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Tuesday, October 31, 2006

Sirna Science

Sirna Therapeutics has reported the final results from its Phase I trial for Sirna-027, a therapy for age-related macular degeneration. Single ascending doses of Sirna-027 were safe and well-tolerated, and all 26 patients showed visual acuity stabilization eight weeks after a single injection. In addition, at the same time point, five of 26 patients experienced clinically significant improvement in visual acuity, indicated by an increase of at least three lines on an eye chart.

Translation: Five of 26 patients read the first three lines on an eye chart. None read 4. Single ascending doses is over the Cargo Cult Scientists head. I'm not an investor.

Patients received a single intra-vitreal injection of the drug in doses ranging from 100 to 1,600 micrograms. Three months after a single injection, 24 of 26 patients showed visual acuity stabilization, with four of 26 patients experiencing clinically significant improvement in visual acuity. Only two of 26 patients experienced a reduction in visual acuity of three lines or more. A decrease in foveal thickness was observed in some patient groups, which is an indication of biological activity of Sirna-027.

Translation: 26 people received siRNA through a needle injection direction into the eyeball. The range is 0.2 to 1.6 (!!!) mgs but how that range was divided up among the patients is not revealed. RNAi effects, which generally last less than 72 hours, are given the credit for improved visual acuity three months later. Dose dependence of the improvements is not mentioned. There is no control group of 26 who received scrambled RNA. Scrambled RNA is a sequence not known to have homology with any mRNA. There is no control!!!

Sirna is now into a Phase II trial with Sirna-027. Merck has offered 1.1 billion for the company.

Mercks Big Bet

Merck announced today that they have entered into a definitive agreement under which Merck will acquire Sirna. Sirna stands for short interfering RNA. The company describes themselves as a publicly held biotechnology company and a leader in developing a new class of medicines based on RNA interference (RNAi) technology. I guess when you name your company Sirna you had better call yourself a leader in the technology.

Mercks press release states that "the acquisition of Sirna complements the cutting-edge research on RNA expression that Merck has been doing since the 2001 acquisition of Rosetta Inpharmatics, Inc."

Rosetta Inpharmatics was founded in 1996 to design and implement DNA microarray gene expression technologies. Merck bought Rosetta for about $630 million in July 2001 with high hopes that Rosetta would make a difference in screening cancer compounds and genetic targets, which is not one of the company's strengths. As one Merck exec put it, "we're in a low-probability-of-success business." The acquisition of Rosetta and now (5 years later) Sirna, Merck has all the tools to begin to do higher probability of success research.

However, Sirnas lead candidate is in Phase II trials, which the Cargo Cult Scientist points out has a high probability of success relative to Phase III trials. That is to say, they haven't done much so far. Rosetta is also perplexing. In 2005 they published a report on the discovery of 3 genes linked to obesity. Obesity is a condition most often caused by an improper balance between diet and exercise. The genetic aspects of obesity have never been properly studied. Rosetta has shown a profound lack of productivity. In 2006 no news worthy discoveries have come from Rosetta. If RNAi and bioinformatics were so powerful, one would have expected bigger and better things from the past year.

Now that these two companies are subsidiaries of Merck, we at the Cargo Cult Scientist are going to keep an eye out for their success stories. Will Sirna knock out targets identified from Rosetta? Will Merck sink the big bucks in developing RNAi drugs that result from this collaboration. The Cargo Cult Scientist has experience in this sort of project. In 2002 the CCS worked for a bioinformatics company who wanted RNAi work to knock out genes they were identifying. The problem was that only one bioinformatics target was pursued by white lab coat members of the "wet lab". Either it, or RNAi failed to disrupt the protein pathway. We pursued other targets but mostly tried to optimize RNAi effects. Eventually we ran out of money. No airplanes landed.

For businessmen, it makes sense. The two companies should be able to develop drugs rapidly. The Cargo Cult Scientist however, is not a businessman. He sees Rosetta and Sirna as two burning flames on the runway. Merck has made a couple of very expensive mistakes. Their only hope is that Rosetta identifies some real targets someday and they get into the antiody therapy business. Sirna has no hope.

Monday, October 30, 2006

Start-Up.Com

I watched a documentary this weekend called Start-Up.com. In this film two young men started a dot-com business in the mid 90s that was suppose to simplify the process of dealing with government agencies. It was a good idea. You shouldn't have to lose half a day of work to renew your drivers license or to pay a traffic ticket. They obtained millions of dollars in investor money. They hired hundreds of employees. They created a nationally recognized name, govworks.com. In the end however, they failed.

The most relevant part of the movie to the Cargo Cult Scientist came when the business was starting to unravel. The 28 year old technical executive was having trouble with the head software engineer. They called an emergency meeting to discuss the disconnect between the product and the executive staff. The engineer pointed out that he needed specific directions in how to design the software, not just "make a fantastic website".

As we now know the dot-com era was a bust. Everyone was selling a fantastic website but few actually had one. The Cargo Cult Scientist can use the lessons learned to apply to the biotech business. Biotech companies are selling fantastic cures for disease. The Cargo Cult Scientist has sat in on many meetings where the product was discussed. The leadership was concerned quite often at the rate of advancement of the science. They wanted RNAi to work. They wanted antibodies that bound with high affinity and stopped a protein from working. They wanted a cure for cancer and it just wasn't happening. What do you do when the drug development program that was started by executives (and is being sold by executives) begins to look like it might not work?

Todays example of a fantastic cure being sold by an executive staff come from GSK.

LONDON, England and RIXENSART, Belgium, October 30 /PRNewswire-FirstCall/ -- Mathematical model projections predict that vaccinating all 11-13 year old girls with Cervarix(TM), GSK's cervical cancer candidate vaccine, has the potential to reduce the incidence of cervical cancer by up to 80%, based on available clinical data.[1] The projections model was constructed in two stages. In the first, vaccination with GSK's cervical cancer candidate vaccine -- which has shown excellent protection against the two most cancer-causing HPV types, 16 and 18[2] -- accounted for a projected 74% reduction of cervical cancer in France. This constituted the base-case analysis of this model.

In a further analysis, the model incorporated preliminary evidence that GSK's cervical cancer candidate vaccine has been shown to provide substantial protection against pre-cancerous lesions beyond that expected from HPV vaccine-types 16 and 18.[2] When this additional protection is added to the model, a further 6% reduction is predicted, making a total reduction of 80% of cervical cancers.[1] These findings were presented today at the International Society of Pharmacoeconomics and Outcomes Research 9th Annual European Congress (ISPOR) in Copenhagen, Denmark.

This is the equivalent to telling investors that your govworks dot-com is going to mean big bucks. The scientists now have to develop a product that has been sold as a drug that will prevent 80% of cervical cancers. We'll call this American Airlines 80, departing from CervicalCancer Norms. Arriving???

