Cargo Cults Red Flag

Ever wonder how so many drugs fail their big trials? It begins with the scientific foundation that goes into the development of a drug. This "foundation" is the softest and most manipulated area of corporate science. Generally you will find higher paid PhD scientists who work in cubicles bullying low paid white lab coat wearing individuals around. When you move a drug further along you run into tougher customers. Human trials for example can be hard to work around. No one wants to flat out fabricate the data. There are tricks to work around less than stellar data. If that fails you make up an excuse such as a placebo response being unexpected. But how honest people with no stake in the outcome of a drug company predict what will fail and what might just make it?

I am going to predict a failure. The company name is Medivation, Inc. and they have a drug to treat Alzheimer's disease. The first red flag is of course a Biotech company pursueing Alzheimers disease. You have a patient population that has just lost their mind. The only way to tell if your drug is helping them is to invent some endpoints that you think are important. You certainly won't be able to ask the patient if they're feeling better. Medivation today is announcing that they have successfully demonstrated efficacy in not one but all five efficacy endpoints they went after. What are the endpoints?

The primary endpoint was the Alzheimer's Disease Assessment Scale-cognition (ADAS) The key secondary efficacy endpoint, the Clinical Global Impression of Change (CGIC). Dimebon-treated patients also achieved statistically significant improvement (p less than 0.01) compared with placebo patients on all three of the other secondary efficacy endpoints - the Activities of Daily Living, the Neuropsychiatric Inventory and the Mini Mental State Examination.

It's curious that they did so well. Were they really double blinded? Has no one else come this close? Is there a positive control to compare this drug to? There certainly has been no shortage of corporate R&D projects on the disease. Have we finally seen something to throw millions of dollars at or do we throw that kind of money around with little provocation?

If you're going to lie you should throw in some failure. It looks better that way. Now I'm not saying that Medivation is lying. They do however employ some unusual measurements which have worked out in their favor. The measurements were taken in support of a Phase 2 clinical study of 183 patients with mild to moderate Alzheimer's disease conducted at 11 sites in Russia. Russia?

A Dr. Hung explains that, ""The Phase 2 data that we are announcing today are an important step in validating Medivation's business model. We secured our first equity financing less than two years ago, and to date have used less than $20 million in funding our operations. With that investment of time and cash, we have not only generated positive results in a large Phase 2 Alzheimer's disease trial, but also initiated new development programs in Huntington's disease and hormone-refractory prostate cancer, both of which are scheduled to enter the clinic in the next three quarters. We also remain committed to finding new technologies to reach our targeted portfolio of four to six programs."

It's not so much that they've developed an effective treatment for Alzheimers, but that they have validated a business model. They most assuredly saved money by using Russian doctors and their patients in their clinical trials. Could this indicate a cheapness in the research? Again, were these truly double blind tests? Based on my biases against Russians and Biotechnology I'm going to say that this is all bullshit. It's a non-scientific hunch but I think I spot a Cargo Cult. Not only are they successfully treating Alzheimers but they are also taking on Huntingtons and prostrate cancer. That's too much science for the money. Cargo Cult!

Failed Airports

From Biospace:

Sept. 20 /PRNewswire-FirstCall/ - NUCRYST Pharmaceuticals Corp. (NASDAQ: NCST - TSX: NCS) today announced preliminary top line results from the company's Phase 2 clinical trial examining the safety and efficacy of drug candidate, NPI 32101 in a topical cream formulation, in children and adolescents with atopic dermatitis. NPI 32101 is NUCRYST's patented active pharmaceutical ingredient.

Treatment success was defined as "total clearance" or "almost total clearance" of disease signs. An intent-to-treat analysis with 387 patients demonstrated no significant difference in disease clearance among the three treatment groups.

