The Arrivals

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. -RF

If we could make one change that could turn the cargo cults into real airports it would be to create a place where the results of all experiments are published. In Cargo Cult Airplane terms, what cargo planes were scheduled to land and did they report on the landing? If you are looking for a big deal struck between big pharma and biotechnology (the departure) you will have no problem finding the publicity. If you are looking for the results of a big pharma/biotech deal you will have to begin conducting research.

Let's look at a deal between Pfizer and Scripps back in 2006.

Under the terms of the agreement, Pfizer will pay Scripps Research $100 million over a five-year period, during which time scientists from Pfizer and Scripps Research will work together to identify and perform specific projects of mutual interest.
Pfizer will pay Scripps Research milestones and royalties on therapeutic compounds created through the collaboration. In addition, Pfizer will have the first right to license many discoveries made at Scripps Research during the agreement.

This particular deal was given journalistic coverage by the San Diego Union Tribune. (Beware the trade PR publications such as Fiercetech and Xconomy)

Pfizer would pay Scripps $20 million a year for five years, he said. Scripps would have full control over how the money is spent.

In return, Scripps would give Pfizer the right to review all of the institute's discoveries, plus the right to license up to 47 percent of them. Pfizer would be able to make such actions only during the five-year funding period.

In order to evaluate the results of this collaboration it is important to know that Pfizer was given access to all of Scripps publicly funded research, not just the work initiated and researched during the five year $100 million deal. It makes the 2011 arrival time even more interesting.

The Pfizer deal replaced Scripps' controversial 10-year alliance with Novartis. The institute came under scrutiny in the early 1990s after the NIH questioned aspects of its initial deal with Sandoz Pharmaceuticals Corp., who later became Novartis. According to the Union Tribune:

During a congressional inquiry, federal officials said the agreement gave Sandoz too much control over Scripps' research priorities, stifled academic freedom and prevented smaller biotechnology companies from competing for access to Scripps' scientific discoveries. The partnership allowed Sandoz to license nearly all of the institute's inventions.

Some legislators suggested that the Scripps-Sandoz deal made the federal government, through its grants to Scripps, a patron of a foreign corporation.

We certainly don't want that to happen. We want pills that make people better when they get sick. After the Scripps-Sandoz partnership, the NIH established policies to clarify how institutions that receive its funds should enter into licensing agreements with for-profit companies.

The institutions' responsibilities include:

Preserving the academic freedom of its scientists.

Ensuring that findings based on taxpayer-funded research are disclosed in a timely manner.

Not entering into agreements that permit a corporate partner to acquire exclusive licensing rights to a discovery without plans to actively develop and commercialize it.

Promoting the manufacturing of its products in the United States.

That is a positive outcome, although not the one intended. A cargo plane landed here, bringing with it a new set of rules. If you are a drug exec or a politician in charge of funding massive organizations like the NIH, this is cargo. This set of rules effects how you do your job. It effects how scientists do their jobs.

What did we get from this deal? What did Pfizer get? One benefit was offered up from the citizens of Palm Beach County Florida. They ponied up $310 million to get Scripps to set up shop in Florida and bring with them high paying jobs. A quick Google search finds a story of hope via the Pfizer deal and an unrelated spin-off from Scripps, Xcovery. On their website Xcovery lists one job. Scripps Florida lists 3 jobs. 4 jobs currently available after $410 million. Are both investments drying up or was there a surge in hiring and thus scientific progress is ? We can't say.

Another potentially related story, "Scripps Research/Pfizer Team Produces a Potential New Painkiller". The team reports on the promising new compound in the April 24, 2009 issue of the journal Chemistry & Biology. The Cravatt group began collaborating with Pfizer in 2003 however to pursue, among other goals, development of fatty acid amide hydrolase (FAAH) inhibitors. This collaboration (began in 2003) led to the discovery of a promising class of inhibitors known as piperidine ureas. This potential painkiller appears to have been sold off as a research tool and can be purchased at various chemical companies. Although not a blockbuster, this is scientific progress. This is a cargo plane that landed with an alternative cargo. It all began in 2003 however.

What really became of this deal? The extensive Pfizer pipeline may contain candidates from this collaboration. Novartis may have picked over the carcass leaving little behind after their ten year manipulation of scientific activity at Scripps. For the Cargo Cult Scientist, this is where research begins. If you want to know what the leaders have been up to you start with a press release. You wait the advertised amount of time and you draw a conclusion on what happened. It really is no different than a laboratory experiment. But who is conducting this research? The NIH and Pfizer executives are the foxes guarding the coup. Quite often a failing project begins to lose favor and piece by piece it begins to disappear. Which brings us back to Feynmans rule of reporting results regardless of outcome. By simply trying to evaluate the outcome of a $100 million dollar deal, we begin to see the complexity of such a human undertaking. Yet we know it is being done everyday by some group of people. They are who we are studying in this research project. What did they do with the money and how are they reporting the value of the investment?

