with your own eyes that the tumors did not grow. You don't want to sit in a board room and here about it from someone else. You want to be there. The only way to get that rush is to work as a scientist with a white lab coat.
Tuesday, August 01, 2006
When to Say When
"It takes a wise doctor to know when not to prescribe." - Gracian.
Modern day doctors sometime take the helm at large biotech/pharmaceutical companies. That creates an interesting situation. M.D.s have often taken it upon themselves to solve some of the mysteries of medical science. Scientists are trained to do the job but any reasonable person should be able to spot obvious things like Dr. Listers observation that washing ones hands prior to surgery cuts back on infections.
Dr. Louis Bianco is an M.D. and the CEO of a company called Cell Therapeutics. He decided long ago to prescribe a drug called XYOTAX. The patient was all of society. XYOTAX is a biologically enhanced chemotherapeutic that links paclitaxel, the active ingredient in Taxol, to a biodegradable polyglutamate polymer. The idea with this is that the glutamate will render paclitaxel inactive until it enters a tumor cell. Thus it would be the perfect solution for delivering this drug. The only problem is that XYOTAX doesn't work any better than paclitaxel alone. Nonetheless, Dr. Bianco is adamant on prescribing this drug to those who have cancer.
I think this would be a good time to not prescribe. It would be a good time to find another drug to invest in. What's stopping Dr. Bianco from making the obvious decision? As of March 31, 2006, Cell Therapeutics had incurred aggregate net losses of approximately $(878.5) million since inception. That's what is stopping them. Without the approval of XYOTAX, the company has no other means of generating an income.
878.5 million dollars of investor capital went into a company that is now sitting on roughly 80 million bucks and a potentially ineffective drug. Where did the money go? Who made that money in the process of getting the drug where it is today? If you've ever wondered about the figure of 800 million dollars to get a drug to the market, you have to figure in fiascos like this. Investors can be hoodwinked quite easily when it comes to science. The entire executive team at Cell Therapeutics have a reputation for being long on hype but short on results. Three years ago, James Bianco confidently predicted that XYOTAX would be on the market by 2005. He now claims that it will be done by early 2007.
CEOs and executives continue to reap the rewards from just working in the business. You don't have to have a good drug. You have to have the juevos to keep going back for more. You tell the investors, "next year, trust me," and if they bite, you are in business. The Cargo Cult analogy is clear, the promise of the airplanes landing is enough to get paid. In fact you can have a fabulously successful career and never have an airplane land.
Modern day doctors sometime take the helm at large biotech/pharmaceutical companies. That creates an interesting situation. M.D.s have often taken it upon themselves to solve some of the mysteries of medical science. Scientists are trained to do the job but any reasonable person should be able to spot obvious things like Dr. Listers observation that washing ones hands prior to surgery cuts back on infections.
Dr. Louis Bianco is an M.D. and the CEO of a company called Cell Therapeutics. He decided long ago to prescribe a drug called XYOTAX. The patient was all of society. XYOTAX is a biologically enhanced chemotherapeutic that links paclitaxel, the active ingredient in Taxol, to a biodegradable polyglutamate polymer. The idea with this is that the glutamate will render paclitaxel inactive until it enters a tumor cell. Thus it would be the perfect solution for delivering this drug. The only problem is that XYOTAX doesn't work any better than paclitaxel alone. Nonetheless, Dr. Bianco is adamant on prescribing this drug to those who have cancer.
I think this would be a good time to not prescribe. It would be a good time to find another drug to invest in. What's stopping Dr. Bianco from making the obvious decision? As of March 31, 2006, Cell Therapeutics had incurred aggregate net losses of approximately $(878.5) million since inception. That's what is stopping them. Without the approval of XYOTAX, the company has no other means of generating an income.
878.5 million dollars of investor capital went into a company that is now sitting on roughly 80 million bucks and a potentially ineffective drug. Where did the money go? Who made that money in the process of getting the drug where it is today? If you've ever wondered about the figure of 800 million dollars to get a drug to the market, you have to figure in fiascos like this. Investors can be hoodwinked quite easily when it comes to science. The entire executive team at Cell Therapeutics have a reputation for being long on hype but short on results. Three years ago, James Bianco confidently predicted that XYOTAX would be on the market by 2005. He now claims that it will be done by early 2007.
CEOs and executives continue to reap the rewards from just working in the business. You don't have to have a good drug. You have to have the juevos to keep going back for more. You tell the investors, "next year, trust me," and if they bite, you are in business. The Cargo Cult analogy is clear, the promise of the airplanes landing is enough to get paid. In fact you can have a fabulously successful career and never have an airplane land.
Monday, July 31, 2006
FDA Hard At Work
"During the Middle Ages there were all kinds of crazy ideas, such as that a piece of of rhinoceros horn would increase potency. Then a method was discovered for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course, into science. And it developed very well, so that we are now in the scientific age. It is such a scientific age, in fact, that we have difficulty in understanding how witch doctors could ever have existed, when nothing that they proposed ever really worked--or very little of it did. "
That's the first paragraph in Richard Feynmans Cargo Cult Science. He started off real simple. Some things don't work. Why did people think they did? That's a good question. Science is simple if you look at it that way. Yet not everyone looks at science that way. Let's see how the FDA regards this new thing called science.
Pseudoephedrine, the active ingredient in Sudafed, is also the main ingredient in methampetamine. It's a big problem. New regulations will be pulling the drug off the shelves soon. To combat a loss in revenue the scientists at Pfizer developed Sudafed PE. The active ingredient is phenylephrine.
From Forbes.com:
In a peer-reviewed letter released this week to the editor of the Journal of Allergy and Clinical Immunology, University of Florida researchers argued that there's little evidence to suggest that the active ingredient in the new Sudafed PE or similar medications will do anything to relieve a stuffy nose.
In their letter, Hendeles and colleague Dr. Randy Hatton contended that when the U.S. Food and Drug Administration approved the use of phenylephrine in 1976, the agency was only able to find four studies that suggested it worked at a dose of 10 milligrams, the size of Sudafed PE pills. Two of those studies were sponsored by drug companies, and all were unpublished and not reviewed by peers, Hendeles said.
Seven other studies, according to the authors, found that phenylephrine didn't work better than a placebo.
"It does nothing," Hendeles said. "Clearly the 10 milligram (dose) does not work."
So what is happening here? We're not living in the middle ages. We're not being sold snake oil from a stage coach. It's 2006. The FDA has examined the evidence on our behalf and approved a drug that does not work. Four studies suggested that it worked, 2 of which were funded by the industry. Seven others said that it did nothing. The FDA however has accepted only the positive results. They had the same opportunity as the scientists at the University of Florida but they came up with a different conclusion.
The science that has escaped the cargo culture has lifted us up as though the entire society were enlightened invidivuals. My question is how far from the truth that is. How many are enlightened and how many would burn a witch if they were presented with "the proper evidence"? How many in the latter group work at the FDA?
That's the first paragraph in Richard Feynmans Cargo Cult Science. He started off real simple. Some things don't work. Why did people think they did? That's a good question. Science is simple if you look at it that way. Yet not everyone looks at science that way. Let's see how the FDA regards this new thing called science.
Pseudoephedrine, the active ingredient in Sudafed, is also the main ingredient in methampetamine. It's a big problem. New regulations will be pulling the drug off the shelves soon. To combat a loss in revenue the scientists at Pfizer developed Sudafed PE. The active ingredient is phenylephrine.
From Forbes.com:
In a peer-reviewed letter released this week to the editor of the Journal of Allergy and Clinical Immunology, University of Florida researchers argued that there's little evidence to suggest that the active ingredient in the new Sudafed PE or similar medications will do anything to relieve a stuffy nose.
In their letter, Hendeles and colleague Dr. Randy Hatton contended that when the U.S. Food and Drug Administration approved the use of phenylephrine in 1976, the agency was only able to find four studies that suggested it worked at a dose of 10 milligrams, the size of Sudafed PE pills. Two of those studies were sponsored by drug companies, and all were unpublished and not reviewed by peers, Hendeles said.
Seven other studies, according to the authors, found that phenylephrine didn't work better than a placebo.
"It does nothing," Hendeles said. "Clearly the 10 milligram (dose) does not work."
So what is happening here? We're not living in the middle ages. We're not being sold snake oil from a stage coach. It's 2006. The FDA has examined the evidence on our behalf and approved a drug that does not work. Four studies suggested that it worked, 2 of which were funded by the industry. Seven others said that it did nothing. The FDA however has accepted only the positive results. They had the same opportunity as the scientists at the University of Florida but they came up with a different conclusion.
The science that has escaped the cargo culture has lifted us up as though the entire society were enlightened invidivuals. My question is how far from the truth that is. How many are enlightened and how many would burn a witch if they were presented with "the proper evidence"? How many in the latter group work at the FDA?
Thursday, July 27, 2006
Archimedes
Imagine a real scientist living before there were computers. These days, long difficult calculations can be done in nanoseconds with a computer. When the groundwork was being laid for our modern conveniences everything came the hard way. Yet to those engaging in the work, it was done for pleasure. Archimedes was one who engaged in finding things out for the fun of it.
The following was taken from an article by J J O'Connor and E F Robertson:
"Archimedes possessed so high a spirit, so profound a soul, and such treasures of scientific knowledge, that though these inventions had now obtained him the renown of more than human sagacity, he yet would not deign to leave behind him any commentary or writing on such subjects; but, repudiating as sordid and ignoble the whole trade of engineering, and every sort of art that lends itself to mere use and profit, he placed his whole affection and ambition in those purer speculations where there can be no reference to the vulgar needs of life; studies, the superiority of which to all others is unquestioned, and in which the only doubt can be whether the beauty and grandeur of the subjects examined, of the precision and cogency of the methods and means of proof, most deserve our admiration. "
One of the things Archimedes deemed worthy of writing about was his method of discovery. In 'The Method' he writes, "... certain things first became clear to me by a mechanical method, although they had to be proved by geometry afterwards because their investigation by the said method did not furnish an actual proof. But it is of course easier, when we have previously acquired, by the method, some knowledge of the questions, to supply the proof than it is to find it without any previous knowledge. "
This is a very complex statement. The modern day scientist has so much information and so many tools at his/her disposal that it's hard to keep track of everything involved in an experiment. Are we certain that we have the proper knowledge of the questions we are asking? Are we Martians who've come to earth to discover that diet coke makes people fat?