Analysis of the data demonstrated that 35.8% of patients receiving 2% NPI 32101 cream, 35.1% of patients receiving 1% NPI 32101 cream and 34.6% of patients receiving placebo cream achieved success in almost clearing or totally clearing their disease after 12 weeks of treatment. The success rates of both 2% and 1% NPI 32101 creams were statistically identical to that of the placebo. Although the study did not meet its primary efficacy endpoint, the higher than expected placebo response rate may have made it difficult to discern efficacy of NPI 32101. A more detailed analysis of the study is underway.

"NUCRYST is continuing to analyze data from this study so that we can evaluate options for our atopic dermatitis program with a complete understanding of the study results," said Scott H. Gillis, President & CEO, NUCRYST Pharmaceuticals. "Based on our preclinical results in a variety of in vitro and in vivo models and the consistently favorable safety data generated in all clinical studies, we believe that NPI 32101 has the potential to treat various inflammatory and infectious conditions. Therefore, we plan to continue our efforts to develop NPI 32101 for a variety of disease conditions."

This is science in the Pharmaceutical world. If at first you don't succeed try try again. Sheesh! Note the "higher than expected response rate" in the placebo group. Expectations trump actual data.

Bias

In order to keep yourself honest you should admit your biases. I, for example, am biased against the drug industry. I believe that once they decide to put a drug in their pipeline they are no longer intested in the scientific method. The only thing that will stop them from moving the drug toward the market is if the safety data spells trouble or if a larger firm collaborates with a smaller company and decides not to go ahead with the deal. In many cases the smaller company will continue to pursue the drug because they have already made a heavy investment and they are not ready to give up yet.

I have that bias. I'm not alone however. There are people out there who think negative thoughts about the drug industry. There are those at the laboratory level, clinical trial level, and drug sales level. You name an aspect of the industry and there are detractors who are biased against the practices that they have witnessed first hand. The question is whether or not these biases are blinding us from the good that drug companies do. Not everyone is bad.

Here is a list of people whom I admire for speaking out against the industry (or at least are trying to be heard).

Me: Shy and afraid of being heard and put in the spotlight. Lab scientist who thinks that survival of the fittest in the drug business goes to those who have no relationship with the scientific method.

Gary Taubes and John Crewdson: Science writers who cover contraversial science issues.

Stewart and Feder: Former NIH scientists who transformed their careers into scientific bullshit detectives

Kathleen Slattery-Moschkau: Former drug sales person who exposed the drug industrys sales practices via a fictional film and a documentary. In the fictional film a drug sales lady explains that she gets doctors to prescribe her companys medicine. She has a degree in science... political science.

John Abramson M.D.: Actual medical doctor who became so fed up with the way medicine was being corrupted by the drug industry he wrote a book called "Overdosed America".

James Randi: This is my hero. Former magician who saw psychics and other charlatans making a killing off of cheap tricks that any amateur magician could easily explain. He is a true scientist. Most PhD scientists couldn't hold a candle to his experimental designs.

The bloggers; Pharma Gossip, Michael Lascelles, Aubrey Blumsohn, Peter Rost: All dedicated to acknowledging the Cargo Cult science of large corporations.

Alright, I'll stop there. There are plenty who are of the same mind as me. But if science were a political system, we have to admit that we are but one party. There are very honest people who disagree about things. AIDS research has people on both sides of that debate who are apparently serious about their convictions. Who is right? The Cargo Cult Scientist would like to see HIV studied more as a virus and less as a world wide enemy. Even amongst members of the same party, differences of opinion will arise. Since science is practiced by human beings we must admit that our biases are a source of strength but also a source of folly. It is a tricky rope to walk but one we must walk. This is where we find allies and foes alike. This is where we identify ourselves with ideas that others had before they entered our minds. How could we be wrong when others have the same thoughts? Biases are undeniable.

Bias is not something that we want shoved in our faces when we are argueing a point however. If you oppose the way Halliburton is billing the tax payers for the war you want to make sure that people don't think you are just sore about Bush and the war. If you know a right winger with the same opinion towards Halliburton you will be sure to point out that two people with different biases towards the war can have the same opinion towards the issue of Halliburtons billing policies. We use the biases of others against them so why would we suspect that others won't hold ours against us. The thing to do is to admit it right from the start and to explain how they do not affect what we think is happening. Whether or not I believe in Stan Prusiners prion theories does not have any affect on a mad cows demise from TSE.