Saturday, October 28, 2006

GSK Blows Biodefense Project


GlaxosmithKline is shutting down its Bothell Washington facility and laying off 80 people. The facility specialized in biodefense. After ten months of searching for someone to take it off their hands they are giving up.

Although I did not know much about GSK in Bothell I am sure they were a bright flaming torch on the runway of the Seattle area Cargo Cult of Biotechnology. The torch was lit and nobody knew what to do next. It has now burned out. What will we do about biodefense now?

To the workers I say it is not your fault. There can only be a few decision makers. They must rely on a keen understanding of what is needed to be done. Those individuals lead a team into a failed project. The airplanes did not land.

Friday, October 27, 2006

Using Phage Display to Demonstrate a Lack of Scientific Reasoning


Long story short, phage display is a method used to find peptides that bind to proteins. You can also screen antibody fragments that bind to proteins. It's not a difficult research project. You buy a kit, buy or purify a protein and you go through the procedure. In the end you must verify that the peptide you found binds to your protein. Therein lies the wild west of phage display. You do not have a kit to tell you what is binding to what.

When a researcher starts a phage display project he/she has a loftier goal than fishing out binding peptides. Those peptides must also have a function. Most often that function is to inhibit the function of the protein they bind to. Let us look at one example of this work, keeping in mind that there are many others that make the same mistake. The mistake is made, it is published, and sometimes pursued as a drug candidate.

Several phage display projects have came up with peptides that are the same. The sequence SVSVGMKPSPRP has been found by many researchers. They further their findings by attaching a function that is done by the peptide. The problem is that this sequence is carried on a contaminating phage that comes from New England Biolabs PhD kits, lot 3. The phage can be found by anyone after several round of panning. Phage usually appear as blue dots in a lawn of bacteria. After several rounds you sometimes will see clear plaques. The clear plaques are the contamination. Early on NEB claimed that this came from sloppy lab techniques that resulted in contamination from phage floating around naturally in your lab. They have never admitted that any contamination exists in their libraries.

To Live and Die in Yutan NE


I grew up in a small town just outside of Omaha. People like to make fun of that but it wasn't an unpleasant experience. I can remember walking to school and meeting Mark and Tony along the way. Marks mom would walk him downtown where we would meet up. A couple of blocks later we'd see Tony goofing around on the front porch waiting for us. At the beginning of the school year we'd walk through the falling Maple leaves and discuss our Halloween plans.

I was a bad boy however and Marks mom soon came to dislike me. He wasn't allowed to hang out with me after the third or fourth grade. His mom was a bit over protective. I mean how bad could I have been at that age? Tony grew up to be a biker. I joined the Navy and later went to college in Colorado. Mark went straight to college at UNL and became a school teacher. He died of non-Hodgkins Lymphoma at the age of 32.

There weren't too many kids my age in this small town in Nebraska. Most of them are still there. They are farmers, truck drivers, mechanics, Walmart workers, nurses and any other job that absolutely must get done on a daily basis. I moved around the country after college working in University labs and biotech companies. The work I did, did not need to get done on a daily basis. At least that is the way it felt. A co-worker at UCSF once came to work, said hello then crossed the street for eight solid hours of studying for her pilates test that she had to take that night. No one noticed she was gone. We met her for lunch to see how she was doing. "Anyone ask for me yet?" she asked. We laughed. We sat there outside the University deli that overlooks Golden Gate Park and the rest of the city. We had it made. Not a lot of money but we were overpaid no matter what they gave us.

I knew back home the people worked harder. They had to get their work done or someone would notice. What I didn't know was that Mark was dying. I hadn't kept in touch. I e-mailed an old friend about a Husker game. He said that Mark had died. If anyone should have been working hard everyday, it should have been those of us in laboratories and who spend money allotted for medical research. Of course our research at UCSF was on a disease that hardly no one died from, mad cow. It soon became clear that this was a disease that was sold rather than researched. The cause of the disease was still in question but our job was to hammer home the labs forgone conclusion. To me, this attitude was not justified by the power of the research. We couldn't test for mad cow. We couldn't slow down the disease. We couldn't prevent it. All we did was tell the same old story over and over. But what did it matter, no one died from it. Just some cows.

At my next job in Los Angeles we did study cancer. A professor had made a pretty niffty antibody that would bind to denatured collagen, but not the properly folded collagen. He claimed it prevented angiogenisis, the formation of blood vessels, which would result in starving a tumor. Every tissue needs blood to provide oxygen and the carry away waste. We were all confused because the professor did not have a clue as to what denatured collagen had to do with angiogenisis. He said that angiogenisis "factors" bound to collagen when tissue was being torn down by an invasive tumor. There was no evidence of this and we weren't there to falsify his notions. He wanted us to prove that the antibodies shrunk tumors and that was it. Of course we couldn't. This antibody is now a leading candidate for a company in Germany. The larger company that bought us up has since failed with their cancer vaccine. They were forced to sell their licenses to the German company. The Cargo Cult Scientist is waiting for news of this drug failing. It WILL be posted in this blog. The antibody WILL NOT become a drug.

I wonder how we would have approached our research if we had been working on Marks disease? If we had to see Mark everyday as he slowly deteriorated. Would we have been so casual? This is what really motivates me to write the Cargo Cult Scientist. One of my first friends in life died 7 years ago. Since then I've been travelling the country like a vagabond, looking for work as if I were a farm hand. I haven't worked for 8 months now and I'm still lacking motivation. I apply for work but only half heartedly. Even the Universities seem to select for individuals who are more concerned about publications rather than pursueing the truth. The truth can help those who are now dying of what Mark died of. A cancer is taking over their body. Perhaps we could do something about that. The problem is that your Nebraska mechanic has more experience at his job than your big city cancer researcher. The guy in the lab doing the work is most likely in between college and their next attempt at a career. It's not a grown up career. I graduated in 96. What will I be doing in December, my ten year anniversery from graduation? Will I be using my education and experience to conduct research or will I be driving a cab? People need to get places in the city. It could cover the bills.

One thing I'm not too worried about is a lack of insurance. I have a good excuse to never see a doctor. Can't afford it. If I come down with a cancer I'll run my last experiment. Drug free cancer therapy.

Thursday, October 26, 2006

Mad Cow







Winning the Nobel Prize and starting a biotech company is what modern day biology scientists strive for. Fame and fortune for boring biology folk. Back in 1986 people were starting to talk about Stan Prusiner. http://www.slate.com/id/2096/sidebar/42786/ In 1997 Dr. Prusiner won the Nobel Prize in Medicine. In 2000 he founded a biotech company called InPro Biotechnology, which focused on a Mad Cow test developed in his UCSF lab.