Plutarch, an ancient historian, describes Archimedes genius; "It is not possible to find in all geometry more difficult and intricate questions, or more simple and lucid explanations. Some ascribe this to his natural genius; while others think that incredible effort and toil produced these, to all appearances, easy and unlaboured results. No amount of investigation of yours would succeed in attaining the proof, and yet, once seen, you immediately believe you would have discovered it; by so smooth and so rapid a path he leads you to the conclusion required."
I can recall a professor in college describing the PCR method discovered by Kary Mullis. He said it was so simple that everyone who first read about it immediately slapped their forehead and cursed themselves for not thinking of it. It was as if the professor was saying it was too simple for his big brain. Yet he didn't think of it and he never would have. He was never put in the position to ask the question of how to make more DNA. Everyone had accepted the laborious methods being used prior to PCR. Kary Mullis was bored with what his superiors wanted him to do. He thought up a better way to amplify DNA. When you saw what he did you were impressed. Heath, a mathematical historian, described Archimedes work in a more eloquent way:
"The treatises are, without exception, monuments of mathematical exposition; the gradual revelation of the plan of attack, the masterly ordering of the propositions, the stern elimination of everything not immediately relevant to the purpose, the finish of the whole, are so impressive in their perfection as to create a feeling akin to awe in the mind of the reader."
The following was taken from an article by J J O'Connor and E F Robertson:
"Archimedes possessed so high a spirit, so profound a soul, and such treasures of scientific knowledge, that though these inventions had now obtained him the renown of more than human sagacity, he yet would not deign to leave behind him any commentary or writing on such subjects; but, repudiating as sordid and ignoble the whole trade of engineering, and every sort of art that lends itself to mere use and profit, he placed his whole affection and ambition in those purer speculations where there can be no reference to the vulgar needs of life; studies, the superiority of which to all others is unquestioned, and in which the only doubt can be whether the beauty and grandeur of the subjects examined, of the precision and cogency of the methods and means of proof, most deserve our admiration. "
One of the things Archimedes deemed worthy of writing about was his method of discovery. In 'The Method' he writes, "... certain things first became clear to me by a mechanical method, although they had to be proved by geometry afterwards because their investigation by the said method did not furnish an actual proof. But it is of course easier, when we have previously acquired, by the method, some knowledge of the questions, to supply the proof than it is to find it without any previous knowledge. "
This is a very complex statement. The modern day scientist has so much information and so many tools at his/her disposal that it's hard to keep track of everything involved in an experiment. Are we certain that we have the proper knowledge of the questions we are asking? Are we Martians who've come to earth to discover that diet coke makes people fat?
Plutarch, an ancient historian, describes Archimedes genius; "It is not possible to find in all geometry more difficult and intricate questions, or more simple and lucid explanations. Some ascribe this to his natural genius; while others think that incredible effort and toil produced these, to all appearances, easy and unlaboured results. No amount of investigation of yours would succeed in attaining the proof, and yet, once seen, you immediately believe you would have discovered it; by so smooth and so rapid a path he leads you to the conclusion required."
I can recall a professor in college describing the PCR method discovered by Kary Mullis. He said it was so simple that everyone who first read about it immediately slapped their forehead and cursed themselves for not thinking of it. It was as if the professor was saying it was too simple for his big brain. Yet he didn't think of it and he never would have. He was never put in the position to ask the question of how to make more DNA. Everyone had accepted the laborious methods being used prior to PCR. Kary Mullis was bored with what his superiors wanted him to do. He thought up a better way to amplify DNA. When you saw what he did you were impressed. Heath, a mathematical historian, described Archimedes work in a more eloquent way:
"The treatises are, without exception, monuments of mathematical exposition; the gradual revelation of the plan of attack, the masterly ordering of the propositions, the stern elimination of everything not immediately relevant to the purpose, the finish of the whole, are so impressive in their perfection as to create a feeling akin to awe in the mind of the reader."
Tuesday, July 25, 2006
Curing Cancer
A common form of biotech R&D is finding something that binds to a drug target and seeing what affect that has on the disease. Antibodies are very popular because they bind to proteins. They were designed to do so by God (insert your god here). The immune system makes antibodies against foreign proteins, they bind to the foreign protein and the rest of the immune system removes the antibody and what it is binding to.
One approach to curing cancer was to make an antibody against denatured collagen. The concept was that it will bind to areas who tissue is breaking down. If a cancer is invading a tissue the antibody will go to that area. Good idea so far. The leap of faith in this research was that denatured collagen held a criptic binding site for angiogenisis factors. There is no evidence of this. The way around it was to simply inject the antibody into a mouse with a tumor and see if it prevented the tumor from growing. A tumor needs blood vessels to provide oxygen and carry away its waste. If you inhibit angiogenisis then the tumor will shrivel up.
Another protein target to prevent tumor grown was VEGF (vascular endothelial growth factor). The antibody against this target binds to the target and it prevents tumors from growing in mice. This I have witnessed first hand. As a control for the anti-angiogenisis antibodies we had, we used the anti-VEGF antibody. In this group of mice the most you could see was a red swelling where the tumor cells had been injected. In all other groups tumors had formed, of all different shapes and sizes. Our antibody didn't come close to the results of the anti-VEGF antibody.
The concept has been proven, in mice at least. An antibody can be developed and used as a drug. Rituxan, (anti-VEGF) does not work as well in humans but it is for sale for cancer treatment. The anti-collagen antibody is in preclinical development, just where it was when I left the project over four years ago. Each year a presentation is given at a biotech seminar on how well it reduces tumors. 57% in nude mice, 67% in female Balbc mice. The truth is, it doesn't work at all. It didn't work in laboratory assays such as adhesion and cell migration assays. It didn't work in mice. A graduate student showed us how to measure the tumors to get "better data". After measuring and getting the numbers she wanted she made the mistake to ask if I had any questions. I handed her one of the mice she had already measured. She was immediately embarrassed. "Which one is this?" she asked. "If I told you it would take away from the experiment of testing the reproducibility of what you just demonstrated," I answered. She took a shot. She was off by 30%. Imagine how the measurements of entire groups of mice are treated. Then think about the presentation to the big time scientists at the biotech conferences. Any questions?
By the time it's all said and done, we still do not have a good anti-cancer drug. We have a ton of molecules that bind to something that may be involved in cancer. How do we know when our drugs reach their targets? How much is needed and where? Biotech is swinging for homeruns by finding targets and finding something that binds to them. Peptides, antibodies, enzymes, phage, viruses, small molecules and other sythetic compounds. One thing can be said about an antibody however. It binds to a protein but it also is part of a system that protects us from harm. It does not work alone. Binding alone is not enough.
One approach to curing cancer was to make an antibody against denatured collagen. The concept was that it will bind to areas who tissue is breaking down. If a cancer is invading a tissue the antibody will go to that area. Good idea so far. The leap of faith in this research was that denatured collagen held a criptic binding site for angiogenisis factors. There is no evidence of this. The way around it was to simply inject the antibody into a mouse with a tumor and see if it prevented the tumor from growing. A tumor needs blood vessels to provide oxygen and carry away its waste. If you inhibit angiogenisis then the tumor will shrivel up.
Another protein target to prevent tumor grown was VEGF (vascular endothelial growth factor). The antibody against this target binds to the target and it prevents tumors from growing in mice. This I have witnessed first hand. As a control for the anti-angiogenisis antibodies we had, we used the anti-VEGF antibody. In this group of mice the most you could see was a red swelling where the tumor cells had been injected. In all other groups tumors had formed, of all different shapes and sizes. Our antibody didn't come close to the results of the anti-VEGF antibody.
The concept has been proven, in mice at least. An antibody can be developed and used as a drug. Rituxan, (anti-VEGF) does not work as well in humans but it is for sale for cancer treatment. The anti-collagen antibody is in preclinical development, just where it was when I left the project over four years ago. Each year a presentation is given at a biotech seminar on how well it reduces tumors. 57% in nude mice, 67% in female Balbc mice. The truth is, it doesn't work at all. It didn't work in laboratory assays such as adhesion and cell migration assays. It didn't work in mice. A graduate student showed us how to measure the tumors to get "better data". After measuring and getting the numbers she wanted she made the mistake to ask if I had any questions. I handed her one of the mice she had already measured. She was immediately embarrassed. "Which one is this?" she asked. "If I told you it would take away from the experiment of testing the reproducibility of what you just demonstrated," I answered. She took a shot. She was off by 30%. Imagine how the measurements of entire groups of mice are treated. Then think about the presentation to the big time scientists at the biotech conferences. Any questions?
By the time it's all said and done, we still do not have a good anti-cancer drug. We have a ton of molecules that bind to something that may be involved in cancer. How do we know when our drugs reach their targets? How much is needed and where? Biotech is swinging for homeruns by finding targets and finding something that binds to them. Peptides, antibodies, enzymes, phage, viruses, small molecules and other sythetic compounds. One thing can be said about an antibody however. It binds to a protein but it also is part of a system that protects us from harm. It does not work alone. Binding alone is not enough.
The CEO of a Few Cargo Cult Airports
He was a smart young man. After receiving his PhD and MD from the University of Michigan he began teaching at Stanford. Not satisfied with the slow pace of life in academia he went into business. In 1984 he convinced a few venture capital groups to back him. He was now the founder of a biotech company. As the clinical-trial process ate up early funding, he returned for two more rounds of funding causing his hown financial interest in the company to dwindle. This loss of control grated on him. His backers, seeking more seasoned management, brought in a new CEO, who began spending heavily on a large building and dozens of new employees. By the time they were ready to go to market with their first drug, the company needed more money--and its backers were looking for a way out. The founder reluctantly agreed to sell the company. He left bitter, a year later, convinced that more patient investors could have reaped far higher returns in a year. But he also pocketed $7.5 million.