The modern day politician wants you to believe that his bias is protecting the American people from evil doers. The modern day scientist wants you to believe that his bias is getting to the truth. We here at the Cargo Cult Scientist believe that a persons main bias is themselves. Their career goals, their family and their security interests dictate what biases they will have. There is nothing wrong with that as long as you are aware of what your biases are. Remember, biases can help and they can hurt. Don't ignore them, at least not to yourself.

Help Wanted

A lot of laboratory jobs that are offered require you to perform things that haven't been succesfully performed on a regular basis within the business. They want the technician to do what the PhD population has yet to clearly define. For example:

The successful candidate will function as part of an interdisciplinary team to characterize and validate proteins and monoclonal antibodies for the XXXXX pipeline.

What does "characterize and validate" mean? It probably means that you will have to go into the laboratory and provide charts and graphs that demonstrate that a protein or antibody interacts with the molecules that they are suppose to and that it results in certain endpoints. So what the company is asking you to do is to come in and close the deal. They've come up with some proteins that they have managed to build a company around or at least an R&D program. You'd think they would have characterized and validated these before they sold someone on investing on it. Let's see how they interpret characterize and validate.

Strong experience with development and implementation of a variety of mammalian cell based assays such as proliferation, soft agar and apoptosis is required.

They have already determined that the proteins will be affecting cell proliferation. That's why they want you to run these assays. But how many times will you need to do it? If they have developed the proteins shouldn't the assays also be developed? The only help they need is someone who knows how to operate a pipette. Apoptosis assays can be purchased. What experience do you need other than the ability to run new assays as they go on the market?

Extensive experience with mammalian cell culture, transfections, use of retroviruses, gene knock down tools and basic protein analysis required.

Okay, if you've got cell based assay experience, you've done some cell culture. Transfections are not rocket science. Retroviruses? Gene knock down tool probably means siRNA. Basic protein analysis is as difficult as any of the other assays. Again, they need only a person who has used a pipette before.

Experience with monoclonal antibody characterization using cell biology tools and use of fluorescence microscope strongly preferred.

How does experience with monoclonal antibody characterization differ from basic protein analysis? Does this differ from the other requirements such as mammalian cell culture and apoptosis assays? One would assume that the monoclonal antibody binds to a known target and it has been well characterized. What this company wants is someone who will come in and produce all of the charts and graphs necessary to make thier antibody drugs work. The problem is that it is up to the antibodies to do the work. The assays and other techniques should already be known. All the company needs is a lab tech. Train the tech on the specific assays and wait for the data to come. But here is the problem. They don't know what the charts and graphs will look like. They don't know the form of the evidence that will make their antibody drug a success. They want a 40 thousand dollar a year science geek, without a PhD to come in and close the deal with nature.

Corporate scientists do not design experiments. They hire lab techs and vaguely direct the research by insisting on certain assays and other methods. What you will not find is a chart that needs to be filled in. For example, if I wanted someone to run a "basic protein analysis" BCA to determine a protein concentration I would require the protocol be followed exactly, duplicate standards and various dilutions of the unknown to ensure that one of the values falls within the linear range of the standards. I would not have to ask if the standards were prepared in duplicate or just ran in duplicate because I would be designing the experiment that I am asking someone else to run. Biotech companies do not design experiments in this manner. They design job descriptions and sit back and wait for the technician to do everything else for them.

Pipelines thoughout the business are empty. They may have some spiders and rats creeping around in the rusty water of the pipes but they are not pumping out what they were meant to pump out. Useful drugs require experimental design. This does not mean designing a job description.