Before InPro, Prusiner signed on with Chiron. They put up the money and Prusiner provided the brain power. By 2000, Chiron had enough and chose to cut their losses at 5 million rather than continue to fund the assay development. Prusiner marched forward. In 2004 Prusiners InPro signed a deal with Beckman Coulter and put the assay on the European market. InPro is still in business in South San Francisco. They are not alone.

NEW YORK, Oct. 10, 2006 (PRIMEZONE) -- Genesis Bioventures, Inc. (GBI) (OTCBB:GBIW) announced today that Prion Developmental Laboratories ("PDL"), its minority owned subsidiary company, entered into a contract manufacturing agreement with InBios International, Inc. ("InBios"), a leading biotechnology company in Seattle, Washington, to manufacture PDL's Mad Cow Disease ("BSE") and other TSE Rapid Diagnostic Tests.

Bio-Rad has a mad cow assay that is the most widely used in Europe for testing cattle for BSE, and it is used almost exclusively in Japan to test all its slaughtered animals.

Washington State University is asking the federal government for $25 million to build a facility to test for BSE at the University’s College of Veterinary Medicine, and $2 million to continue research related to a live-animal BSE test and other food-borne disease agents.

The Cambridge Health Institutes 9th Annual meeting on Transmissible Spongiform Encephalopathies, The Definitive TSE Meeting, two diagnostic assays were presented.

A Rapid Pre-Symptomatic Diagnostic Test for PrPsc in Tissue and Blood Using Conformationally Sensitive PrP Peptide Ligands Dr. Cindy S. Orser, Adlyfe, Inc. and Georgetown University

Development of an in vitro TSE Infectivity Assay: Application to Validation of Manufacturing Processes Dr. Benoit Flan, LFB, Laboratoire Fran├žais du Fractionnement et des Biotechnologies

After all that you would think that there is a reliable test available. You would be wrong. 99.999999999 percent of all cows do not come down with mad cow. You could be wrong that one time when there is a mad cow but right the other millions of times when the cow is not mad. Those are good odds. If all you have to do is test every cow they throw at you, you will have over a 99% accuracy IF your assay says negative 100% of the time.

Here is what the mad cow testers do not do. Obtain brain samples from 999 normal cows. Add in one mad cow brain to the group. If anyone can pick out the mad cow, and only the mad cow, they move on to round 2 where the same material is sent out again. Repeat a third time. Not going to happen.

I'm going to end on a positive note. You are not going to die of mad cow. No matter who you are or where you live, the odds of you dying of mad cow are slim to none. It's all part of the Cargo Cult Science. There is nothing to it but a lot of adults pretending to do work. InPro joins the Cargo Cult as a charter member. Their logo is a flame that illuminates the runway.

Wednesday, October 25, 2006

Free Government Money for Drugs!!!



BOTHELL, Wash., Sept. 26 /PRNewswire-FirstCall/ -- Nastech Pharmaceutical Company Inc. announced today that the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), awarded the Company a $1.9 million Research Project (R01) grant. This award combined with an earlier SBIR Phase 1 Small Business Innovation Research (SBIR) grant award brings total program funding to approximately $2.3 million from the NIH that will be used to further develop the Company's small-interfering RNA (siRNA) therapeutics to prevent and treat influenza. A grant for additional program funding is still pending.

Last year Nastech Pharmaceutical Company CEO, Steven Quay brought home nearly 9.5 million dollars. The company has a market valuation of over 300 million. Nastech hopes to find a major partner to fund the development of an RNAi therapeutic approach to fighting flu. So why did the NIAID give them 2.3 million dollars? How much more are they asking for?

Last week Nastech filed a shelf registration statement on Form S-3 with the U.S. Securities and Exchange Commission (SEC), pursuant to which Nastech may issue commonstock from time to time, up to an aggregate of $125 million.

Why is the NIAID giving Nastech money? Nastech has lots of money. They are in business to make money, but not necessarily drugs. Nastech has been in existance for over 20 years and has produced only one product, which was sold for 18 million dollars in 2003. That product was a vitamin B-12 gel. Not exactly a cutting edge breakthrough. Considering this lack of productivity and the problems Nastech ran into last year with their PYY and calcitonin programs, should we be paying to help a publicly traded biotech company fund their for profit research? Considering that the anti-influenza RNAi drug program began at MIT before becoming patent protected at Galenea, why is the federal government still funding this research?

Tuesday, October 24, 2006

The Drug Rep

Carl Elliott, The Drug Pushers,The Atlantic Monthly, April 2006:

"Back in the old days, long before drug companies started making headlines in the business pages, doctors were routinely called upon by company representatives known as “detail men.” To “detail” a doctor is to give that doctor information about a company’s new drugs, with the aim of persuading the doctor to prescribe them. When I was growing up, in South Carolina in the 1970s, I would occasionally see detail men sitting patiently in the waiting room outside the office of my father, a family doctor. They were pretty easy to spot. Detail men were usually sober, conservatively dressed gentlemen who would not have looked out of place at the Presbyterian church across the street. Instead of Bibles or hymn books, though, they carried detail bags, which were filled with journal articles, drug samples, and branded knickknacks for the office.

Today detail men are officially known as “pharmaceutical sales representatives,” but everyone I know calls them “drug reps.” Drug reps are still easy to spot in a clinic or hospital, but for slightly different reasons. The most obvious is their appearance. It is probably fair to say that doctors, pharmacists, and medical-school professors are not generally admired for their good looks and fashion sense. Against this backdrop, the average drug rep looks like a supermodel, or maybe an A-list movie star. Drug reps today are often young, well groomed, and strikingly good-looking. Many are women. They are usually affable and sometimes very smart. Many give off a kind of glow, as if they had just emerged from a spa or salon."

Marcus Welby discusses medicine;

1970










2006


Thursday, October 19, 2006

Human Resources

Let this image represent the Biotech/Pharmaceutical industries talent for putting the right people in the right place.

Blue truck = scientist

Garage = scientist job

Photograph = the human resource skills of the industry

From time to time I'll use this image to alert you to hot jobs in the industry.

Todays whopper stems from the company who I previously reported on for losing their CCSO. This company has 140 employees, many of them human resource professionals. Notice their use of a staffing agency.

We are currently working with a biotechnology company in Bothell, WA who is in search of an Analytical Biochemist. This is a contract position estimated to last 6 months.

Description:
Develop analytical techniques for characterization and assay of protein therapeutics.
Perform assays to support protein formulation development and production process development.

Requirements:
B.S. in analytical chemistry, biochemistry or related discipline.
Two or more years relevant experience in an industrial or academic lab is preferred.
Experience with protein analytical techniques such as SDS-PAGE, isoelectric focusing, spectrophotometry, ELISA, and HPLC of proteins and peptides.
Attention to detail in the execution and documentation of experiments.
Good scientific problem solving skills.
Strong interpersonal and team skills, and effective oral and written communication.
Local candidates only, please!