Cargo Cult Scientist note: No drug was brought to the market. The airplanes did not land. A company was sold, not a drug.
In 1991 he founded his next biotech company. The product was almost identical to the previous companies product. They spent years developing the company. During that time the drug was under development as well but it wasn't all that impressive. In spite of the products weak performance they filed an IND (Investigational New Drug application) with the FDA. In 1998 the FDA issued a warning letter to the CEO. The FDA found that the company was promoting their product as safe and effective for numerous applications. None is this had been approved by the FDA. The CEO and his company had 14 days to comply with the FDAs demand to cease promoting the drug. All managers within the company were to receive a copy of the warning letter.
Disappointed with the progress of work and the arrogance of the CEO, the board voted to replace him in 1999. In 2000 the company withdrew its NDA (New Drug Application) and ceased development.
The airplanes, once again, did not land.
In 2000 he began his latest adventure. This time the product was different. They would focus on generic products delivered nasally with a new technology that employed biological materials instead of the standard nasal formulations. However, there has been no INDs filed that employ the highly touted delivery technology. A major deal with a Merck was shut down to to lack of efficacy. Nonetheless they continue to pump money into the project. The decision was labeled as one of the top five stupidest things on Wallstreet that week. One investor on a blog commented, "I was never a big fan of (the Company) because I remember (the CEO) from a company he ran called (previous company). In my opinion he wasn't always truthful."
The latest disappointment was a letter by the FDA stating that the most advanced drug in their pipeline was not approvable. The good news for investors was that this drug did not employ the delivery system so highly touted. The rest of the pipeline, which may or may not use the delivery technology, was safe.
The highly touted biological drug delivery system simply does not exist. It was an idea or a hypothesis but it was not what they claimed it to be. Once again, investors have been duped. Only white lab coat wearing individuals know of the trouble. Every week they have to report on the progress of the "technology". But a hypothesis is not technology. Only a cargo cult would believe it is. The cargo cults beliefs are what prevent them from making progress in the field of aviation. The same goes for biotechnology.
The CEO of this story is another hypothesis. He is said to posess great skills in running a business. I suppose he is no different than many of the leaders running biotech companies. He's got the PhD and the MD as well. He's ran other companies. He has assembled a team and they run the daily operation. In the end, nothing happens. People lose their jobs. Investors lose their money. Is there another way? Is there another hypothesis that we could apply to making money and drugs at the same time? I can only think of one. Develop a highly effective drug and bend over backwards to prove that it doesn't work. If you fail, you win.
Give up the pedigreed CEOs. Search out useful drugs and everyones work will be easier.
Cargo Cult Scientist note: No drug was brought to the market. The airplanes did not land. A company was sold, not a drug.
In 1991 he founded his next biotech company. The product was almost identical to the previous companies product. They spent years developing the company. During that time the drug was under development as well but it wasn't all that impressive. In spite of the products weak performance they filed an IND (Investigational New Drug application) with the FDA. In 1998 the FDA issued a warning letter to the CEO. The FDA found that the company was promoting their product as safe and effective for numerous applications. None is this had been approved by the FDA. The CEO and his company had 14 days to comply with the FDAs demand to cease promoting the drug. All managers within the company were to receive a copy of the warning letter.
Disappointed with the progress of work and the arrogance of the CEO, the board voted to replace him in 1999. In 2000 the company withdrew its NDA (New Drug Application) and ceased development.
The airplanes, once again, did not land.
In 2000 he began his latest adventure. This time the product was different. They would focus on generic products delivered nasally with a new technology that employed biological materials instead of the standard nasal formulations. However, there has been no INDs filed that employ the highly touted delivery technology. A major deal with a Merck was shut down to to lack of efficacy. Nonetheless they continue to pump money into the project. The decision was labeled as one of the top five stupidest things on Wallstreet that week. One investor on a blog commented, "I was never a big fan of (the Company) because I remember (the CEO) from a company he ran called (previous company). In my opinion he wasn't always truthful."
The latest disappointment was a letter by the FDA stating that the most advanced drug in their pipeline was not approvable. The good news for investors was that this drug did not employ the delivery system so highly touted. The rest of the pipeline, which may or may not use the delivery technology, was safe.
The highly touted biological drug delivery system simply does not exist. It was an idea or a hypothesis but it was not what they claimed it to be. Once again, investors have been duped. Only white lab coat wearing individuals know of the trouble. Every week they have to report on the progress of the "technology". But a hypothesis is not technology. Only a cargo cult would believe it is. The cargo cults beliefs are what prevent them from making progress in the field of aviation. The same goes for biotechnology.
The CEO of this story is another hypothesis. He is said to posess great skills in running a business. I suppose he is no different than many of the leaders running biotech companies. He's got the PhD and the MD as well. He's ran other companies. He has assembled a team and they run the daily operation. In the end, nothing happens. People lose their jobs. Investors lose their money. Is there another way? Is there another hypothesis that we could apply to making money and drugs at the same time? I can only think of one. Develop a highly effective drug and bend over backwards to prove that it doesn't work. If you fail, you win.
Give up the pedigreed CEOs. Search out useful drugs and everyones work will be easier.
Monday, July 24, 2006
The FDA Can't Do It's Job
The FDA is trying to decide if they should ban scientists with financial interests in certain drugs from serving as advisors to the agency. There are review panels set up by the FDA to assess the value of a drug. The FDA argues that banning certain scientists would deny the FDA access to advisers with the expertise and experience it seeks.
"We probably couldn't recruit department chairmen. It would hinder us from recruiting all but junior faculty members" said Dr. Scott Gottlieb, the FDA;s deputy commisioner for Medical and Scientific Affairs.
Congress argues that scientists with a financial interest in a drug, serving as advisors for the scientific assessment of the drug have a conflict of interest. The FDA does not deny this fact. They just don't want to admint that the conflict of interest manifests itself as decisions based on financial gain. They believe that what they do is pure science and thus they need scientific advisors.
The question is however, why can't the FDA do their job without having to hire consultants? They hire people to explain things they should really have a firm grasp on themselves. The budget for approving, labeling, and monitoring drugs is roughly $290 million per year.. Still they cannot make decisions without consulting with the experts who have a conflict of interest?
Congress is simply trying to get the FDA to make better decisions. The conflicts of interests cause the FDA to make bad decisions. The reason the FDA was set up was to protect the American people from potencially harmful food and drugs. We needed a government agency who had only the interest of the people to protect. We needed people who could protect us from harmful products sold by people whose main interests were in making money. Now our FDA is telling us they can't make good decisions without hiring people who cause them to make bad decisions.
"It just doesn't make any sense to me. When you have this problem-conflicts of interest on critical panels-the solution is eliminate the conflict. It's simple and easy to do," said Rep. Maurice Hinchey D-NY.
1937 — Over 100 people died after consuming a raspberry-flavored sulfa elixir which had been rushed to market by the S.E. Massengill Company without any testing. About 70 percent of the elixir was diethylene glycol, which is now known to be poisonous (related to antifreeze). However, the FDA was able to remove the sulfa elixir from the market because elixirs at the time were to contain alcohol as a solvent (not diethylene glycol).
1938 — The resulting sulfa elixir scandal and public outcry led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938, which gave the FDA the power to preapprove all new drugs introduced into interstate commerce.
It is important to point out that the scientist who developed the rasberry-flavored sulfa elixir was so devestated by what happened that he committed suicide. Most of the deaths he caused were young children. No one in their right mind would purposely kill young children by poisoning their medicine. This was a tragic mistake that was corrected by making the FDA our guardians. They are now telling us that they can't do their job.
"We probably couldn't recruit department chairmen. It would hinder us from recruiting all but junior faculty members" said Dr. Scott Gottlieb, the FDA;s deputy commisioner for Medical and Scientific Affairs.
Congress argues that scientists with a financial interest in a drug, serving as advisors for the scientific assessment of the drug have a conflict of interest. The FDA does not deny this fact. They just don't want to admint that the conflict of interest manifests itself as decisions based on financial gain. They believe that what they do is pure science and thus they need scientific advisors.
The question is however, why can't the FDA do their job without having to hire consultants? They hire people to explain things they should really have a firm grasp on themselves. The budget for approving, labeling, and monitoring drugs is roughly $290 million per year.. Still they cannot make decisions without consulting with the experts who have a conflict of interest?
Congress is simply trying to get the FDA to make better decisions. The conflicts of interests cause the FDA to make bad decisions. The reason the FDA was set up was to protect the American people from potencially harmful food and drugs. We needed a government agency who had only the interest of the people to protect. We needed people who could protect us from harmful products sold by people whose main interests were in making money. Now our FDA is telling us they can't make good decisions without hiring people who cause them to make bad decisions.
"It just doesn't make any sense to me. When you have this problem-conflicts of interest on critical panels-the solution is eliminate the conflict. It's simple and easy to do," said Rep. Maurice Hinchey D-NY.
1937 — Over 100 people died after consuming a raspberry-flavored sulfa elixir which had been rushed to market by the S.E. Massengill Company without any testing. About 70 percent of the elixir was diethylene glycol, which is now known to be poisonous (related to antifreeze). However, the FDA was able to remove the sulfa elixir from the market because elixirs at the time were to contain alcohol as a solvent (not diethylene glycol).
1938 — The resulting sulfa elixir scandal and public outcry led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938, which gave the FDA the power to preapprove all new drugs introduced into interstate commerce.
It is important to point out that the scientist who developed the rasberry-flavored sulfa elixir was so devestated by what happened that he committed suicide. Most of the deaths he caused were young children. No one in their right mind would purposely kill young children by poisoning their medicine. This was a tragic mistake that was corrected by making the FDA our guardians. They are now telling us that they can't do their job.