If in fact the drug industry has lost over a trillion dollars in the past decade, this $100 million deal is small potatoes. It tells a story however. Each deal tells a story that is fascinating and worthy of research. There is the psychology of the major players. The structure of scientific research organizations can be studied. Did the Pfizer/Scripps deal solve the productivity issues facing big pharma/biotech R&D?

Greatest Loss of 2011

Daily Hitchens: UK Channel 4 Tribute

Imagine an articulate curmudgeon who would dedicate his career to fighting the abuses of scientific authority. Who is the Christopher Hitchens of the scientific community?

While Hitchens was no scientist, he was a brave man who derived his courage from the truth. When you believe you are on the side of the truth, regardless of the accuracy of your assumption, you are empowered to speak up. Hitchens relished a good argument and made a living out of speaking up. I don't believe he engaged in any Cargo Cult intellectualism.

We could use a man like him in our ranks. It would be amusing, as we look to the sky for our Cargo planes, to hear a lone voice, slightly inebriated with a British accent... "They're not coming you God-damned fools!"

"Beware the irrational, however seductive. Shun the 'transcendent' and all who invite you to subordinate or annihilate yourself. Distrust compassion; prefer dignity for yourself and others. Don't be afraid to be thought arrogant or selfish. Picture all experts as if they were mammals. Never be a spectator of unfairness or stupidity. Seek out argument and disputation for their own sake; the grave will supply plenty of time for silence. Suspect your own motives, and all excuses. Do not live for others any more than you would expect others to live for you.” ― Christopher Hitchens

Most Signficant Fire Burning Out in 2011

In January of 2010 Alan Sachs of Merck was interviewed about SIRNA, a subsidiary of Merck who specialized in RNA interference. SIRNA was purchased for 1.1 billion dollars. Before the end was announced they had burned through 1.5 billion dollars. Alan Sachs was their leaders and well aware of the hype:

My background in molecular profiling was around when the Human Genome Project sequence came out in 2000 and 2001, and living through that bubble. What you realize is that the essence of the excitement is correct, and the reduction to practice may make it less-than-anticipated, but it’s still real. The same thing will be true of the RNA therapeutics space. There is a lot of expectation and anticipation. The reality will be somewhere between that and zero. We’d like to think because of the experience we have in our company that we have a clear line of sight on what’s practical within a certain time frame.

This will settle down. The acquisition of Sirna by Merck really set this thing off. We’re three years past that. I think in two more years, you’ll see this settle down, much like in the genomics space. In genomics, many of the opportunities consolidated into a few big players. The same thing will happen here. But the big companies like Merck, Roche, Novartis and Pfizer, that have committed to do this, ultimately will be there. Because of the long-term potential of the modality, not the immediate potential, but the long-term potential. It’s huge.

All of the companies mentioned have ended their RNAi programs, including Alan Sachs' Merck. Alan was correct, It was a huge promise. A huge investment followed and a huge fall from grace has finally been completed. Among the Cargo Cults, Merck had the biggest RNAi airport.

Some investors still believe there is a pot of gold at the end of this rainbow. Here is why the CCS places the science into question.

The talking point among RNAi sympathizers is that monoclonal antibodies had likewise been left for dead back in the 90s. The difference however is that RNAi is a nucleic acid therapy like gene therapy. It is different than protein therapy. The diagrams and animations that depict the mechanism of action (MOA) of RNAi failed to depict the delivery of the small RNA pieces to the gene expressing cell targets. It offered a crisp clean MOA that had the same end result of monoclonal antibody therapy, a reduction in the amount of a specific protein. Without changing the highly simplified approach to biotech research, office bound PhDs ordered their white lab coat staff to run the same ELISAs and western blots to demonstrate knock-down. As a white lab coat staff member, I worked through a microcosm of what was to come back in 2002. My first blog post on RNAi was on May 10, 2006. After four years of thinking about RNAi, working with RNAi, watching others work with RNAi, and most importantly, watching the Cargo Cult leaders deal with the lack of efficacy in RNAi, I had come to the conclusion that this stuff is snake oil. That was several months before Merck bought SIRNA.

Since RNAi didn't work very well in the laboratory, it seemed preposterous that it would work in the clinic. The pharmaceutical industry relies heavily on pharmacy and much less on pharmacology. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies the effects of the drugs on biological systems, and the latter the effects of biological systems on the drugs. In broad terms, pharmacodynamics discusses the interactions of chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion of chemicals from the biological systems. In contrast, pharmaceutical research is primarily concerned with preparation, dispensing, dosage, and the safe and effective use of medicines. Biotech and Big Pharma leaders put up the money to put RNAi through the latter forms of research. The lack of efficacy left RNAi companies scrambling to explain why RNAi wasn't panning out as a drug. Delivery of the little pieces of RNA to a cell that was actively translating the drug target became a hot topic. In other words, they needed to get a handle on the pharmacology. Delivery of the little pieces of RNA was the reason the leaders decision making had hit a snag.