The company wants to hire someone to DEVELOP the methods to test their drug candidates. The company does not know how to test their drugs. They are not hiring someone to come in and run the tests that they have designed. They have no idea how to test their drugs.

So if you have a bachelors degree, two years experience and 6 months to kill, go help them out. Every biotech company needs to test their drugs. Do you know how it's done? They don't!

Obama Said There'd Be Days Like This


While perusing the television stations to find the Cardinals/Mets baseball game I was suddenly privy to an interview on Oprah. Honestly, I wasn't watching Oprah! I was looking for the ballgame! The man being interviewed was Barack Obama. I listened long enough to take away one very valuable piece of advice.

He said that we all need to be useful. That's the advice, now think about it. If you look at someone like Paris Hilton you might wonder what use she is to society. In spite of her lack of talent, she is useful. People like looking at her photos apparently and reading about her escapades. She has put herself in the spotlight and thus she is used to sell magazines and movies. She has a book out about her life up to the age of 20. It's not useful to me, but there are some book publishers out there that felt she was useful. People pay her just to show up at their parties. So, in spite of what some might think about her talents, she is useful.

The question we have to ask about the Biotech/Pharmaceutical industry is this. How useful are scientists? The take over of Icos by Eli Lilly sent out the message that the end result of scientific research is very important. The path taken to discovery is not. We here at the Cargo Cult Scientist are waiting for the job cuts to be announced. It's not an if, but a when issue. Will all of the research be halted at Icos? Will experienced researchers be tossed out on the street again?

In the golden age of Hollywood, silent movie actors became more famous than any human beings had ever been. When the talkies began these actors soon became obsolete. Actors with stronger voice skills became more useful. The golden age of biotechnology seems to gone the way of the silent movies. The industry still cranks out pills, but the scientific research that goes into them has changed. Real science is not as useful as having a good friend in the FDA. A bad idea backed with a lot of money will go further than a good idea with no money. For the short attention span leaders, sales people are more useful than early stage scientists. The universities and the industry do not hone the skills of it's laboratory work force. They are not as useful as a pretty drug rep moving the product. The message is clear. If you develop pills, you are failing us. If you sell the pills, you make the company go. You are useful.

What do you do if you've spent your career working with DNA and proteins in the lab? What do you do if you are an Icos employee who was working on the next molecule to be tested as a drug? In the Northwest, Icos was the biggest success story since Immunex. There is no one in line ready to snatch up your talents. The golden age of biotech is over. You're now like a silent movie star circa 1935. You need to reinvent yourself to become useful again.

Barack Obama made a very important point. Be useful. What does that mean if you are a scientist in the drug industry? To the Cargo Cult Scientist it means tack on more degrees and position yourself in front of drugs that are headed to the market. Get a PhD and supervise a crew of HPLC operators. Get an M.D. and run clinical trials. Finish up that masters degree and get into a CRA certification program. If you stay back and try to develop new drugs, you will fail. You will be a part of the problem that is no longer being tolerated by the industry. There is one hope that the Cargo Cult Scientist has however. If you feel like you are the type of person who thinks scientifically, take a chance. Stay back anyway and learn how DNA works. Work in a lab. Learn how to measure protein levels inside the human body. Learn learn learn. That doesn't mean tack on degrees to further your career. Learn how it really goes down in the laboratory. When the industry runs out of new and expensive drugs to sell, you just might be useful again.

Wednesday, October 18, 2006

Jenna Teaches Us A Lesson

There is something about this girl. She plays a shy receptionist from Scranton Ohio on the TV show "The Office." They put her in dork form, much like a Cargo Cult will put the tribe into airport form. But you can see right through the disguise. This is a pretty girl who can really turn it on if she wants to.

Now check out the girl dressed up to hit the town in LA. Nice!

I knew it. Totally hot. How many women can do this? The Cargo Cult Scientist sees them everyday. They do not know that they are beautiful because it's not inside them. Someone has made them feel less than attractive.

In order for the lovely Jenna to play her character she has to go in the opposite direction. She must pretend that she is working at a nowhere job and going home to her cat and their empty apartment in Ohio. She has to get into the character who does not feel comfortable in clothes that show off her curves. Somehow she plays the part well.

How does this pertain to the Cargo Cult Scientist blog? It's about appearances. We must all go out into the world and act the part that others have taught us to play. Universities mold us into the actors that we are in our professional lives. Family and friends mold us by encouraging certain types of behavior and discouraging others. But we all have something inside us that is unique. How can we tap into that and break away from playing the part we have been assigned?

Trubion

It has a fabulous view. From the 11th story offices you have a 180 degree view of Elliot Bay. Happy workers mill about in a laid back office setting. They are there to develop the next big thing in biotechnology. They call them SMIPs which is short for small modular immunopharmaceuticals. They are single-chain polypeptides engineered to have the same binding and activity function of a monoclonal antibody (mAb). They are one-third to one-half the size of conventional therapeutic mAbs, yet maintain the same in vivo half-life.

Leading candidates:

TRU15 Rumatoid arthritis non-Hodgkins Lymphoma

TRU16 non-Hodgkins Lymphoma

TRU17 cancer

Remember the pipeline standards in biotech. RA and cancer are highly desirable diseases. Targets are established so no discovery needs to take place. Binding to the known target is step one.

Trubion uses the success story of Rituxan. This is a monoclonal antibody that binds the same TRU15 target, CD20 which is expressed on the surface of B cells. A phase III studiy with Rituxan has shown that the antibody binds to B cells and results in B cell depletion. B cell depletion results in significant clinical improvement. Trubion thus has to merely follow in the path being stomped down by the makers of Rituxan.

The Cargo Cult Scientist has used Rituxan in mice studies. The antibody works. None of the mice who recieved Rituxan developed tumors. There was no need to manipulate the data as we did with mice in the group who received our drug. I believe I've talked about this shameful day in a previous post. Since Rituxan was the positive control, we simply did not mention these results. Our drug was an antibody against denatured type IV collagen. Our negative control was PBS. We manipulated the data to show a double digit percentage difference in tumor size between our anti-collagen Ab and the PBS. This made for a nice bar graph.

It's easy to show an antibody binding to a target. What about a SMIP? Did Trubion use the curves? Did they make any attempts to assign an affinity value for TRU15? How did they evolve to a number 15? What about the first 14? Were any related? Was affinity improved from a previous SMIP?

In my laboratory experience I have yet to meet a PhD scientist who has ever measured protein to protein affinity. Measuring affinity is different than claiming high affinity. Using surface plasmon resonance will provide the investigators with an affinity constant. The affinity of an interaction is determined from the level of binding at equilibrium (seen as a constant signal) as a function of sample concentration.