Monday, July 17, 2006
A Place to Think
Is it true that our best thinkers wind up in board rooms, senate floors, or behind college classroom podiums? What about the farmer who sees his crops growing better after planting in a new formation? Who told him to change the formation? Did he take his own idea from start to finish resulting in the desired outcome? If that same farmer was placed in a different situation could that brain work to solve other kinds of problems?
I am certain that there are people who work in low level jobs who have the kind of mind that can solve complex problems that are not being solved by people who are currently in the highest levels. With the system that we have however, it is difficult for certain types of thinkers to be put in a place where they can do the most good.
Perhaps the current popularity of the blogs is that it's a place where people can rest their thoughts. There are tons of blogs with zero comments. No visitors yet the bloggers continue to post their thoughts. This is a place to think until you find a better place to send your ideas. Just start searching through the blogs. You'll find some good ideas just sitting there.
I am certain that there are people who work in low level jobs who have the kind of mind that can solve complex problems that are not being solved by people who are currently in the highest levels. With the system that we have however, it is difficult for certain types of thinkers to be put in a place where they can do the most good.
Perhaps the current popularity of the blogs is that it's a place where people can rest their thoughts. There are tons of blogs with zero comments. No visitors yet the bloggers continue to post their thoughts. This is a place to think until you find a better place to send your ideas. Just start searching through the blogs. You'll find some good ideas just sitting there.
Wednesday, July 12, 2006
Time to Think
Whenever you write an angry letter it's best to leave it for awhile. Come back and read it see if it is as forceful as you thought or if it is just some angry guy blowing off steam. One of my first e-mails was to the editor of the college paper. I vented about everything I could think of. I felt pretty stupid as I read it published in the paper. I was out of control, not making any points, just bitching about things. Should have sat on it for awhile.
We need time to think. There is a scene in "Planes, Trains and Automobiles" where John Candy is driving down the wrong side of the interstate. He looks across the median that separates the two roads (going in opposite directions). The people in the car parallel him yell out, "you're going the wrong way"! He hears them, thinks about it, then says, "how do they know which way we're going"?
It makes you wonder what is going on when our leaders vote on tax reform legislation that is written up in 10 thousand page documents. It makes you wonder about the decisions made in board rooms in 1 hour meetings. Is the proper way of conducting business always done in meetings? Is there enough time to properly process the information that goes into making a decision?
In science we have come up with statistical analysis. The more data you have the better off you'll be at determining what it means. For instance, if you have 20 people in a clinical trial you may come to a different conclusion than if you have 2000. This is called the N value and as it increases the more accurate your data analysis will be. As you increase the N value you may just be increasing the time needed to gather the data. You need that time.
By slowing down we give ourselves a better chance. We can't always wait but when we can we should. The Cargo Cult Scientist often times does not have the time to wait for the best data. It could be that there is another lab working on the same problem. If they publish first the competitors might lose the race. One less publication. This is just one of the problems associated with the publishing of scientific papers. They don't allow enough time due to the competition. Believe it or not, competing scientists don't call each other up with congratulations for getting to the answer first. Even if it's validation of their own work, scientists must be first. Now one would think that it would be exciting to see someone else come up with the same conclusions you did. It is validation of you thoughts and experiments. Sadly, that is not how the real world works.
The cargo cult airport is forever looking to the skies to see the airplanes. They don't arrive but there is still a sense of urgency down below. Deadlines are set for the shape of the coconuts that go over the air traffic controllers ears. Management has to get things done! That's different than really getting things done. Just like when the senators sign tax bills, there is no chance that they information is fully understood and acted upon accordingly. Things needed to get done so they were.
Make time to think. If you want a better job, take the time to figure out what you really want to do and where you can do it. If you want to divorce your spouse, take time to think about what life will be like as a divorcee. When signing that mortage make them wait while you read the whole contract. Take time to think. Complicated issues need time.
We need time to think. There is a scene in "Planes, Trains and Automobiles" where John Candy is driving down the wrong side of the interstate. He looks across the median that separates the two roads (going in opposite directions). The people in the car parallel him yell out, "you're going the wrong way"! He hears them, thinks about it, then says, "how do they know which way we're going"?
It makes you wonder what is going on when our leaders vote on tax reform legislation that is written up in 10 thousand page documents. It makes you wonder about the decisions made in board rooms in 1 hour meetings. Is the proper way of conducting business always done in meetings? Is there enough time to properly process the information that goes into making a decision?
In science we have come up with statistical analysis. The more data you have the better off you'll be at determining what it means. For instance, if you have 20 people in a clinical trial you may come to a different conclusion than if you have 2000. This is called the N value and as it increases the more accurate your data analysis will be. As you increase the N value you may just be increasing the time needed to gather the data. You need that time.
By slowing down we give ourselves a better chance. We can't always wait but when we can we should. The Cargo Cult Scientist often times does not have the time to wait for the best data. It could be that there is another lab working on the same problem. If they publish first the competitors might lose the race. One less publication. This is just one of the problems associated with the publishing of scientific papers. They don't allow enough time due to the competition. Believe it or not, competing scientists don't call each other up with congratulations for getting to the answer first. Even if it's validation of their own work, scientists must be first. Now one would think that it would be exciting to see someone else come up with the same conclusions you did. It is validation of you thoughts and experiments. Sadly, that is not how the real world works.
The cargo cult airport is forever looking to the skies to see the airplanes. They don't arrive but there is still a sense of urgency down below. Deadlines are set for the shape of the coconuts that go over the air traffic controllers ears. Management has to get things done! That's different than really getting things done. Just like when the senators sign tax bills, there is no chance that they information is fully understood and acted upon accordingly. Things needed to get done so they were.
Make time to think. If you want a better job, take the time to figure out what you really want to do and where you can do it. If you want to divorce your spouse, take time to think about what life will be like as a divorcee. When signing that mortage make them wait while you read the whole contract. Take time to think. Complicated issues need time.
Friday, June 30, 2006
GETRAPL
There is a technique that is used in biotechnology known as phage display. In this technology a virus that attacks bacteria is used to display a short peptide. Without boring the reader with the details, this is a technique known as evolution in an instant. What you do is subject a library of peptide displaying phage to a protein target. You wash away non-binding phage, amplify binding phage and repeat. What you hope to end up with are peptides that bind to a target. You are repeating because it takes a while to get rid of non-binding phage. They must be slowly selected against in an evolution like process.
During the selection process many other things can happen. Contamination of the library of phage can happen. Most interesting however is the selection of phage that are in the original library. These phage will predominate after a while because they grow faster than the other phage. At least that is the theory. A company called New England Biolabs sells the phage libraries. Each lot appears to have a set of contaminants that will come out after a period of selection. They do not seem to appear because they bind to a protein target. They lack a gene that the rest of the library has. This gene causes the phage plaques (formed on bacterial lawns) to turn blue. The contaminating phage form white plaques. Perhaps this is part of the selection of the phage since the normal state of the DNA lacks the blue plaque gene.
One such phage that has been seen displays the peptide GETRAPL. That is code for 7 amino acids, glycine-glutamic acid-threonine-arginine-alanine-proline-leucine. A co-worker of mine found this sequence. I recognized it and ran it in our database. Sure enough, it showed up several times. There was not particular protein linked to it however. It was linked to later stages of selection however. We noted that the plaques were white in all cases. We typed it into Google and found an interesting group of papers.
Researchers at a different laboratories had found this sequence while using phage display against their targets. The first paper "Design and Assay of Inhibitors of HIV-1 Vpr Cell Killing and Growth Arrest Activity Using Microbial Assay Systems". The next, "Development of efficient viral vectors selective for vascular smooth muscle cells". Completely unrelated, yet they used the peptide to validate their work. They published and ...?
In physics you set up a system. In that system many things are happening. Pressure changes, concentration of molecules changes, heat is given off and so on. One of the question you can ask about a system is whether or not work has been done at a certain period of time. For example, you load a box onto a conveyor belt that takes the box and drops it onto another conveyor belt that puts the box back you to load onto the first conveyor belt. You are sweating. Boxes are moving but only in a circle. Work is not really getting done.
The GETRAPL story is like that. Did work get done? Did anything scientific get done? The papers on GETRAPL appear to have ended. No one is talking about the peptide but there was a time when this little contaminant from a phage display library made two labs get out their typewriters and type of the story of how they got the peptide and what they did with it. And it did something! The circle here is starting with the library, getting the same sequence, publishing and moving on to something else. The way to stop the non-working cycle is to publish a paper on the sequence and let people know when they are being misled. The system here is science as it is being practiced by PhD scientists and journal editors. The people who sell the libraries can also stop the non-work cycle. The system is not producing work.
Feynman said that he hoped we learned something during our educations. Something you can't teach. You can easily learn how a phage library is made and used. You can learn some computer software that will help you assess the peptides you end up with. Finding a protein binding peptide is a rare event, but that is not what is taught. To me, that is the interesting thing about the technique. It is just one of many techniques that can be used to study a protein and it's interactions. You can learn all about the protein prior to using phage display. You can get up a give a talk to the Academy of Sciences on the details of your work. But in the end you have to look at your results. You have to use something inside of you that is not taught. Critical thinking perhaps. Can it really be binding to the target? How can I prove that? How can I disprove that? How can I be sure of any result?
One way of looking at GETRAPL is very obvious to laboratory people. You look at the DNA sequences of each phage that displays GETRAPL. Are they identical or are there various sequences using different codons that code for GETRAPL. This would be strong evidence that it is not being selected for because the original phage grows faster than the rest of the library. Another modern day trick that we applied was to Google the sequence and see if anyone could back up your hopes and dreams that it binds to a specific target. Your education can teach you about the tools. It is up to you to use them.