Currently, delivery of little RNA pieces remains the missing link to the promise. It keeps the promise alive. If the pharmacology techniques were in place we could check on the likes of Alnylam and Tekmira. We should not take their word for the promise of SNALPs, Stable-Nucleic-Acid-Lipid-Particles. We should have a separate organization that works for the FDA and the NIH. This group of scientists would development methods ahead of time to test the claims of for profit organizations who can both profit and cause harm. Other possibilities with RNAi is that they can do no good or they can help what ails us. The important thing for scientists to work on is in the development of a science that will help evaluate claims.

In July of this year Merck ended their RNAi efforts after 5 years and $1.5 billion. They claimed that this was a difficult decision based not on science but on financial needs for the Merck corporation. As usual a learning opportunity was lost. As Feynman said;

In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.

It is our biased opinion here at the CCS that 2011 witnessed a most significant ending to biotechnology's biggest promise of the past decade. I didn't present any data that might have suggested that RNAi works. I left that up to the experts who still claim that RNAi works. As far as putting ones money where ones mouth is, the verdict is in. RNAi is not moving forward in the world of BigPharma.

Here at the CCS we began in 2006 with a strong opinion and we end in 2011 with the same opinion, backed by a huge failure of RNAi in biotechnology and BigPharma. Alan Sachs was right, the promise was huge. That is why the failure is also huge. Huge shifts in thinking are fun places to be in science. Not just in the beginning, like those who jumped on the RNAi bandwagon, but in the end like those who kept the story of N-Rays and cold fusion alive. We have much to learn in the psychology of Cargo Cults. It remains and area in the philosophy of science that is itself a mystery. How do these things happen and why are so many people successful leading failures? What RNAi has taught us is that, in fact, science corrects itself. How do we stray from the truth and how much work goes into correcting ourselves?

Don't believe in the hype of a trendy science story. Believe in the truth. As Alan Sachs would say, there is power in the long term potential of the modality.

RNAi Strikes Again

It appears that the only thing RNA interference has accomplished thus far is a whole lot of disappointment. After my first RNAi experiment worked I was on board. We knocked out IL2 which led to an inhibition of osteoclast formation. Of course that was early on in the research. I later came to the conclusion that the inhibition of osteoclast formation was a fluke. Did I forget to add RANK-L? Would another day of observation have resulted in a full bloom of osteoclasts? As is normal in unreported science, the result was unclear. The probability of what we were hoping for (RNA interference) seemed to diminish with each new attempt at repeating the IL2 knockout.

The company I was working for soon ran out of cash and shut down having never repeated that experiment. Many laboratory workers tried but none could reproduce the results of that simple experiment. The way this type of science works is to have a desired result or even better, a one time observation, and force it to be the truth. The Beer and Pizza diet began. What concentration of RANK-L was used? Where did you buy the cells? Different technicians were brought in to overcome the incompetence of the last. All the while our successful experiment was presented to the investment world in 3 perfectly understandable slides. Just add RNA and away goes osteoclastogenesis.

The reason we went after IL2 was because we were a Bioinformatics company. We alone made the connection of IL2 to the RANK pathway using Bioinformatics. For that brief moment of success, we had added laboratory evidence. It brought out the worst in everyone. We needed this to be true. Our company was hurting and eventually filed for Chapter 7 bankruptcy. If IL 2 had become a drug target for Osteoporosis it would have changed everything.

RNA interference and IL 2 research continue however, with expected outcomes. AVI Biopharma (self proclaimed global leader in RNA based therapeutics) is axing 28% of its staff after missing out on a potentially huge federal contract to make an RNA-based treatment against pandemic flu. RNAi is also used by Dr. Steven Elledge.

Using the power of small interfering RNAs (siRNAs) to silence gene expression, we are now undertaking loss-of-function screens in mammalian cells.

Why is such a powerful research tool involved in such a curious story as the one coming from Dr. Elledge's laboratory?

IL 2 is in the news lately with a new retraction from the Bulfone Paus saga.

RNAi and IL2 research could one day lead to important information that will advance the life sciences. What I do is merely research. We find pieces of evidence and we try to figure out what is really going on. The complexity of a pathway is not simply understood by knocking out one of the many proteins involved. Nor is the complexity of RNAi understood by witnessing the many cases of gel manipulation in major publications from Harvard professors. It is odd but not direct evidence that RNAi does not work. IL2 is involved in a few sketchy cases of misconduct as well. It proves nothing.

All we have here is job loss and possible scientific misconduct associated with a couple areas of popular research being conducted by highly successful scientists. Are they Cargo Cult leaders? No comment. Is science correcting itself? Yes.

A Trillion

One of the interesting 2011 reports on the drug industry came from Burrill and Company. They made the claim that Big Pharma hasn't been doing very well.

During the past decade large pharmaceutical companies have pursued an aggressive strategy of mergers and acquisition in an effort to grow their businesses. But an analysis from Burrill & Company suggests the approach has been a failure as these companies have seen the loss of $1 trillion in value during the past decade.