The next step is to determine the biological effect of the binding. How does it get to its target. How many mols reach the target? These are the questions. High above Elliot Bay is a company who intends to develop drugs better than monoclonal antibodies. They are not providing binding constants, curves, nor methods of comparinig SMIPs to antibodies. Before any biological functions can be claimed, they must provide some data that shows that SMIPs have reached the target and that they function in a safer way the an antibody. Human antibodies have been developed by evolution. How well do Trubions SMIPs match up.

Is there a scientist in the house who can compare a SMIP to an antibody?

Icos

Besides Amgen, Icos was the only biotech company in the Seattle area that had ever turned a profit. They did so last year. Yesterday they were bought by Eli Lilly for 2.1 billion dollars. Good work guys. Significant layoffs are coming your way.

Icos CEO, Paul Clark, said employees greeted the news with sadness and anxiety but there was enormous "pride in what they built and what they accomplished." The deal was just too good to pass up. Icos has been working with Lilly since 1998 on an erectile disfunction drug called Cialis. It's not a cure for cancer but it's a money maker. Worldwide sales of the drug are on track to bring in between 920 to 950 million dollars. Contrast this with the other leading biotech in Seattle Trubion. They raised 52 million dollars from investors, the low end of what they intended to raise. Their goal was 86 million. If that's a success, imagine being a part of a company that has a drug that will bring in 950 million. Some of that money will count towards a profit! But it's all going away.

The first activity in this deal will involve Eli Lilly handing over 2.1 billion to the investors of Icos. Paul Clark said it would have been "really wonderful from a geographic standpoint" if Icos remained an independent company in the Pacific Northwest. As a businessman, he had to make the best decision for his shareholders. Lilly paid 32$ per share, an 18% premium over Mondays stock price and 32% over the 90 day average. Still rumors of the buyout had people estimating around 36$ per share.

The decreased valuation did generate some discussions on Icos mistakes. First they had a deal with Lilly that prevented outside bidders from jacking up the price. Second they failed to come up with a second drug. Only one airplane landed. Since most biotech companies are actively engaged in futile drug development projects, this piece of Icos was not an asset. Only Cialis is expected to make this deal worth the 2.1 billion. Still, Icos had to try. You must have several drugs in the pipeline. In spite of their mistakes, they made money.

For the investor, Icos is a rare success. One investor, Bill Gates will walk away with 173 million dollars. Here in the Northwest we're not too concerned if Bill gets any more money in his time here on planet earth. In fact, we'd like some of that money to go to some of the others living up here. People who once worked at Icos, making it a company worth 2.1 billion dollars. True, Cialis was what Lilly bought. But there were a lot of people working and earning a living. Now there will be less. It's sad when the Cargo Cults of biotechnology suddenly rise above the norm and actually produce a product. Then they make a profit. Then they go away.

Tuesday, October 17, 2006

Cantwell and McGavick

The Cargo Cult of our government is something I avoid. My stance on government is that they quite often fail to inform their public that they have little power over certain things. The best they can do for education for example is to fund it sufficiently. The little rules they insert into their bills create paperwork the takes up the time that should be spent teaching. They create bureaucracies that eat up the money that is allocated. In short, I beleive that any decrease in a Cargo Cults activity is best.

So tonight we had our senate debate. Cantwell and McGavick are the two main party candidates. McGavick, the Republican, made the comment that we should somehow test welfare recipients for drugs and alcohol use. The non-Dem/Rep candidate who had to shell out 1.2 million bucks to be there, made a comment related to McGavicks. We should test members of the house and senate for drugs and alcohol. Ha!

Do we not test these guys? They are steering our country into the future. Are they doing so under the influence? Why worry about the lower levels. They are definitely going to have a high percentage of their population using. What about the guys who are making the big decisions? If the use of drugs and alcohol is detrimental, then they should be tested. I don't want these politicians out there having the freedoms that they rule out for us.

If a Cargo Cult is one that sets up an airport that has no idea how airplanes work or where they come from, then our government qualifies as a Cargo Cult. The highest ranking officials do not know how to build a bridge. They do not know when they are capable of real change or just plain chatter. They talk and they talk. When the day is over they meet with their lobbyists for fine dinners and who knows what. Are they home reading the bills they are there to vote on? Probably not. If we could just pass a law that prohibition is back in effect, only in the House and Senate, then we could assure good sober government. Next we go after the money. There is no drug in Washington greater than money. Nevermind the big debate where you have to convince people that you will fight against abortion or immigration. We must pass laws that prevent our elected officials from making bad decisions. If we think it's a good idea for welfare mothers we sure as hell should apply the same logic to senators and congressmen.

Monday, October 16, 2006

Bad Apples at Bayer

Last week Bayer suspended two senior scientists over their handling of data related to its heart-surgery drug Trasylol. Back in February of this year the FDA started to reassess the safety of the drug after two separate studies suggested the drug was linked to heart attack, stroke and kidney problems.

The FDA sought advice from a panel of outside experts on Sept. 21 over how to address the potential safety concerns. The advisers ruled Trasylol was acceptable for preventing blood loss in certain patients undergoing heart bypass surgery.

Days later, Bayer said it had mistakenly withheld another study based on 67,000 hospital patient records that suggested the drug could increase the chances of death, serious kidney damage, congestive heart failure and stroke.

What did the FDA do wrong? They failed to discover the study of 67,000 patients. They hired experts! They had a high level meeting that involved life and death decision making. One can be sure that there were men with suits and ties, women in smart business outfits. PhDs, M.D.s were all around. The talk must have been highly articulate and spoken in tones of complete understanding. Yet they made the wrong decision. If Bayer had continued to hide the data, as the two senior scientists believed was okay to do, the committee would have never known about this.

The FDA needs to be aware of any test that is initiated. What were the results? Was the experiment cancelled? Why? Are the results trustworthy? In their defense the two fired scientists claimed that the study methods were suspect and the results were preliminary. This is no defense, as far as science is concerned. A test was initiated and the data suggested something. The FDA should be able to determine if the methods were good or bad.

In a previous job I had an electronic notebook. When I began an experiment I wrote it out in the materials and methods section. I tracked down my materials and logged lot numbers in the notebook. I put everything together. I laid out some assumptions that I was making so I could reassess them after the experiment. When I had finally documented every detail of the experiment, I went to the bench and ran the experiment. Every piece of data I got went into the notebook. If I accidently used a wrong buffer I noted it in the book. I was practicing science. If I made a mistake, I logged it into the book. If you fail to log a mistake, you are committing a sin in the world of science.