There are many phage like GETRAPL. There is a paper published by one of the leading phage display scientists that discusses their existance. What is selecting these phage is still unknown. Developing an explanation and proving it is science. There are scientists who currently work on software that can take a list of sequences that come out of a phage display selection process and help you understand what you've got. If you sequence 100 phage and they are all the same sequence for example, the computer only sees one sequence. The computer is weeding out repeated sequences because it indicates selection based on non-binding factors such as faster growing phage. The computer software continues to add new features to help you find binding phage. Someday you could simply put files into this software and it will give you a list of possible binding targets. It could search your own database as well those on the internet or in Pubmed. This is still not going to tell you the whole story. You have to develop an assay. They teach you about assays. The assays however, give you another set of data that you have to interpret. This is what Feynman was hoping you would know how to do. Think scientifically. Ignore your hopes and dreams of getting published and moving on to more interesting projects. Don't act on your desire to take that peptide and fuse it into some elaborate molecule you designed and toss that into an elaborate assay and prove that you can cure AIDS! Slow down. Is the data really saying what you think it is. Think critically and proceed logically.
There are many other peptides that have been discovered that are mere contaminants. The claims that their finders have made on their behalf are quite fancy. Big science words were used and put together in a way that is certainly feasible. No work was done however. Just words used to describe a set of letters that represent amino acids. What is really going on can open doors. What is really going on can make the planes land! But they fade away, these research projects. No resolution. No work was done. No planes landed.
During the selection process many other things can happen. Contamination of the library of phage can happen. Most interesting however is the selection of phage that are in the original library. These phage will predominate after a while because they grow faster than the other phage. At least that is the theory. A company called New England Biolabs sells the phage libraries. Each lot appears to have a set of contaminants that will come out after a period of selection. They do not seem to appear because they bind to a protein target. They lack a gene that the rest of the library has. This gene causes the phage plaques (formed on bacterial lawns) to turn blue. The contaminating phage form white plaques. Perhaps this is part of the selection of the phage since the normal state of the DNA lacks the blue plaque gene.
One such phage that has been seen displays the peptide GETRAPL. That is code for 7 amino acids, glycine-glutamic acid-threonine-arginine-alanine-proline-leucine. A co-worker of mine found this sequence. I recognized it and ran it in our database. Sure enough, it showed up several times. There was not particular protein linked to it however. It was linked to later stages of selection however. We noted that the plaques were white in all cases. We typed it into Google and found an interesting group of papers.
Researchers at a different laboratories had found this sequence while using phage display against their targets. The first paper "Design and Assay of Inhibitors of HIV-1 Vpr Cell Killing and Growth Arrest Activity Using Microbial Assay Systems". The next, "Development of efficient viral vectors selective for vascular smooth muscle cells". Completely unrelated, yet they used the peptide to validate their work. They published and ...?
In physics you set up a system. In that system many things are happening. Pressure changes, concentration of molecules changes, heat is given off and so on. One of the question you can ask about a system is whether or not work has been done at a certain period of time. For example, you load a box onto a conveyor belt that takes the box and drops it onto another conveyor belt that puts the box back you to load onto the first conveyor belt. You are sweating. Boxes are moving but only in a circle. Work is not really getting done.
The GETRAPL story is like that. Did work get done? Did anything scientific get done? The papers on GETRAPL appear to have ended. No one is talking about the peptide but there was a time when this little contaminant from a phage display library made two labs get out their typewriters and type of the story of how they got the peptide and what they did with it. And it did something! The circle here is starting with the library, getting the same sequence, publishing and moving on to something else. The way to stop the non-working cycle is to publish a paper on the sequence and let people know when they are being misled. The system here is science as it is being practiced by PhD scientists and journal editors. The people who sell the libraries can also stop the non-work cycle. The system is not producing work.
Feynman said that he hoped we learned something during our educations. Something you can't teach. You can easily learn how a phage library is made and used. You can learn some computer software that will help you assess the peptides you end up with. Finding a protein binding peptide is a rare event, but that is not what is taught. To me, that is the interesting thing about the technique. It is just one of many techniques that can be used to study a protein and it's interactions. You can learn all about the protein prior to using phage display. You can get up a give a talk to the Academy of Sciences on the details of your work. But in the end you have to look at your results. You have to use something inside of you that is not taught. Critical thinking perhaps. Can it really be binding to the target? How can I prove that? How can I disprove that? How can I be sure of any result?
One way of looking at GETRAPL is very obvious to laboratory people. You look at the DNA sequences of each phage that displays GETRAPL. Are they identical or are there various sequences using different codons that code for GETRAPL. This would be strong evidence that it is not being selected for because the original phage grows faster than the rest of the library. Another modern day trick that we applied was to Google the sequence and see if anyone could back up your hopes and dreams that it binds to a specific target. Your education can teach you about the tools. It is up to you to use them.
There are many phage like GETRAPL. There is a paper published by one of the leading phage display scientists that discusses their existance. What is selecting these phage is still unknown. Developing an explanation and proving it is science. There are scientists who currently work on software that can take a list of sequences that come out of a phage display selection process and help you understand what you've got. If you sequence 100 phage and they are all the same sequence for example, the computer only sees one sequence. The computer is weeding out repeated sequences because it indicates selection based on non-binding factors such as faster growing phage. The computer software continues to add new features to help you find binding phage. Someday you could simply put files into this software and it will give you a list of possible binding targets. It could search your own database as well those on the internet or in Pubmed. This is still not going to tell you the whole story. You have to develop an assay. They teach you about assays. The assays however, give you another set of data that you have to interpret. This is what Feynman was hoping you would know how to do. Think scientifically. Ignore your hopes and dreams of getting published and moving on to more interesting projects. Don't act on your desire to take that peptide and fuse it into some elaborate molecule you designed and toss that into an elaborate assay and prove that you can cure AIDS! Slow down. Is the data really saying what you think it is. Think critically and proceed logically.
There are many other peptides that have been discovered that are mere contaminants. The claims that their finders have made on their behalf are quite fancy. Big science words were used and put together in a way that is certainly feasible. No work was done however. Just words used to describe a set of letters that represent amino acids. What is really going on can open doors. What is really going on can make the planes land! But they fade away, these research projects. No resolution. No work was done. No planes landed.
Wednesday, June 28, 2006
Ben Franklin
I watched an old documentary on Ben Franklin last night. As a young man he owned and operated print shops and newspapers and made a lot of money at it. He was editor, writer, and printer. Currently, newspaper editors go to meetings and review union dispute contracts and so on. The point is that people did not have as much information to deal with back then. Ben Franklin could do all of the above jobs because each one was managable. As populations grow and industries grow more details get spread out to the point that no one really knows the whole story.
After Franklin turned 42 he decided to quit running his businesses and focus his time on science. This was during a time when most scientists were men of liesure. They were amatuers who were amusing themselves by observing nature and trying to discover something no one had yet discovered. Franklins field was electricity. Like other amatuer scientists he had to make much of his own equipment. He relied upon his understanding of electricity to create electrodes and electron generators. He ended up getting famous from harnessing this energy and telling about it in a manner far different than the way scientists talk today. He gave us the lightning rod which is still in use today, unchanged from Franklins time.
Scientists today are paid to do science. Most of the profit generated from science comes from selling scientists equipment and kits. I have sat in meetings where a scientist will describe how he developed an assay. Step one, purchase assay. Step two, change a few buffers. Step three, use charts and graphs to describe the postive effects of the changes. Controls optional.
In Ben Franklins time it appeared that the scientists were the ones in the lab observing and doing experiements. They did not have to keep notebooks if they didn't want to. They occasionally caused themselves harm such as when Ben shocked himself unconcious accidentally while revving up enough volts to try and kill a turkey. Some scientists were extremely diligent when it came to measurements. Some were more qualitative when studying completely unknown phenomena. They all worked because so much was unknown and knowledge was ripe for the picking. Who wouldn't want to wake up, dream up ways of testing ideas and watch the results happen first hand? For this Ben Franklin gave up running his business and spent ten years pursuing. The end results were very successful and rewarding.
Back to biotechnology, the cargo cult science industry. You've got 100 billion dollars and PhDs from the finest universities. You've also got the research from the universities flowing out with zero resistance from the schools. There is money and there are the nations best educated people working every day to contribute to scientific progress. Where are the results?
In this Benjamin Franklin documentary there were dramatizations of Ben and his comrades standing around the lab watching experiments from start to finish. There was a parlor game that they performed where everyone would hold hands in a circle. At one end of the circle someone held the cathode. At the other, someone would touch the anode and everyone in the circle would get a cute little shock all at the same time. Watching everyone jump at the same time, some hair sticking up, was of great entertainment value in those days. People wanted to see the results first hand.
These days we have computers. We have computer software that sets up graphs, runs statistical analysis and so on. Meetings are always held in board rooms. Never, even in small companies, do PhD scientists hold meetings in laboratories where the work is done. No one goes to the laboratory bench to watch any part of an experiment. In the board room, computer screen up on the wall thanks to the latest technology from Microsoft, graphs are shown, one after the other. They are meant to explain the binding powers of antibodies or the knock-down effect of siRNA. They show the "score" of an arthritic set of mice, with and without the next big anti-arthritus drug.
In my previous job there were several boxes of dead mice sitting in jars of formaldehyde, waiting to be "scored" for their degrees of arthritus. The problem was that you didn't need to be a great scientist to tell that nothing had happened. The work would have taking weeks and very little would have came of it. Worst of all you would have the charts and graphs to prove it, blasted up on that board room wall where the scientists would look on with disapproval of these uninteresting results. They didn't want to watch the mice get the injections. They didn't want to monitor the disease progression. They didn't want to help score the mice. They wanted the results, up on the board with bar graphs. Arthritus was measured by the height of a bar on a graph sitting next to another bar that represents the drug affect. A smaller bar meant less arthritus.
They never did get the siRNA cure for arthritus. As in most science project they slowly let it fade away, hoping that no one noticed. As a corporation they do not have to tell the scientific community anything about their work. Failure is described to non-scientific investors and par for the course. Got to keep the pipeline diversitified, just like a stock portfolia. Some things just don't work. You understand. And slowly billions and billions of dollars disappear. It's not an easy living, but it beats getting in that lab and testing your ideas in front of others. That type of work requires real scientists who want to see what is happening. Like Ben.