We lost a trillion bucks in a decade? Those of us who enjoy math will stop and reflect on that number. For example, a million seconds lasts about 11 days. A billion seconds lasts about 31.5 years. To be exact, a trillion lasts 31688 years, 269 days, 1 hour, 46 minutes, 40 seconds.

In order to have lost a trillion dollars in ten years we would have to lose $100 billion each year or about $274 million a day.

What does it mean to lose that much money? In that decade I received some of that money in the form of an income. I also spent that money buying reagents and equipment. We paid Retrogen to sequence our DNA and Alphalyse for protein sequencing. While that money was being "lost", others were finding it. Some companies, like Retrogen and Alphalyse, were smart businessmen and women and they positioned themselves to be in line for some of the biopharma largesse.

My car has aged and is now worth less. The value was in fact lost. During the course of the devaluation I enjoyed the usage of my car. It had value and still does, just not as much. Likewise, BioPharma has aged and decreased in value. Unlike my highly reliable Honda Accord however, this baby was a lemon. One of the experts you would trust to make sure you don't pick a lemon is Cargo Cult leader biotech visionary G. Steven Burrill. As the industry was busy losing a trillion dollars G. Steven Burrill was succeeding.

During the course of the trillion dollar loss G. Steven Burrill must have given a warning. Leaders know that losing a trillion dollars is not the goal of any investment. We couldn't actually find any warnings that a trillion dollars was going to be lost. Did G. Steven Burrill succeed in spite of the loss or as a result of the loss? Was the industry loss his gain? How do the Cargo Cults select their leaders when the planes never land?

Prior to the loss of a trillion dollars there were warnings.

Biotech losses 94 to 04

biotech losses 90 to 93

Then came the new millennium.

biotech job losses 00 to 11

To G. Steven Burrill I offer up a different kind of award. The first ever Lifetime Achievement Cargo Cult Leader Award.

A leader is a dealer in hope.
Napoleon Bonaparte

The first ever Annual Cargo Cult Scientist Awards are coming! Silvia... you're getting one. The rest of you will have to wait and see.

Don Polderman

One of the things I do from time to time is check the stats on my blog. Most recently I've been getting a lot of hits from people typing Don Polderman into their search engine. There are people who want information. What has Don been up to lately? Has he found a new job, issued some statement regarding his dismissal, published a new paper, invented a new drug, started a biotech company... But a curious thing is happening. If you type Don Polderman into Google, the Cargo Cult Scientist is third on the list!

Are people concerned about the impact of a scientist who published over 500 articles and was fired for scientific misconduct? Are they willing to talk about it? Why hasn't this incident generated a public discussion?

My answer to that question would be cynical. I would cast dispersions on the world of science. I will join the rest of the scientific community who type his name into Google and stumble across this crazy blog. I will skip a detailed research project into the impact of Dons Sins Against Science.

This blog is really about the scientific method. The method can be applied to finding out whether or not your kid is lying to you about brushing their teeth. It can be used to find out if a drug can be manufactured at a 50,000 liter scale or if that drug is useful in treating human disease. The method can be used to find out how much BS Don Polderman has put into the scientific discourse. But professional scientists talk like Don. Judging by the amount of publications, Don was very good at talking. Now we have more information on Don however. Somewhere between the proper application of the scientific method and the kind of scientific misconduct Don Polderman is accused of lies the truth. Was he an outright fraud? Did he really make unintentional mistakes? Is it worth finding out? What about those 500 papers. If they were worth publishing in the first place, is it worth revisiting them? Why, at this point in Dons career, are we abandoning the scientific method? In our opinion now is the most important part of a scientists career to be analyzed using the scientific method. Instead we will brush this one under the rug.

Don Polderman will fade away. But here at the Cargo Cult Scientist, we will hold him in high regard as one of our leaders. Our airports do not bring in cargo. Our airport is a place where people who have no idea how airplanes operate (or even where airplanes come from) become experts in airports and airplanes. The tribesmen are suppose to be obedient and not talk about embarrassing moments experienced by our leaeders, best described in The Emperors New Clothes. We don't know where airplanes come from. But some of us know that our leaders don't either.

A Tale of Two Janets

Janet had an important job. Unfortunately, just as she was about to wrap up the show, her boob fell out. The exposure was an embarrassment to those who placed their confidence in her. The exposure of that one boob led to a Congressional investigation!

Of course I'm talking about Janet Jackson, not Janet Allen the director of research at the Biotechnology and Biological Sciences Research Council. Janet Allen had an important job as well, director of research for the Biotechnology and Biological Sciences Research Council. She finished her career there with a boob exposed in the form of a former PhD student and world class Cargo Cult Scientist Alirio Melendez. There was no federal government investigation into her culpability in this boob incident however. She let this boob out into society. This boob should have turned her face red and sent her scrambling to find a solution to reversing the damage that was done. Instead:

Douglas Kell, chief executive of the BBSRC, publicly thanked Professor Allen for her work at the research council. He said her "leadership and personal drive" had led to "noteworthy" contributions to the delivery of every aspect of the organisation's strategic plan, including multipartner programmes and the move to longer, larger grants.