What the two scientists did was more than a sin. They knew that the conclusions from the study they hid was detrimental to a drug that was already in the spotlight concerning its safety. They did not provide the FDA with the information because their job is to protect the drug, for their employer, Bayer. Favorable data is highlighted and unfavorable data is hidden. It can be hidden via corporate confidentiality policy. It can simply not be brought up. The FDA is not operating in a manner that will uncover such deceptions. We have a system that is not working. In the Cargo Cult arena, the FDA is a blind person in charge of verifying the airplanes arrivals. The drug companies work on creating the sound and smells of airplanes landing. The blind FDA must rely on honesty. That is not science. The FDA is not a scientific organization. They hold meetings and talk but they do not practice the art of science. As such, we must now officially label the FDA as a charter member of the Cargo Cult Scientist.

Wednesday, October 11, 2006

Bad News for Medivation


The UK government will move ahead with plans to restrict the use of drugs to treat Alzheimer's disease to patients with moderate symptoms, according to the National Institute of Health and Clinical Excellence (NICE).

In a statement, NICE chief executive Andrew Dillon said: "we realise that today's announcement will be disappointing to people with Alzheimer's and those who treat and care for them. But we have to be honest and say that based on all the evidence, including data presented by the drug companies themselves, our experts have concluded that these drugs do not make enough of a difference for us to recommend their use for treating all stages of Alzheimer's disease."The ruling, due to come into effect in November, affects the cholinesterase inhibitors on the UK market, namely Eisai/Pfizer's Aricept (donepezil), Shire's Reminyl (galantamine) and Novartis' Exelon (rivastigmine).

Head of Oncology, Craigslist 10-11-06


Where do you go when you want the best? That's right, craigslist.

The relavence of the picture is this. You have money to fight cancer. All you need to do is put the right people in the right place. Think of the blue truck as the head of research. You've been told to get someone in that job. Think of the garage as the job... you get the picture?

This is the first paragraph of an ad placed on craigslist today.

Head of Research Oncology

Creates, implements, and leads research strategies for target identification and validation and therapeutic candidate identification in oncology. Works closely with Development to define and implement a global strategy for oncology pipeline development and growth of the oncology research department.

They're look'n for a PhD or MD/PhD ' 10 years min industry experience in Oncology drug discovery.

There is no cure for cancer yet. But don't worry, we're putting the right people in the right places. Don't give up those cigarettes and that lazy lifestyle just yet. Help is on the way. (see photo). Ha ha ha...

A Few Pictures Might Help


Time to start adding color and pictures and links. I've got the color.

Ken Keseys magic bus. See Cargo Counter Culture. Get on the damned bus!






And drop out of the mainstream science business!
http://www.uow.edu.au/arts/sts/bmartin/pubs/92prom.html

As Richard Feyman said, "So I have just one wish for you--the good luck to be somewhere where you are free to maintain the kind of integrity I have described (READ CARGO CULT SCIENCE), and where you do not feel forced by a need to maintain your position in the organization, or financial support, or so on, to lose your integrity. May you have that freedom."

It's here on the Cargo Cult Scientist. I give you the freedom. Climb on the bus and lets take a ride. Your degrees, titles, credentials, or anything, don't matter here. Do you have something to say that is the truth? Do you think the rest of the world is ignoring that truth? That's what this bus is for. Even as it deteriorates in Keseys front lawn, it stands as a symbol for people to open up and do what they think is right. Enjoy your life. Speak your mind. Don't worry what others may say.

Monday, October 09, 2006

Academic Inflation

When I lived in San Francisco times were tough. They were tough because things were booming down in Silicon Valley. The dot.com explosion at one point was minting 60 new millionaires per week. All that wealth had negative consequences for those of us without a dot.com job. If you lived in a nice little house, you had to move to a nice little apartment. The resident of the nice little apartment had to move to a crappy apartment. The resident of the crappy apartment had to move to a hotel on skid row. The skid row hotel renter was out on the street.

This effect can be seen in education as well. Years ago, if you had a college degree, you had a job. If you had a PhD you were considered an important person. Flash forward. A college degree is required to be a cop. The guy whose father was a cop now has to shell out tens of thousands of dollars and four years of his life to do what his dad did right out of high school.

If you have a bachelors degree, no one is taking that to mean that you have any skills or knowledge. Many jobs in biotechnology for example are as mundane as anything job in a factory in Omaha Nebraska. Can you run an HPLC? In spite of the requirement to learn the equipment in college, no on believes that this education in any way prepared you to operate this piece of equipment. If you don't have a years experience using it in the biotech/pharmaceutical business, you are incapable of learning how to use it in any feasible amount of time. The same goes for LC/MS and all of the other techniques used in biotech research.

These techniques are merely tools to be used in research. With the increase in PhDs and other degrees, it is not unusual to find PhDs running HPLCs and LC/MS as a profession. In essence, the PhD in chemistry or biochemistry is a vocational degree. What does it take to actually conduct research? Will we have to start accumulating PhDs behind our names? Is one just for whimps. It takes three to be somebody?

How They End

Just a quick example of how a Cargo Cult ends. Not a lot of attention is given to the end of a multi-million dollar failure but here at the Cargo Cult Scientist we believe that there is always something to learn from trying. If you fail you have to understand why or you are doomed to fail again. The Cargo Cults of biotechnology have not learned this lesson yet. If they did, they wouldn't be looking for experienced executives. In the biotech biz, experience means failure.

Astralia LTD is a company who has ran out of money. Unable to obtain further funding for their efforts, they are forced to cease operations. Their main candidate was against psoriasis, which is on the list posted previously (in the pipeline). Like Medivation, most of their smashing success occured long ago in a country other than the one they are currently working in. They were not approved in the old country prior to coming to the U.S. The inventor has a PhD and M.D. The have a website covered with happy healthy people and a couple of white lab coat wearing individuals. They will be forced to cease operations in a few days.

After the majority of the people leave the HR director will follow the CEO out of the building. They'll go to Applebees for a drink. They won't blame themselves, but rather the investors and others who did not do their job as well as they should have. A liquidation company will come in and set to the task of selling off everything they can. Phones, desks, pipettes, faxes, HPLCs, cabinets, electrophoresis apparati, and every last thing that has value. At the auction everything will be laid out for easy inspection. The bidders will have a form to fill out to make their offers. The financial officers of the company will approve the big sales and the investors will split the take. Not what they were expecting but they did try. Why didn't the planes land? They did everything right. The disease was a lucrative one. The drug worked so well in phase I and II trials. Where are the planes?

Where are the want ads?

Sunday, October 08, 2006

Chief Cargo Cult Scientific Officer, CCCSO

I went down to San Diego to use the latest technology for counting cells. It was a flourescent microscope, some fancy robotics and software. It didn't work. The limitations were not the machine but rather the techniques used to stain cells. We went into a large lab space. It was empty. Like so many other biotech companies I had visited, this was a dying enterprise. There were a few men in a board room discussing business. In the empty lab there were three of us. We were about to try and use the machine that was the only product of this company. It didn't work.