After Franklin turned 42 he decided to quit running his businesses and focus his time on science. This was during a time when most scientists were men of liesure. They were amatuers who were amusing themselves by observing nature and trying to discover something no one had yet discovered. Franklins field was electricity. Like other amatuer scientists he had to make much of his own equipment. He relied upon his understanding of electricity to create electrodes and electron generators. He ended up getting famous from harnessing this energy and telling about it in a manner far different than the way scientists talk today. He gave us the lightning rod which is still in use today, unchanged from Franklins time.
Scientists today are paid to do science. Most of the profit generated from science comes from selling scientists equipment and kits. I have sat in meetings where a scientist will describe how he developed an assay. Step one, purchase assay. Step two, change a few buffers. Step three, use charts and graphs to describe the postive effects of the changes. Controls optional.
In Ben Franklins time it appeared that the scientists were the ones in the lab observing and doing experiements. They did not have to keep notebooks if they didn't want to. They occasionally caused themselves harm such as when Ben shocked himself unconcious accidentally while revving up enough volts to try and kill a turkey. Some scientists were extremely diligent when it came to measurements. Some were more qualitative when studying completely unknown phenomena. They all worked because so much was unknown and knowledge was ripe for the picking. Who wouldn't want to wake up, dream up ways of testing ideas and watch the results happen first hand? For this Ben Franklin gave up running his business and spent ten years pursuing. The end results were very successful and rewarding.
Back to biotechnology, the cargo cult science industry. You've got 100 billion dollars and PhDs from the finest universities. You've also got the research from the universities flowing out with zero resistance from the schools. There is money and there are the nations best educated people working every day to contribute to scientific progress. Where are the results?
In this Benjamin Franklin documentary there were dramatizations of Ben and his comrades standing around the lab watching experiments from start to finish. There was a parlor game that they performed where everyone would hold hands in a circle. At one end of the circle someone held the cathode. At the other, someone would touch the anode and everyone in the circle would get a cute little shock all at the same time. Watching everyone jump at the same time, some hair sticking up, was of great entertainment value in those days. People wanted to see the results first hand.
These days we have computers. We have computer software that sets up graphs, runs statistical analysis and so on. Meetings are always held in board rooms. Never, even in small companies, do PhD scientists hold meetings in laboratories where the work is done. No one goes to the laboratory bench to watch any part of an experiment. In the board room, computer screen up on the wall thanks to the latest technology from Microsoft, graphs are shown, one after the other. They are meant to explain the binding powers of antibodies or the knock-down effect of siRNA. They show the "score" of an arthritic set of mice, with and without the next big anti-arthritus drug.
In my previous job there were several boxes of dead mice sitting in jars of formaldehyde, waiting to be "scored" for their degrees of arthritus. The problem was that you didn't need to be a great scientist to tell that nothing had happened. The work would have taking weeks and very little would have came of it. Worst of all you would have the charts and graphs to prove it, blasted up on that board room wall where the scientists would look on with disapproval of these uninteresting results. They didn't want to watch the mice get the injections. They didn't want to monitor the disease progression. They didn't want to help score the mice. They wanted the results, up on the board with bar graphs. Arthritus was measured by the height of a bar on a graph sitting next to another bar that represents the drug affect. A smaller bar meant less arthritus.
They never did get the siRNA cure for arthritus. As in most science project they slowly let it fade away, hoping that no one noticed. As a corporation they do not have to tell the scientific community anything about their work. Failure is described to non-scientific investors and par for the course. Got to keep the pipeline diversitified, just like a stock portfolia. Some things just don't work. You understand. And slowly billions and billions of dollars disappear. It's not an easy living, but it beats getting in that lab and testing your ideas in front of others. That type of work requires real scientists who want to see what is happening. Like Ben.
Thursday, June 22, 2006
Education
A story in the paper yesterday asked the question, is a college education still a good investment? On one hand, a college education is an experience that young people can have. You live on your own, with thousands of other kids. You go to classes and learn about things that you will be asked about on a test. On the other hand it's a very expensive four years of your life. You will have little time to earn money. At the same time the spending of money will be accelerated. You are hoping that later in life your earning potential will be accelerated. If your parents can help you are ahead of the game. If you are putting yourself through college this is a major risk of an investment. What guarentees are there that you will have a good job some day?
People like to bring up the fact that Bill Gates never finished college and now he's the riches guy in the world. The link to education and money however is pretty solid. One of the main reasons is that all higher paying jobs require a degree just to get your foot in the door. If you're like some people you have contacts through family members are other associations who can give you that little extra something that gets you the job. If not you are forced to pay your dues. Get the education and then get the rest of the package that will land you your high paying job. Bill Gates had the rest of the package to begin with.
What is the rest of the package? I have a degree in Biochemistry. During the course of my education I used a Mass Spectrometry machine to analyze the compounds that I produced in organic chemistry lab. When a potential employer wants someone with these skills however, I cannot use my education. They are looking for hands on experience. What they are saying is that my education was superficial. They want something real because you won't be taking tests on Mass Spec on the job. You will be using the machine for what is was intended. Education is thus a mere introduction to the world you might be working in. As time marches on during this rapid advancement in technology, is education keeping pace with it's Bachelors, Masters, and Doctorol programs?
Vocational schools teach people how to perform such jobs as mechanic, plumber and so on. Plumbing has remained the same for a long time. Cars have become a little more advanced. In most new cars you have to take your car back to the dealer where specialized mechanics can run computer diagnostics. They have specialized tools fit to particular models. I'm no expert but I am guessing that individuals with basic mechanic degrees from vocational schools have additional training required if they are to work in a dealers garage.
Feynman talked about educators assuming that what they were teaching was actually learned. In math you can teach a student that 2 plus 2 equals 4. In the real world, does the student understand that 2 apples and 2 oranges equal 4 pieces of fruit and not 4 apples? I see hiring managers these days requiring education and experience.
For example, take this description for a researcher position:
People like to bring up the fact that Bill Gates never finished college and now he's the riches guy in the world. The link to education and money however is pretty solid. One of the main reasons is that all higher paying jobs require a degree just to get your foot in the door. If you're like some people you have contacts through family members are other associations who can give you that little extra something that gets you the job. If not you are forced to pay your dues. Get the education and then get the rest of the package that will land you your high paying job. Bill Gates had the rest of the package to begin with.
What is the rest of the package? I have a degree in Biochemistry. During the course of my education I used a Mass Spectrometry machine to analyze the compounds that I produced in organic chemistry lab. When a potential employer wants someone with these skills however, I cannot use my education. They are looking for hands on experience. What they are saying is that my education was superficial. They want something real because you won't be taking tests on Mass Spec on the job. You will be using the machine for what is was intended. Education is thus a mere introduction to the world you might be working in. As time marches on during this rapid advancement in technology, is education keeping pace with it's Bachelors, Masters, and Doctorol programs?
Vocational schools teach people how to perform such jobs as mechanic, plumber and so on. Plumbing has remained the same for a long time. Cars have become a little more advanced. In most new cars you have to take your car back to the dealer where specialized mechanics can run computer diagnostics. They have specialized tools fit to particular models. I'm no expert but I am guessing that individuals with basic mechanic degrees from vocational schools have additional training required if they are to work in a dealers garage.
Feynman talked about educators assuming that what they were teaching was actually learned. In math you can teach a student that 2 plus 2 equals 4. In the real world, does the student understand that 2 apples and 2 oranges equal 4 pieces of fruit and not 4 apples? I see hiring managers these days requiring education and experience.
For example, take this description for a researcher position:
Bachelor’s degree in a scientific discipline.
Minimum 2 years laboratory experience in molecular and/or cell biology.
Demonstrated working knowledge of scientific principles and standard laboratory practices.
Familiarity with Virology and/or Immunology.
Knowledge and experience in the correct handling of hazardous and radioactive substances.
Does familiarity with virology and/or immunology mean that these two fields are almost the same? Does the scientific degree mean that you can have a degree in physics? There is more to this job description:
Perform general molecular biology techniques, including PCR, cDNA cloning, RT PCR, RNAi, expression cloning, and cDNA mutagenesis.
Perform cell culture and FACs analysis.
Assist in sample preparation for Mass Spec. analysis.
Assist in design and development of in vitro assays.
That's a lot of stuff to know in two years. All of these skills are taught in 4 year degrees but not in a four year physics degree. There are no degrees that train hiring managers to write up job descriptions. Human resource people are generally considered to be the experts here but this is not a science. It is an attempt to hire the right person for a a job. You could just say you are looking for someone with a degree in Biochemistry who can do some molecular biology work. RNAi? The field is too new to have any meaning. FACs? Just a machine that is complicated but not beyond the learning curve for a college grad. Development of assays? It's more of an art that people know or do not. I don't think it can be taught. Kits can be sold but developing an assay is real science. If we had an assay for cancer for example we would understand cancer much better.
The real issue of education and employment is the same as a Cargo Cult ceremony and airplanes landing. If you are in charge of hiring, do you know the difference between a typist and a secretary? If you are seeking employment do you know that having the skills and education is what you need to get an interview? Doing well at the interview gets you the job. The additional skills are what make the airplanes land. Many human endeavors fail because someone started with a lack of knowledge or finished with a lack of knowledge. True knowledge is what education should lead to. A college degree is a weak substitution for evidence of true knowledge.
Monday, June 12, 2006
Assays and Reality
When you work in a laboratory in the biomedical world you have to learn a few assays. An assay is a qualitative or quantitative analysis of a substance to determine its components. You put on your white lab coat, grab your pipettes and go do an assay. Are you doing science?
The cargo cult theory says that people will follow the form what they see others do in hopes of acheiving the same results. Scientists run assays so if you want to be a successful scientist someone had better get in that lab and run some assays. Let's say you are an office scientist and you do research on HIV. You will have to hire someone to work in the lab who knows how to test for the HIV virus. There will be an HIV assay. The fastest assay involves testing for antibodies against HIV. This is often the case for assays. You don't test for the component directly but for things associated with the component. The further you get away from the lab however, the less you know about the details of the assay.