I Have a Dream

I have a fantasy where I win the lottery for 150 million bucks. That's enough for my little dream job to take place. I start a science journal. Only this one comes equiped with a laboratory. That's why I need 150 million dollars. I'm not messing around here. What the journal does is accept papers that we think are falsifiable. In addition to being falsifiable, the consequences of either true or false outcomes are of no matter to us. What matters is where the truth lies.

Like Feynman said in Cargo Cult Science, "If you've made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish BOTH kinds of results. "

The trick of this new science journal is to have no conflicts of interest in either outcome. We must publish the results and base our reputation on how many things we get right. Unlike the modern day journals who rely on peer review, we will rely on that lab that is a part of the journal. Peer review is an unscientific method. This journal would be the first of it's kind. It's purpose would be to shame the major journals into returning to a more scientific method of reporting science. Here is how we will deviate from the status quo.

When a paper is recieved it will be reviewed for falsifiable conclusions. The methods that are reported will be written up for experimentation within our lab. If someone reports a western blot of a hamster brain for example, we will get the brain material and every other material used in the western and we will run the very same gel. Only the falsifiable experiments will count towards the final review. Once the experiments have been repeated the review will begin. In the journal you will first read the paper that is under the gun. Next there will be 3 separate reviews. Each review will go over the data obtained from repeating the experiments. They will break down the conclusions and discuss how their data was interpreted with relation to the original author. The final review will be purely philisophical. Was the experimental design Cargo Cult or was it good science? Were the methods hard science or soft? Was there ample room for statistics to come into play? In essance we will be testing the tests and analysing the analysis. In the end we will simplify the conclusions down to the shortest explanation of their significance.

We will seek out the simplicity of things. It's easy to make complicated arguements that others find too cumbersome to question. We will seek out the simplest of questions that most people think have been fully answered. What is a protein. Can we measure it? Can we measure gene expression? What are the micro-environments inside a cell and how do they regulate gene expression. There are so many questions to answer. The dream I have of this journal is to take on basic questions, slowly and methodically, and to get to the best possible answer we can get to. We will never be able to know the whole truth. Again, quoting Feynman, "We can't define anything precisely. If we attempt to, we get into that paralysis of thought that comes to philosophers… one saying to the other: "you don't know what you are talking about!". The second one says: "what do you mean by talking? What do you mean by you? What do you mean by know?" But we can get as close to it as is humanly possible. The most important aspect of the process will be to take our hopes and dreams out of the picture. There must be no conflicts of interest. No egos to shatter. No careers to worry about. The only thing that matters will be the truth.

Anyone Got Anything To Share?

So far this blog has mostly been a diary of thoughts I have regarding the philosophy of science. Having worked in a science related field I have been surprised at how unscientific most people are, including most scientists. I use this blog to try and understand what motivates someone to be dishonest or sloppy with the facts or whatever their deviations from the truth are. I am willing to bet that there are hundreds of others like me. They work in laboratories. The work for people who do not work in laboratories. They have to use unforgiving scientific equipment to tell the tall tales predetermined by their superiors. They have as much to add to this blog as I do. It's a Dilbert blog that needs some new stories.

My hope is that one day someone who works in a laboratory will read this blog and it will hit them like a ton of bricks. They will find this as a forum to share their stories. We could write up all of the silliness without the risk of being caught by the pharma industry. Outsiders could read about how science is conducted by those who otherwise get lots of respect. This is a place to air out the dirty laundry of the science religion and those who rank the highest.

What we care about here most is the truth. If a full professor of mathematics from MIT states that 2 plus 2 equals 5 and a mentally challenged mongoloid from West Viginia says that it equals 4, we say that the mongoloid is correct. The truth is the only thing that matters here. Unlike the scientific journals, we don't care about your credentials. We want to hear your your story of the truth or the deviation from the truth. Always, the truth must be lurking someone nearby.