About two years later one of the men that was in the board room was now the Chief Scientific Officer of the company I was working for. When your job is to run an RNAi project I suppose you are as much of an expert as anybody. The CSO was previously working on a flourescent microscope. Now he was an RNAi scientist. Since these guys never enter the laboratory, this made sense. RNAi is easy to explain. It's unproven and thus there will be little flack from those who can throw other failures in you face. But no amount of experience can make the RNAi ship sail. The CSO's job was to convince investors and other cubicle scientists that we had a product in the RNAi world.

If you look at the biotechnology companies trying to make RNAi products, my old company is still high on the list. Our old CFO was fired and went to a company called SIRNA, as in short interfering RNA. I guess he was an RNAi financial expert. Make sense? My old company is different than a lot of other companies. They are one of the fastest growing companies in the area. While other companies were cancelling their RNAi projects, we were hiring. Our new CSO was reporting amazing results from an RNAi experiment that involved 3 mice. An experiment with an N of 3 caused quite a bit of exitement among the biotech cargo cult scientists and our CSO was turning heads. Not bad for a man who left a sinking ship that specialized in counting cells with a microscope/robot/computer.

This week there will be an announcement from my old company company. The CSO is "retiring". That's corporate talk for being fired. Because he was an older gentleman they will try and use the angle that he is retiring. He's been fired. RNAi doesn't work, CSO doesn't work. Working in these Cargo Cults has never been easy.

The departure of the CSO should send chills down the spines of the investors. If they knew enough they would have to wonder about the stability of the research. Why would the leader leave? What does the laboratory staff do while a new CSO is sought? A man who made over 300 thousand dollars a year shoud be sorely missed. But this is RNAi. Whether or not you've got no one or Watson and Crick in that position, the drug will not work. Might as well retire and enjoy your life.

What did this CSO do in the course of his life. He has numerous publications. None of them was powerful enough to provide a steady income. The CSO had to move from state to state. For awhile he worked in San Diego and lived in Northern California. He'd fly home for the weekends. But the pay was high. Higher, at least, than the normal pay for someone who actually provides a product or service. It is pay to sell a companies image of a product or service. It's pay to convince everyone that the planes are on their way. As a high paid PhD scientist he knew what others could not. But now he is gone. The CEO and the board no longer care. They told him what to think and he did a bad job at convincing them that they were correct. Such is the game. Another couple of years, another job. How long can these cults last?

Tuesday, October 03, 2006

The Cargo Cult Cargo (The Pipeline)

In order to have a successful run at a Biotech company you don't need to produce a product. As an individual with a PhD or M.D. you can make more than your counterparts in adacemia or in hospitals by working at a biotech company. Your salary, bonuses and stock options will provide you with a nice life until the company goes down. Then you've got the experience needed to land the next job. Make sense?

What are the diseases the Biotech favors? We've talked about the websites and the hubs meant to attract biotech. What areas of human affliction capture the attention of biotechnology? In other words, what kind of cargo are they looking for? What airplanes would they like to see land? The following is a list that comes from surfing the internet to find the patterns formed by Biotech interests. Me thinks money might have something to do with the general pipeline.

Cancer: It's a tough one but a cure is not needed. Paclitaxel is the active ingredient in Taxol. One way of adding a drug to your pipeline is to modify paclitaxel by adding sugar or some tumor targeting molecule. It's been done and the result was one more billionare to the list of filthy rich human beings on this planet. That kind of promise will get your investors purse strings loose. Monoclonal antibodies against cancer proteins are also an easy way to go.

Obesity: Let's face it, we live in a fat country. We're fat because we eat too much and exercise too little. People want a way around that reality. They want a pill. Ka Ching.

Inflammation and arthritus: As we grow older we suffer from stiffness in our bodies. Everyone will want a pill to ease the pain of a stiff knee or a sore shoulder. By classifying these common afflictions of growing old and lethargic as diseases that pills can treat has provided a gold vein in the hills of the human condition that is just beginnig to be tapped.

Alzheimers: This group of sickos can live on for ten or more years. They won't be able to tell you if the drug is helping or not

Type II diebetes: Caused by poor lifestyles. Priime target to sell pills to.

Pain: What comes after aspirin and ibuprofen?

Osteoporosis: Women are afraid of this one. You've got half the population to work with.

Psoriasis: A lot of inflammation drugs can be funneled into programs that work on this condition. It's an easy target where little is expected. No one is going to die but the market is big.

And so we look to the skies for these airplanes to land. Their cargo is money! That is what we really want so we can go out and buy things that are tried and true. Houses, cars, travel, and on and on. It's a beautiful world. You've got to find that one angle and you are in. The paths have been beaten flat. Take the walk. It's not like you have to use science to make discoveries. Just go.

Me and RNAi

RNAi is too good to be true. We live in an era where we want things now. In science we have created a situation where a young researcher must publish or parish. That doesn't give one much time to go out and make a knock-out mouse. The skills required to make the mouse, along with the resources, puts such a project out of reach for someone who has 4 to 6 years to complete a PhD and get a few publications under his/her belt. Along come RNAi. You can buy the RNA, grow some cells and run whatever asssays you would like to demonstrate what it was you had set out to do.

My first experience with RNAi came when I joined a failing bioinformatics company. They had software that identified proteins in pathways not formerly suspected of being their. Of course, none of the protein I was asked to knock out were identified by the software. I was asked to knock out IL6 because it was a favorite of the new CSO who came from a large company that just ended his project in osteoporosis. My job was to knock-out IL6 in RAW cells. To measure the effect I had to stimulate osteoclastogenisis by adding RANK ligand and wait until the RAW cells formed osteoclasts. Once this occured in the negative control (scrambled RNA) I had several assays. First I had to keep track of cell viability. Second there was an assay for tartrate resistant alkaline phosphatase (TRAP). Lastly, I had a bone pit assay that measured the formation of osteoaclasts from the RAW cell precursors.

As everyone who wears the white lab coat can tell you, you start by checking on several transfection reagents. The best one is measured by the best knock down. As a technician things are getting busy. You also have cell cultures that need to be kept in an incubator. One day however, it all worked. Cell viability was the same for scrambled and my chosen siRNA. The TRAP assay showed no TRAP activity in my siRNA but the usual activity in the scrambled. The plate where the osteoclastogenisis assay (pit assay) was taking place showed osteoclast formation in the scramble siRNA group but none in my siRNA treated cells. Eureka! Every assay had worked out. And I was never able to repeat this work again.