The office scientist usually knows about the assay. An ELISA assay involves using an antibody against a protein. The antibody has an enzyme physically linked to it. The enzyme is tested for by adding a substrate that will create a color when cleaved by the enzyme. Remember you are really interested in the protein that is bound by the antibody that is linked to the enzyme that causes the substrate to make the color. How do you assess the significance of the simple development of a color?
The ELISA assay was developed long ago. Someone else did the work to determine that this assay could be used as an assay. Those who come along and choose to use it must determine of the things they are testing for can be used in a similar manner. Here is the cargo cult moment. An office scientist could instruct the young lab worker to run an ELISA assay to determine of protein X is present in some sample. The young lab worker buys a kit, runs the assay and looks for the presence of a color. This is similar to setting up an airport and looking to the skies for airplanes.
You have a sample that you suspect contains your protein. You want to know if it is there and how much of it is there. If you accidentally use too much antibody you will get a strong color. If you use too little you will get a weak color where a strong color should have been observed. You must have controls. If you want to know how much you must have a standard curve. The standard curve must involve y = mx + b and linear regression if it is to be understood quantitatively. Your standard curve must be prepared in the same medium as your sample. Your color must be read at the proper wavelenght. All samples must be stopped at the same time with the acid. If you were to seriously teach about the ELISA there would be more time spent on these issues than on any discussion involving antibodies and substrates. Light absorbance readings for example, have limitations. There is a linear range for reading the absorbance of a color in the machines used in the lab. That means there are limitations that must be known and accounted for. The standard curve is also a test of the limitations.
I bring all of this up because of the limitations of measurements in any science. The machine that measures the abosorbance of a colored solution has limitations. The ELISA assay has an upper and lower limit of detection no matter what you are measuring. That means there is a range where useful and accurate information can be obtained. Do you know what your range is?
Beyond ELISAs there are many assays used in basic biomedical research. They all have limitations that are woven together in a way that can cause great confusion. Even if you have 100% pure samples you will have a margin of error in your assay measurements. Imagine then trying to measure the amount of a protein in a blood sample or in kidney cells. Can you find an internal standard in blood? Are proteins sometimes upregulated and downregulated in times and concentrations that are out of our range to measure? I say hell yes they are yet we constantly read about people claiming to have accurately made the measurements nonetheless. Their measurements conveniently support their assumptions underlying the purpose of the research.
I once worked with RAW cells which are precursors to Osteoclasts. If you add RANK ligand to a RAW cell culture they will fuse together and form large multinucleated osteoclasts in about five days. I observed this process many times. I tested for the presence of tartrate resistant alkaline phosphatase (TRAP) every day. I could see TRAP on the surface of the Raw cells just after adding the RANK ligand. As the cells began to fuse I could see the TRAP on one side of the new ball of cells. By the fourth day the TRAP was nearly gone and the osteoclasts were predominant. These were simple observations. If I wanted to know more about TRAP and it's role in osteoclastogenisis I would have to get more clever than cell staining and microscopic observation. That's when I leave the cargo cult world and figure out what to do. I still have the lab coat and the microscope but I have to do something scientific. I have to know my limitations. I have to think about the location of the TRAP and how the cells pH or polarity might be affecting that location. How might the cells pH or polarity affect my measurements? In the end I would not propose any reasons for the TRAP regulation. I would merely describe what I think is going on. That's all. Next I would follow a lead that came up during the TRAP research. The goal would not be to cure osteoporosis. It's simply to observe nature.
It's like a reality show that only a few can watch. Do you get that channel? If so do you turn it on? If so is the picture fuzzy or clear? If it's clear do you have the ability to tell others about it? If so are you telling the right peope about it?
The cargo cult theory says that people will follow the form what they see others do in hopes of acheiving the same results. Scientists run assays so if you want to be a successful scientist someone had better get in that lab and run some assays. Let's say you are an office scientist and you do research on HIV. You will have to hire someone to work in the lab who knows how to test for the HIV virus. There will be an HIV assay. The fastest assay involves testing for antibodies against HIV. This is often the case for assays. You don't test for the component directly but for things associated with the component. The further you get away from the lab however, the less you know about the details of the assay.
The office scientist usually knows about the assay. An ELISA assay involves using an antibody against a protein. The antibody has an enzyme physically linked to it. The enzyme is tested for by adding a substrate that will create a color when cleaved by the enzyme. Remember you are really interested in the protein that is bound by the antibody that is linked to the enzyme that causes the substrate to make the color. How do you assess the significance of the simple development of a color?
The ELISA assay was developed long ago. Someone else did the work to determine that this assay could be used as an assay. Those who come along and choose to use it must determine of the things they are testing for can be used in a similar manner. Here is the cargo cult moment. An office scientist could instruct the young lab worker to run an ELISA assay to determine of protein X is present in some sample. The young lab worker buys a kit, runs the assay and looks for the presence of a color. This is similar to setting up an airport and looking to the skies for airplanes.
You have a sample that you suspect contains your protein. You want to know if it is there and how much of it is there. If you accidentally use too much antibody you will get a strong color. If you use too little you will get a weak color where a strong color should have been observed. You must have controls. If you want to know how much you must have a standard curve. The standard curve must involve y = mx + b and linear regression if it is to be understood quantitatively. Your standard curve must be prepared in the same medium as your sample. Your color must be read at the proper wavelenght. All samples must be stopped at the same time with the acid. If you were to seriously teach about the ELISA there would be more time spent on these issues than on any discussion involving antibodies and substrates. Light absorbance readings for example, have limitations. There is a linear range for reading the absorbance of a color in the machines used in the lab. That means there are limitations that must be known and accounted for. The standard curve is also a test of the limitations.
I bring all of this up because of the limitations of measurements in any science. The machine that measures the abosorbance of a colored solution has limitations. The ELISA assay has an upper and lower limit of detection no matter what you are measuring. That means there is a range where useful and accurate information can be obtained. Do you know what your range is?
Beyond ELISAs there are many assays used in basic biomedical research. They all have limitations that are woven together in a way that can cause great confusion. Even if you have 100% pure samples you will have a margin of error in your assay measurements. Imagine then trying to measure the amount of a protein in a blood sample or in kidney cells. Can you find an internal standard in blood? Are proteins sometimes upregulated and downregulated in times and concentrations that are out of our range to measure? I say hell yes they are yet we constantly read about people claiming to have accurately made the measurements nonetheless. Their measurements conveniently support their assumptions underlying the purpose of the research.
I once worked with RAW cells which are precursors to Osteoclasts. If you add RANK ligand to a RAW cell culture they will fuse together and form large multinucleated osteoclasts in about five days. I observed this process many times. I tested for the presence of tartrate resistant alkaline phosphatase (TRAP) every day. I could see TRAP on the surface of the Raw cells just after adding the RANK ligand. As the cells began to fuse I could see the TRAP on one side of the new ball of cells. By the fourth day the TRAP was nearly gone and the osteoclasts were predominant. These were simple observations. If I wanted to know more about TRAP and it's role in osteoclastogenisis I would have to get more clever than cell staining and microscopic observation. That's when I leave the cargo cult world and figure out what to do. I still have the lab coat and the microscope but I have to do something scientific. I have to know my limitations. I have to think about the location of the TRAP and how the cells pH or polarity might be affecting that location. How might the cells pH or polarity affect my measurements? In the end I would not propose any reasons for the TRAP regulation. I would merely describe what I think is going on. That's all. Next I would follow a lead that came up during the TRAP research. The goal would not be to cure osteoporosis. It's simply to observe nature.
It's like a reality show that only a few can watch. Do you get that channel? If so do you turn it on? If so is the picture fuzzy or clear? If it's clear do you have the ability to tell others about it? If so are you telling the right peope about it?
Friday, June 09, 2006
siRNA Pathology
The Cargo Cult Airport has leaders. They send the people out with coconuts over their ears. They make sure the fires are lit along the side of the runway. If it's anything like the American corporate style of leadership, it is assumed that the leaders know more about why these things are done. The followers just follow. Leaders instruct because they are "in the know".
siRNA has been in existance a relatively short period of time. As soon as it began however, scientist began positioning themselves into the leadership role. There were rules set up for how to design siRNA. There were papers written on the best way to get the most out of your siRNA knock-out. Like a Cargo Cult Airport however, it wasn't known how siRNA really worked. The experts seemed have a disdain for research that involved a mechanism of action. One of "the rules" for example was that the siRNA had to consist of a certain percentage gaunisine and cytosine. What was the data used to come to that conclusion? Five siRNA KOs? Ten? Were they in mice or hamsters?
Eventually the scientists have to come up with a MOA, mechanism of action. It has been decided that the mechanism of action involves mRNA interacting with an enzyme called Dicer. One of the leading siRNA researchers, Dr. Kazunari Taira of the University of Tokyo describes it this way:
The mechanism responsible for dsRNA-induced gene silencing, which proceeds via a two-step mechanism, appears to have been strongly conserved during evolution. In the first step, long dsRNAs are recognized by a nuclease in the RNase III family known as Dicer, which cleaves the dsRNA into small interfering RNAs (siRNAs) of 21–23 nt. These siRNAs are incorporated into a multicomponent nuclease complex, known as RISC, that is then responsible for the destruction of cognate mRNAs.
Dr. Taira was a leader in siRNA research. More specifically he was ranked number 4 (most cited authors) out of the 25,000 researchers who have published papers on siRNA. He took on the toughest piece of the puzzle, the MOA and he got burned. A panel at the university where he worked said that he "likely fabricated papers on a potential medical breakthrough". As I've stated before, big time scientists do not work in laboratories. They work in offices. They communicate on the things that take place in labs but they rarely go inside their labs. One of the people who did work in the lab was Hiroaki Kawasaki. Dr. Kawasaki was most likely fabricating the data and Dr. Taira either couldn't figure that out or he was complicit in this scam.