Contrast this praise with the fallout from Janet Jackson boob falling out. The NFL Commissioner Paul Tagliabue was apologetic before Congress! How much control would he have over such an incident? How much warning did he have that this boob would be exposed? Perhaps we need science commissioners to apologize and help make sense of our own boobs.

What Janet Allen did was have a successful career. She did increase her organizations grants and their duration. Who could ask for more? Well... I could. Did the planes land? What was the outcome of those longer more expensive grants? Who benefited most? I would have to say that it was the brass at the BBSRC.

Those of us who watched Janet Jacksons boob falling out at halftime of the superbowl on national tv had something to talk about the next day. It was funny to me and I knew there would be outrage amongst our conservative branch of society. Yet in science, we are not seeing that branch who are outraged by people who direct bogus research. We don't think they have any responsibility controlling rogue scientists who blatantly manipulate data and spin yarns in scientific journals.

And so we continue on with another saga in the Cargo Cults of Biotechnology. A director of scientific misconduct offers no apology. Janet Allen stepped down as director citing personal and private reasons. Her relationship to Melendez and the research they did together is not something she wants to revisit. Another unsatisfactory ending to a possible learning experience. I'm guessing we will see many more cases of scientific misconduct before we see another female breast on mainstream TV.

Geron Research

What is research? Wiki says, "Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method."

Geron conducted research into the use of human stem cells for use in spinal cord injuries. What we at the CCS would like to spend our days doing is conducting research into research. Measuring the measurements. We would love to learn everything we could about stem cell research. That is to say, we want to research the research. A prime target of our research would be the Roslin Institue and Geron.

The curiosity of Keith Campbells departure prior to the Roslin Institute selling their cloning technology to Geron followed by the failure of Geron to reproduce the work needs to be understood. Why couldn't Geron scientists do what Campbell could do? Campbell left the Roslin Institue in 1997. In 1998 Campbell in collaboration with PPL (Pharmaceutical Proteins Limited) created another sheep named 'Polly'. She was made from genetically altered skin cells containing a human gene. In 2000, after joining PPL Ltd, Campbell and his PPL team (based in North America) were successful in producing the world's first piglets by somatic cell nuclear transfer (SCNT), the cloning technique. The PPL teams based in Roslin, Scotland and Blacksburg (USA) also used the technique to produce the first gene targeted domestic animals as well as a range of animals producing human therapeutic proteins in their milk.

Geron finally called it quits last month. What went wrong? That is the research question is ask. What were there success stories and how did it all lead to nothing? My hypothesis is that scientists and businessmen do not think the same way. Both groups of thinkers wish to hold the title of scientist. The former adopt the title to help others identify their chosen profession. The latter want to make others think they are like the former.

Ultimately I am trying to get at the understanding of the thinking that separates a scientist from the rest of the human race. An example of scientific thinking comes from a comment given on the link to Gerons decision to hang up the stem cell research.

This company would not walk away from this trial in the absence of an unexpected complication or safety concern, if there was any evidence that it was working," said Dr. Daniel Salomon, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute in San Diego. "The assumption has to be that they designed a study with a purposeful plan to complete it to a certain benchmark of efficacy and that they had the funds for that effort in hand.

Then comes a concept straight out of the Cargo Cult Science speech.

Without seeing the data, one cannot be certain that there was not a clinical reason for stopping the trial," said Dr. Robertson Parkman, professor of pediatrics at the University of Southern California.

Indeed in the research of the research, the data must be seen. We must present all of the data, not just the stuff we want people to see. How could a researcher of research gain access to the data? Who would pay such a person to conduct such research?

The data is piled high but in that pile is Dr. Campbell and his successes. Geron scientists couldn't pull out what was necessary to reproduce the work. The executives steered the research into a profit driven R&D project that failed. The connection between cloning an animal and using stem cells for regenerating human tissue, organs and whole beings is there. That is a separate research project. What I am interested in is how we miss that connection and veer off into the cargo cults.

Like Poldermans 500 papers, the quantity of research is great. The quality is suspect. Stem cell research was and is overhyped. "Embryonic stem cells are not ready for 'prime-time,'" said Dr. Bryon Petersen, professor in the Institute for Regenerative Medicine at Wake Forest Baptist Medical Center. "There are too many variables about these cells that we just don't know about." How do we get to "know about" the variables? Certainly not by starting a biotech company and hoping to make drugs out of the cells. Science conducted honestly will eventually spit out a useful medical application. Pursuing a useful (profitable) medical application will most often not produce anything resembling science.

Avastin Oh Avastin

"Sometimes, despite the hopes of investigators, patients, industry and even the FDA itself, the results of rigorous testing can be disappointing." FDA Commissioner Margaret A. Hamburg

Hamburg said the choice was difficult because so many women and their doctors have put their faith in the drug and lobbied hard on its behalf.