What I later discovered was that TRAP activity (using our assay) produces a bell curve over the course of a 5 day assay. Sometime around day 4 the RAW cells begin to rapidly join together. As this occurs there is an increase in TRAP activity right on the cell surface. This correlates with pit formation. I had a control in my experiment but I could (in my head) justify what had happened by imagining a slight delay in how the osteoclastogenisis occured. It only happened in that one experiment becuase I was never able to repeat the results of the first experiment. Others tried as well and were equally unsuccessful. As a laboratory person who really wanted to know what the hell had happened, I tried over and over. I looked at the cells throughout the five day period that it took for them to become osteoclasts. I let them grow for 7 days, for two weeks! I wanted to know everything about how these cells grew. I started several cultures all at different amounts of cells. Cell density at the beginning was critical for getting osteoclastogenisis. Each new osteoclast that (formed several raw) cells put the nuclei from the individual cells together in one region located on one side. On the other side was where most of the TRAP activity could be seen. A pilus formed and reached out to pull in more cells. In this pilus TRAP activity was high. There was a lot going on.

Back in the offices the scientists were busy trying to save the company from running out of money. They took the data from the first experiment and sold it like RNAi was just one of our little tools that can validate the software. Of course, IL6 was not a target identified by the software but that wasn't the point. The point was that we had a tool that we could use. So we tried. None of the targets were known to be in a pathway which made it added more assays to the mix. As money got low we skipped the assays for the known proteins and measured those in the pathway that we were trying to associate with our knock-out. Nothing worked. The company ran out of money and I had to move out of town because there was no work for me in that area of the country.

I moved up north where the new company I worked for was running RNAi experiments. The CEO was convinced that this was the next big thing and he wasn't going to miss it. They ran the transfection experiments. They struggled as we did with the results. Is the RNA in the cells? Why isn't the knock down lasting forever? When do we measure? What should our measurements be? Should we use flourecent tags and a microscope? What are the most reliable assays. In general, they were left to dream up their own assays to show that it was working. This is not PCR where you are promised more DNA and you get more DNA. This is RNAi where you are promised less protein, and you get... slightly less sometimes for an unknown period of time if you use the right piece of RNA with the right transfection reagent. Whatever. Leave it up to the white lab coat people to show up to the meetings with the proper data to tell the story.

This project is all but dead now at my last company. They have since bought another company who is using siRNA to fight the bird flu. The first thing I saw after they bought the company and the bird flu siRNA license was an advertisement for a scientist who has experience with the bird flu and siRNA. If the technology really worked, you don't need a scientist with expertise. The real work would be done in the cells. You need only set everything in motion. You would need expertise in cell culture and handling dangerous viruses. You would need to know how to set up assays. But Cargo Cults are looking for the proper forms. RNAi is a form for a Cargo Cult. It now has a Nobel prize behind it. Let us now sit back and see the real benifits from RNAi. So far, the benifits have come to companies who sell RNAi research materials. What has come out of the research? Papers. And that is what really matters to the modern day scientist. To the non-scientists/non-cargo cult member, what can we make of these papers? Has anyone done anything yet? It's hard to tell.

Monday, October 02, 2006

RNAi My Ass

I've talked about this before. RNAi is too good to be true. When we begin to look at the cell we take the route that an astronomer takes, only instead of big we have to think small. We have to think short distances. We have to think about microenvironments within a cell that could be as different from each other as the atmospheres of Mars and Earth. Sometimes however, we just look at the data that comes from an ELISA or RT PCR and we apply it to our whole universe. We don't think about internal standards or other kinds of controls. Sometimes we look at the data we get and say, "good enough", and the theories start flying. One thing you can say about cell biology people, they are creative. It's paid off in the past, but overall we've got a lot of bullshit.

I'm not classifying myself as a scientist these days. I look at scientists as professional people who apply for grants and work in offices. The lab is the last place you'll find a modern day scientist. They do not need to figure out nature. They need to figure out human beings who work on grant committees and nobel prize committees. I believe the laws of evolution apply to the business of science. Those at the top are those who best understand the human mind and how to best manipulate. It also takes some dishonesty when all else fails. To really get into the measurements of DNA to RNA to protein requires hands on experience. You've got to get in the hood and see the cells that you've transfected. You've got to run the assays that measure RNA and protein levels. Modern day scientists simply don't get that close to the biological organisms being tested nor the equipment, chemistry, and software employed in the data collections.

In the case of RNAi, we simply can't measure the activity of a piece of RNA as is appproaches a cell, enters the cell, makes it's way to the microenvironment where a homologous gene is being expressed, and how it breaks up the process. This process, gene expression, is the essence of all life. The measurements we make to measure gene expression are not hard science. Chemists and physicists practice hard science. They have given us Avagadros number, rates of reactions, limiting factors, the effects of heat and pressure, closed and open systems and so on. When you get to the science of gene expression we have yet to get down to the hard questions. We have no way to measure the mols of mRNA made from DNA and how many mols of protein they make. We don't know much about the effects of temperature, pressure, and pH in the microenvironment where gene expression is taking place. How do we change the microenvironment when we add RNA swimming in a transfection reagent?

The use of antisense RNA to interfere with a gene's activity in C. elegans was first utilised by Su Guo and Ken Kemphues to study par-1 ; however, it was reported that control sense RNA also produced a par-1 mutant phenotype (Cell 81: 611-20, 1995). Subsequently, it was discovered by Fire et al. '98 that it is the presence of dsRNA, formed from the annealing of sense and antisense strands present in the in vitro RNA preps, that is responsible for producing the interfering activity. The concept thus, had already been dreamed up. Add RNA and watch the gene product disappear. The small interferring concept was an intuitive idea of throwing an incomplete and unwanted piece of RNA into the machinery that turns RNA into protein. Fire and Mello were at the right place at the right time.

Technology is the application of science. So far, applying this science has not been very successful. Most companies who began using siRNA have ended their programs. Kary Mullis won the Nobel prize in 1993 for dreaming up PCR. There is no denying that when you use PCR, you have more DNA than when you began. When you use RNAi, you've got some serious questions about whether or not you've got less protein. We don't know exactly which piece of the mRNA makes the best siRNA. We have questions about loops, methylation, number of nucleotides, transfections reagents. Each lab will use it's own protein quantitation method. Some will try RT PCR to measure mRNA levels but there is no reproducible method. If you work in the laboratory, you may have seen a knock down effect. You may have had all the controls needed. But do you really know how well it worked? Can you do it again and again and end up with a knock out that has a margin of error that is significantly small? Too many soft areas of molecular biology and biochemistry are being exploited here.

The ability to control gene expression is something known by the cell. We do not yet know how to do it. We have seen an effect by adding pieces of mRNA. What exactly the cell is doing when exposed to the RNA is not well known. We still are limited in our measurements. If we truly could measure accurately AND use RNAi, we would be better off mapping out metabolic pathways. We could learn about turning genes on and off. We could learn about protein functions like cell cycle regulation. Instead we are throwing RNA at genes of well known drug targets and trying to get a new drug on the market. The ability to use RNAi will soon tell the real story of this discovery. It will fizz out. It's not powerful and not worthy of the Nobel prize.