The question now is how much this impacts the origins of the science. Does this leave a gap open where Dicers role is not known as a fact. Dr. Taira was saying that he could use recombinant Dicer to make siRNA that will work so that you don't have to experiment with different pieces to find the best one. This is one of his pre-conceived conclusions anyway. However, has anyone ever cloned dicer and shown it to chop up dsRNA? What type of dsRNA modifications are needed for Dicer to grab ahold of it and chop it up. Certainly Dicer isn't running amok inside a cell grabbing any dsRNA it finds and chopping it up. If it did we'd have a hard time making proteins. What regulates the balance between dsRNA breakdown and mRNA protein production? There are many enzymes that are very well understood. We use them for chopping up DNA for cloning genes. We know exactly where they cut the DNA. Where does Dicer cut the DNA? Is it based on size? If it is, then how does the siRNA shut down the genes so specifically. We know that synthisized RNA is a hit or miss gamble. Somehow one enzyme gets it right in many many different genes. How can this be.
This is science. How does siRNA work. What are the unanswered questions? What tiny little piece of the puzzle can we study? Dr. Taira is rightfully getting his work put under a spotlight. What about putting a spotlight on the research area he was working on. Why did they have to lie? Certainly it's important for these guys to publish but why didn't the area they were working on give them the kind of results they wanted? This is the Feynman Cargo Cult edict of bending over backwards to prove oneself wrong. They inadvertantly proved that they could not do what they thought they could do. They were ranked #4 in the siRNA business. In the end their theory did not provide them with the knowledge it would take to simply clone an enzyme and characterize it. Something is wrong here.
siRNA has been in existance a relatively short period of time. As soon as it began however, scientist began positioning themselves into the leadership role. There were rules set up for how to design siRNA. There were papers written on the best way to get the most out of your siRNA knock-out. Like a Cargo Cult Airport however, it wasn't known how siRNA really worked. The experts seemed have a disdain for research that involved a mechanism of action. One of "the rules" for example was that the siRNA had to consist of a certain percentage gaunisine and cytosine. What was the data used to come to that conclusion? Five siRNA KOs? Ten? Were they in mice or hamsters?
Eventually the scientists have to come up with a MOA, mechanism of action. It has been decided that the mechanism of action involves mRNA interacting with an enzyme called Dicer. One of the leading siRNA researchers, Dr. Kazunari Taira of the University of Tokyo describes it this way:
The mechanism responsible for dsRNA-induced gene silencing, which proceeds via a two-step mechanism, appears to have been strongly conserved during evolution. In the first step, long dsRNAs are recognized by a nuclease in the RNase III family known as Dicer, which cleaves the dsRNA into small interfering RNAs (siRNAs) of 21–23 nt. These siRNAs are incorporated into a multicomponent nuclease complex, known as RISC, that is then responsible for the destruction of cognate mRNAs.
Dr. Taira was a leader in siRNA research. More specifically he was ranked number 4 (most cited authors) out of the 25,000 researchers who have published papers on siRNA. He took on the toughest piece of the puzzle, the MOA and he got burned. A panel at the university where he worked said that he "likely fabricated papers on a potential medical breakthrough". As I've stated before, big time scientists do not work in laboratories. They work in offices. They communicate on the things that take place in labs but they rarely go inside their labs. One of the people who did work in the lab was Hiroaki Kawasaki. Dr. Kawasaki was most likely fabricating the data and Dr. Taira either couldn't figure that out or he was complicit in this scam.
The question now is how much this impacts the origins of the science. Does this leave a gap open where Dicers role is not known as a fact. Dr. Taira was saying that he could use recombinant Dicer to make siRNA that will work so that you don't have to experiment with different pieces to find the best one. This is one of his pre-conceived conclusions anyway. However, has anyone ever cloned dicer and shown it to chop up dsRNA? What type of dsRNA modifications are needed for Dicer to grab ahold of it and chop it up. Certainly Dicer isn't running amok inside a cell grabbing any dsRNA it finds and chopping it up. If it did we'd have a hard time making proteins. What regulates the balance between dsRNA breakdown and mRNA protein production? There are many enzymes that are very well understood. We use them for chopping up DNA for cloning genes. We know exactly where they cut the DNA. Where does Dicer cut the DNA? Is it based on size? If it is, then how does the siRNA shut down the genes so specifically. We know that synthisized RNA is a hit or miss gamble. Somehow one enzyme gets it right in many many different genes. How can this be.
This is science. How does siRNA work. What are the unanswered questions? What tiny little piece of the puzzle can we study? Dr. Taira is rightfully getting his work put under a spotlight. What about putting a spotlight on the research area he was working on. Why did they have to lie? Certainly it's important for these guys to publish but why didn't the area they were working on give them the kind of results they wanted? This is the Feynman Cargo Cult edict of bending over backwards to prove oneself wrong. They inadvertantly proved that they could not do what they thought they could do. They were ranked #4 in the siRNA business. In the end their theory did not provide them with the knowledge it would take to simply clone an enzyme and characterize it. Something is wrong here.
Sunday, June 04, 2006
Poetry
Charles Bukowski worked for the Post Office. He would do his job and come home and drink wine and write poetry. He didn't care much for his day job but he loved staying up late drinking alone, listening to classical music on the radio and typing out poems. His canvas was a white sheet of paper shoved into an old type writer. The demons running around inside his head provided excellent material for his work. He was mad and said so. He wasn't trying to hide it. He was trying to tell someone about it in case someone wanted to help.
Those of us who love Bukowskis work refer to the man as Hank. Hank was a grizzly bear of a man. He loved to drink. He loved women. He hated working. Down at the post office you had to do what you're told. You had to take tests putting letters into slots based on the addresses on the envelopes. There were bad bosses and co-workers to deal with. One day Hanks publisher told him to quit the post office job. They worked out the amount of money needed to support Hanks lifestyle and it was provided by the publisher. It amounted to something like 105 dollars a month for rent, food, booze and cigarettes. At the age of 50 he quit his job and became a professional writer. Within the month he had written his first novel. He wrote several more novels and hundreds of poems. The novels served as background material that helped the reader understand where some of those poems were coming from. At the end of his life there was a body of work that came together and told a story.
I'd like to fashion this blog after people like Bukowski. I'd like to bring up the beatniks. In college they teach science and they teach art. So far it's been the arts that have allowed outsiders to make an impact on society. Bukowski was a postal worker. Kerouac was a vagabond. One thing the best of them all shared was a lack of formal education. They wanted to write so they did. A scientist however will have a hard time in the modern realm of the business. Many physical scientists for example, have a hard time renting the time on an atom smasher to prove their theories. It costs money. Writing a book does not. So what I'm trying to do with this blog is create a place where beatnik thinkers can contemplate the possibilities of the natural world. That's not science of the latest fashion. It's science that applied to people who existed in medieval times. Lacking the ability to smash atoms or look at cells left people with no other options than to dream up possibilities. Imagination was king. As I've mentioned before, marketing is now king in science.
Step away from the kings of science and sketch out a possibility that you've been thinking about for awhile. Go to the local pub and sit at a table by yourself and write a long paper that you won't have to worry about getting published. Invent a start-up company in your head and don't worry about the investors. The business of science is run by people who are the best at getting promoted. The best scientists are probably sitting at lab benches all day wondering about the data they get and how it really happens. They don't believe much of the hype coming out of the labs they work in but they are keenly interested in the experiements. The big time scientists have a story they need to tell and they are only excepting data that helps tell that story. The small time scientists are like poets. They wonder about the world they live in. They just don't know how to get anywhere with their ideas so they hold them in. To the poets of science I say, let it out. Write it down. Start a blog. Start a journal. Seek out other disgruntled workers and use your anger to strike at the status quo. Do something to them that they never did for you. Make them think. Make sure that at the end of your life there is a body of work that people can use.
Those of us who love Bukowskis work refer to the man as Hank. Hank was a grizzly bear of a man. He loved to drink. He loved women. He hated working. Down at the post office you had to do what you're told. You had to take tests putting letters into slots based on the addresses on the envelopes. There were bad bosses and co-workers to deal with. One day Hanks publisher told him to quit the post office job. They worked out the amount of money needed to support Hanks lifestyle and it was provided by the publisher. It amounted to something like 105 dollars a month for rent, food, booze and cigarettes. At the age of 50 he quit his job and became a professional writer. Within the month he had written his first novel. He wrote several more novels and hundreds of poems. The novels served as background material that helped the reader understand where some of those poems were coming from. At the end of his life there was a body of work that came together and told a story.
I'd like to fashion this blog after people like Bukowski. I'd like to bring up the beatniks. In college they teach science and they teach art. So far it's been the arts that have allowed outsiders to make an impact on society. Bukowski was a postal worker. Kerouac was a vagabond. One thing the best of them all shared was a lack of formal education. They wanted to write so they did. A scientist however will have a hard time in the modern realm of the business. Many physical scientists for example, have a hard time renting the time on an atom smasher to prove their theories. It costs money. Writing a book does not. So what I'm trying to do with this blog is create a place where beatnik thinkers can contemplate the possibilities of the natural world. That's not science of the latest fashion. It's science that applied to people who existed in medieval times. Lacking the ability to smash atoms or look at cells left people with no other options than to dream up possibilities. Imagination was king. As I've mentioned before, marketing is now king in science.
Step away from the kings of science and sketch out a possibility that you've been thinking about for awhile. Go to the local pub and sit at a table by yourself and write a long paper that you won't have to worry about getting published. Invent a start-up company in your head and don't worry about the investors. The business of science is run by people who are the best at getting promoted. The best scientists are probably sitting at lab benches all day wondering about the data they get and how it really happens. They don't believe much of the hype coming out of the labs they work in but they are keenly interested in the experiements. The big time scientists have a story they need to tell and they are only excepting data that helps tell that story. The small time scientists are like poets. They wonder about the world they live in. They just don't know how to get anywhere with their ideas so they hold them in. To the poets of science I say, let it out. Write it down. Start a blog. Start a journal. Seek out other disgruntled workers and use your anger to strike at the status quo. Do something to them that they never did for you. Make them think. Make sure that at the end of your life there is a body of work that people can use.
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