"It does not improve survival," said Dr. Joanne Mortimer, director of the Women's Cancers Program at City of Hope in Duarte, who served on two of the three FDA advisory panels that debated Avastin's use for breast cancer. "Yes, it keeps your cancer under control longer. But … the risks are pretty huge."

They claim that Avastin will keep your cancer under control but you will have a higher risk of death from stroke or heart attack. The medication raised blood pressure and increased the risk of congestive heart failure. The risk of serious bleeding was five times higher among users of Avastin than it was for those on chemotherapy only. What about survival?

Hopes that Avastin could prolong life for patients with advanced breast cancer rested on a 2007 study in the New England Journal of Medicine. Researchers found that patients who took the drug in combination with the chemotherapy agent paclitaxel experienced an 11.8-month window, on average, during which their cancer was not growing. That compared with an average of 5.9 months of progression-free survival in patients receiving standard chemotherapy alone.

But even in that study, patients on Avastin did not live longer, said Dr. Kerin Adelson, a medical oncologist at Mount Sinai School of Medicine in New York.

A later study confirmed Avastin's failure to extend survival, and brought the drug's risks into better focus, Adelson said. (One of her own breast cancer patients who took Avastin had a massive stroke, she said.)

"Many drugs will improve the amount of time it takes for a cancer to grow but don't improve the amount of time a patient lives," she said.

Alas you would think that an interesting cancer research project would be born. Using tumor growth as an end point to a cancer drug development program is flawed. What could be a better approach? Avastin generated about $3.5 billion in sales in the United States in 2010. Sales have dropped since the FDA made it known that they were concerned about the risks and the lack of efficacy on survival.

That plane did not land. People still want to take it. At $5oK per year, that cargo plane should land and bring with it plenty of health and happiness for those running short due to breast cancer. Since it doesn't, we have to say good by. The choice should not be difficult for the FDA boss. Ah but how reluctantly the mind consents to reality!

500 Papers

Retraction Watch posted the story yesterday of Dr. Don Polderman who was fired from Erasmus University in Rotterdam for scientific misconduct. He studied the risk of complications during cardio-vascular surgery. According to the DutchNews website, "In particular, he failed to obtain patient consent for carrying out research and recorded results ‘which cannot be resolved to patient information."

Having a forum like Retraction Watch allows for a conversation that doesn't always take place among people interested in science. We know people cheat. We know all of us are prone to fooling ourselves. What a forum such as Retraction Watch does is provide a journalistic approach to the fallout of being wrong. You might be purposely wrong or accidentally wrong. Being wrong however is nothing to be ashamed of. In fact finding out that you were wrong is how some of us learn. The greater our concern over right and wrong, the greater our desire is to understand why something is true or false. Retraction Watch opens up room for a conversation on the way in which scientists communicate (publish their work) and how flawed the system can be.

Our analogy of the Cargo Cults provides another way of looking at modern science. We like the philosophy of right and wrong and how subjective the two can be among mere mortals. Let's take two of the four comments currently up on Retraction Watch's story on Dr. Polderman.

Polderman has “some 500 publications to his name”; does that number, 500, alone incite incredulity? A vast undertaking would be to review all of those publications to determine just how unique and how reliable was each study. Conrad Seitz M.D.

It’s a culture in clinical medicine to just look at the quantity, not the quality. You need to get more than 15 publication/year in order to reach 500 in a 30 year career span and this is a theoretically impossible task if you’re doing real science. Jey

These two concerned scientific people seem to be at odds in their philosophy. Dr. Seitz suggests that the quantity of publications is not important. He suggests reviewing each paper. Jey suggests that 500 papers in 30 years is too good to be true. Looking at the quantity of publications versus the quality of them seems to be a part of the culture of success in clinical medicine.

When I was a boy in Boy Scouts we had a contest of who could hold their breath the longest. The winner went about 4 minutes. Of course the winner and everyone who made it past the first minute were cheating. We didn't really need to follow each boy scout to see when they took in a fresh lung full of air. We didn't need to hold a mirror under every kids nose to see if they were breathing. We knew that the max of holding ones breath lasts about a minute. Jey is very astute in his observation regarding the number of papers Dr. Polderman has his name on. Jey goes on to say "Only possibility I can think of is that everyone in the building have been putting his name as a co-author. It’s even difficult to make up over 15 papers/year".

It is very difficult to take a single paper and reproduce the entire set of experiments and come to the same conclusion as the lead author. The list of authors on a paper haven't even taken the time to verify (in the lab) what is being reported. Therefore Dr. Seitz has proposed a far more difficult way of resolving this situation. Rather it would be of some value to assess the main thrust of what Dr. Polderman has put forth for the medical profession and to first look into the papers that support those ideas. Along the way perhaps a pattern will emerge that will lead us to pull out other papers that may contain false information.