If you're a disgruntled postdoc, an undervalued associate, or any other form of lab staff in the bio business (academia or industry), tell us your story. Did David Baltimore try to ruin your career? Did John Darsee make you look unproductive? Talk about it. You're among friends here. We know how airplanes work and where they come from. We know about your airport managers as well. Let's tell funny stories about them and try and make sense of it.

The Airplanes That Never Came

If you want evidence of a Cargo Cult in Biotechnology, you need only google a companys name. You'll end up with some old and new information. Go to the old and see what they were up to a few years back. Then try and find out what happened to some of those projects. You'll find out that the attempt at finding a cure or therapy disappeared into thin air. You'll wonder how it ended but there will be no press release on a cancelled project, at those at the early stages. Just once I'd like to see something like:

Company X has ended it's early stage research and development project to find a cure of Alzheimers because we couldn't make any sense of the data the technicians were providing us. We wanted them to find something that binds to Amyloid beta and then breaks up Amyloid plaques. Turns out things aren't that simple and we realized we were in over our heads. We have switched to easier projects.

When you're in the business of making money on stock performance press releases like that won't work.

Here is an example of what I'm talking about with regards to googling a company to find some projects that disappeared into thin air.

November 8, 2004

Company X announced that the Company has entered into separate agreements with two undisclosed research partners to evaluate the development of proprietary formulations for the nasal delivery of compounds useful for the treatment of type 2 diabetes and Alzheimer's disease.

Here it is September 6, 2006 and there is no drug in the pipeline for Alzheimers disease. Having worked for this company however, I can share a little secret with you. Back in 2004 we had a scientist from the Mayo clinic come and give us a talk. He seemed annoyed at the group of young kids sitting around the conference table. Were we suppose to be colleagues of this grey haired scientist at such a renowned research center? Towards the end of his talk he started discussing the work people do with Amyloid beta.

"Some people think you can just find something that binds to the protein and that will cure the disease. Why? Has someone got a reference that indicates that the protein is the cause of the Alzheimers? Has someone shown that destroying these plaques cures the disease?"

He went on and described our research approach almost exactly. Of course he was talking about the stupidest way of "researching" Alzheimers. Later the people working on Amyloid beta just sort of moved on to other things and never came back to the Amyloid beta work.

The questions I can't find answers to are:

Who were the two undisclosed research partners?
Were the details of the project written up in any form ever?
How did it end?

These questions are basically asking about the airplanes that were promised. We like to hear about airplanes full of cargo coming to an airport near us. But when they don't come, how do the leaders handle the PR? It obviously gets swept under the rug. How do they do it without as little recognition as possible?

Why Is It Allowed?

I was thinking about Dr. Blumsohns problem with Procter and Gambel. They gave him some data from a clinical trial. He was to analyze the data and provide his results to the company. They would then use this as evidence that their drug works. The problem was that they didn't give him the codes so that he could complete his analysis. I wanted to think of an analogy that could describe the case. For the life of me I cannot understand why everyone in the world, including non-scientists, doesn't see what is wrong here. Why isn't this an open and shut case where P&G apologizes and fires the staff who tried to pull this trick on the world?

I thought about the O.J. Simpson murder trial. You label blood samples. Some come from the crime scene. Others come from suspects. Others come from people who were known to be at the crime scence such as the victims and the investigators. You then analyze the blood and put the matches together. You still don't have anything. What makes this process useful is knowing the codes. Let's say you've got samples 2 and 17 matching up. You reveal the codes and you find sample two came from the crime scene and sample 17 coming from a volentary blood draw from O.J. Simpson who is claiming to have not been at the scene.

The technical aspects of matching DNA samples to each other doesn't say anything. What matters here (what brings the cargo) is that a suspect now has a piece of evidence linking him to the scene of the crime. He says he wasn't there. His DNA says he was.

Back to Dr. Blumsohn. Is this similar to his case? He has the data but not the codes. He finds very little differences between any of the subject groups. Perhaps the drug did not do much better than the placebo. Perhaps the placebo worked a little better. I'm going to assume that DNA profiling is much more reliable than data analysis from a clinical trial. None the less, you need to know what group was what in order to really finish the job.