The fact of the matter remains, a successful doctor/scientist has been caught cheating once again. As Jey pointed out, one would have to publish 15 papers a year. In 2001 Jan Hendrik Schon of the infamous Schon Scandal was listed as an author on an average of one newly published research paper every eight days. A pattern is thus already apparent for scientists. The quantity of ones publications may be inversely correlated to the quality.

I have my name, as an author, on a paper that was "published" in the Journal of Biological Chemistry. In fact, that paper is listed as a paid advertisement.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Other than that paragraph, the paper looks like a normal peer reviewed article. It is listed on the authors resumes. I did the work, my supervisor wrote the paper, our CSO signed off on it and a couple others got their names on it as well. And of course it is part of the art of deception.

Those who work inside the laboratories are usually too young, scared and otherwise unfit to take on the likes of a powerful doctor such as Dr. Polderman. It takes a lot to correct someone who has captured the attention of the scientific community. My thanks go out to Retraction Watch for the valuable service they are providing to help shine a light on the dark side of science. We, who have worked or currently work inside the laboratories know all about the pressure to obtain publishable results. It is the Cargo Cult Culture. It is not important whether or not the planes land. Our careers present a conflict of interest in the pursuit of the truth.

The Art of Journalism

Bill Moyers recently quoted a mentor of his: "News is what people want to keep hidden; everything else is publicity."

Does science truly have a journalistic style publication? Does anyone report on the ebb and flow of information being put forth by scientists? Xconomy sponsors the "Biotech is Back" conference. The WBBA organization holds an annual meeting. "This intense program will be a celebration of our successes, and a discussion of the industry’s current challenges and coming opportunities locally, nationally and globally." One of the speakers is the CEO of Eli Lilly who took control of Washington's largest biotechnology and fired the vast majority of its employees in 2007.

This is of course an example of publicity. The public relations groups include WBBA, Xconomy and the governor. They are the leaders. Who could report on their activity? Objective journalism should come from somewhere but who could gain access into these leaders and tell the story of what they do? This is science and the leaders have set up a system that excludes the sharing of information.

It would go something like this: WBBA hosts annual meeting. Guest speakers include governor Gregiore and the CEO of Eli Lilly. In 2007 Eli Lilly gained complete ownership of Cialis, and promptly shut down Icos operations and laid off Icos personnel, except for 127 employees working at the biologics facility. Icos was the largest biotechnology company in the state of Washington at the time of the acquisition, and employed around 700 people. In December 2007, CMC Biopharmaceuticals A/S, a Copenhagen-based provider of contract biomanufacturing services, bought the Bothell biologics facility and retained the existing 127 employees.

In addition to the layoff of Icos employees, other aspects of the acquisition were equally controversial, such as assertions that Icos was being sold too cheaply and that conflicts of interest existed. The latter related to Icos senior executives, who – despite poor stock performance, in part from failed clinical development programs and an inability to successfully license drugs over the preceding years – were to be massively compensated upon a successful acquisition.

Senior executives at Icos received cash payments worth a combined $67.8 million for selling the company to Eli Lilly. Icos chairman, chief executive, and president Paul Clark received "a 'golden parachute' worth $23.2 million in severance pay, cashed-out stock options, restricted stock awards and other bonuses for retention and closing the deal." Nine senior Icos executives received similar packages, each worth more than $1 million.

Pharmaplasia and Us

What ails the pharmaceutical industry? There are many perspectives. The one from the leaders of Seattle is that nothing ails us. We're doing fine. Then there are the others.

I've just started reading Pharmaplasia by Mike Wokasch. He is coming from the executive level in business and marketing. He has worked as a pharmacist, a pharmaceutical sales representative, marketing manager for blockbuster products, and he has held corporate officer positions at large and small companies. He is passionate about the need for expertise and professionalism in any career choice or job function.

Having yet to read the book, I am skeptical about the marketing side of pharmaceuticals. In Cargo Cult terms, his job is to make people believe that the planes are coming. He does not need to have any idea how a real airport works. After all of the business and marketing meetings are over, you still know absolutely nothing about the natural world or how the human body lives and dies. Yet M. Wakasch has taken an important step. He has admitted that there is a problem. In Cargo Cult terms, he acknowledges that the planes aren't going to be landing as advertised.

There is a distinction that has to be made however. A laboratory scientist is not considered a professional. We do not have the same kind of career paths as executives or marketing professionals. We do not make as much money. We are not expected to grow as laboratory professionals. The layoffs, such as Amgens announcement today, make laboratory workers who serve the R&D side of the industry less than professionals. We learn a skill such as running an ELISA and that becomes our "profession". We serve a piece of the puzzle being assembled by higher ranking PhD scientists who work out of offices. When they fail, we fail. A true professional must have some control over their livelihood. The laboratory professional lives each day in fear of the layoffs that result from not curing cancer. The marketing professional at least has some control over how a product sells, whether is works or not.