Dr. Blumsohn also accuses P&G of cherry picking from the data to make up a story different than the one he would have told. How would P&G know what data they needed to weed out? They would have had to know what the codes were. If group A was known as the drug group and it was similar to Group B, the placebo group, then these two groups would have to have some data thrown out. What is the desired outcome? That determines what data stays and what data goes. You can't pull this scam without the knowledge of the codes. And this is what Dr. Blumsohn was trying to get so that he could practice something a little different, known as science. Scams and science require in depth knowledge of the truth.

They wanted Dr. Blumsohn to remain blind. Why isn't this obvious? Why is it allowed? My guess is that there are mortgages to be paid, braces that are needed and so on. These transgressions are thought of as white lies. One data point here and there are not big deal. The little details matter however. It should not be allowed. P&G and Sheffield University should be ashamed. They have a new Cargo Cult ceremony. They've covered the eyes of those standing along the runway. They are making airplane noises. The lack of cargo can be easily explained away, because that is what they who make airplane noises are also skilled at. But the let one of the commoners stand along the runway with his eyes open. He saw what they do and he is trying to share with us what is happening. We still can't see. We heard the airplanes. We know the cargo will be here soon. People are getting ready for it. Isn't that proof enough?

Craiglist Ad, A Cure for the Flu

Some jobs are advertised on craigslist. Notice that craigslist is not capitalized. It's a website where people peddle their used items. They sell old sofas, stereos, and old jobs. The jobs you see are the ones that were recently abandoned for greener pastures. You're not going to see an important executive job posted on craigslist. To fill an executive position we have recruiters who seek out accomplished individuals. We have compensation experts develop a package that will lure the best candidates to serve a corporation. But is all this Cargo Cult science? Could we advertise on craigslist to fill executive spots and still get the same level of performance?

The executives in a biotech company have one thing missing. They don't know what is going on in the lab. There is not enough time to sort through the details that go into a potential cure for a disease. Execs need to know what the gist of it is and they will move along and do their important work. Meanwhile, the kid who got his job off of a craigslist add has to figure out how to make siRNA prevent the next avian flu pandemic. There really is a company who is taking on such a project. They bought the license from a smaller company and now they are "developing" the technology. Shouldn't the technology be developed before you buy it? Imagine the executives negotiating the deal. Millions of dollars are exchanged. People are flying from coast to coast working out details and writing up contracts. After it's all said and done, they look at what they've got. Is it a cure for the flu? Not exactly. We'll send it to R&D and see what they can do with it. The important work has been done.

Laboratory positions for the company curing avian flu with siRNA are listed on craigslist. Currently they are hiring some process development people and some QA types. Other websites are used as well. Just after the executives struck up the license agreement an ad came out on the WBBA website. They wanted a PhD who had experience with siRNA and the avian flu virus. Hmm.

So what do the executives talk about that puts them out of the craigslist arena? They certainly aren't talking about ways of detecting siRNA interacting with the influenza virus inside a human body. When it comes to developing the next big cure, I assume there is much talk about the the cost of the trials, who will run them and so on. But after all is said and done, the real work must begin. Every aspect of the next steps is critical to understanding whether or not the drug will work. It is at this time that the people involved are more than just some schmucks you find on the internet while you're looking for an old sofa on craigslist. All the agreements and legal battles will become useless the day they shut down the trials due to lack of efficacy.

Executives don't cure disease. They make deals. So do scientists however. The deals we make are with nature. If we're smart we get what we're after. If not we have nothing. It's a high risk endeavor but one we enjoy doing because we are convinced that we are indeed smart. We don't want to talk about making deals with other human beings. The only thing that matters is curing the disease. After that let the execs do their job and get the drug made. They are good for some things.

Critical Thinking

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.

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.

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.

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?

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.

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.

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.

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.

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?

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.

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.

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.

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.

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?

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."

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.

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.

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.

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.

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.