The current system is based on the assumption that leaders are the creative types who innovate. Pharmaplasia at least takes on the notion that we have not done well as of late. Here at the Cargo Cult Scientist, we believe that human beings have always had a problem with new and powerful ideas. New and powerful ideas upset the status quo. They elevate true innovators above those who sit comfortably in powerful positions. There is resistance. Imagine sacking the staff who makes the decisions and leaving behind the professionals who can take direction and quickly test the ideas of any leadership. Imagine a research staff held accountable only for executing the experiments set forth by them by the leaders. The outcomes of the experiments must be dealt with intelligently and scientifically by the leadership. When they fail, they shouldn't be allowed to wash it all away by laying off the laboratory staff.

As I read on in Pharmaplasia, I am certain I will find new things to write about. As a former "professional" who was placed into various silos and pigeon holes, I am certain I will be receiving an education as to how those who put me there think. My own inability to effectively communicate with the leaders of my cults is of little concern to me. I see the fallout everyday when I read about "massive layoffs, slowing revenue growth, a major blockbuster “patent cliff”, disappointing R & D productivity, never-ending product liability lawsuits, allegations of illegal marketing and sales activities that lead to billion dollar fines and settlements, and the list goes on" (as stated on the Pharmaplasia website) I know I wasn't exactly wrong about my predictions. I feel we in the industry are average people convinced that we are Einsteins. Certain things prevent us from succeeding but those things can be overcome. You do not hire a group of recent college grads and tell them to go make an airplane. You need experience and not just any experience. You need professionals. Those professionals must then produce new professionals. The most important thing is that the airport works.

I no longer work in the industry. I've moved far from the hubs of biotechnology. Yet I still care. The complexity of the human body makes R&D the most perilous profession out there. Research and development remains an area where human beings will always attempt to employ the scientific method. It is that method and the Cargo Cult Science approach that keeps my interest. I long for the day when we begin to face our failures and learn from them. You can layoff the laboratory staff but you are left with a poorly educated (and I'm not talking about the University education) group of professionals who do the bidding of those who never seem to suffer the consequences of bad science. Good luck to the Amgen R&D folk who have lost their jobs. You are tribesmen. Learn from your experience. Speak out. Tell us what you think went wrong. Read Pharmaplasia. Read. Write. Think. Talk.

Why Quit Now?

I've reached my new location. I'm in a secret hiding place where I have decided to keep taking shots at the Cargo Cults of Science.

First news item. Bristol Myers Squibbs drug, Yervoy, has been rejected by the UK Health Cost Agency.

About 30 percent of patients treated with the drug would have improved survival, with 10 percent potentially experiencing long-term benefits, the National Institute for Health and Clinical Excellence said in a statement today, citing clinical specialists.

The drug costs about 80,000 pounds ($125,600) per patient, said the agency, known as NICE, which advises the National Health Service on whether drugs provide value for money. Yervoy is the first medicine proven to extend the lives of patients with advanced melanoma, the most deadly form of skin cancer.

Has Dendreon tried to get approval in the UK? Would it prove to be cost effective? Should the U.S. form a Cost Efficacy Agency within the FDA? Step A, approve or reject a drug. Step B, decide if the government is going to pay for it. If not, let the drug maker sell the approved drug on the free market. As BMSs mission statement goes, "Bristol-Myers Squibb is a global BioPharma company firmly focused on its Mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases." It is their job to deliver $100K+ drugs to people without government or insurance assistance.

News item number 2: Cargo Cult Scientst #1, Hwang Woo Suk has cloned a coyote.

What did we learn from his stem cell scandal? The disgust we may have for him is merely a personal feeling. It is not what motivates science. Yet we are now faced with a profound skepticism that will bring about the scientific method. Did he clone or not? How do we find out? At least we know that a peer review process isn't enough.

Time to grow. Biotech/Pharma drugs are getting too expensive. They are asking the sick and dying to assist them in extracting undue amounts of money from our government and insurance agencies. Hwang Woo Suk is claiming to have cloned again. They have cloned a dog and it is said that this was verified. It is time to see him hired by Geron. Assemble the same people who gave him the stamp of approval for his stem cell work and let them try again.

A Cargo Cult Tribesman No More

After 18 years in Cargo Cult research (how to get the planes to come), I'm calling it quits. The planes never came. As we looked to the skies, fires lit along the runway, man in tower with coconut headset, the clouds floated by gracefully with no signs of even a distant jet stream. We stared upwards for hours, months, years, but they never came. We rearranged our airports, made new tiki torches to illuminate our ceremonies, changed radio ladies so our leaders could talk to the gods more clearly. It seemed like we couldn't fail. We had so much hope.

As I prepare to leave the Cargo Cults of Seattle, I must draw some final conclusions on what this has all been about. The blog, the work, the career must all come to an end. The traveling from town to town was Woodie Guthrie without a soul. This past summer I had an epiphany about what biotech/pharma is all about. On a dreary gray day early in summer, I made my way to an old theater in the University district that showed mostly documentaries and Indie films. The film was called Forks Over Knives. The two doctors featured in the film came from farms. They grew up eating food that they grew and/or killed themselves. They studied other cultures and learned that what we eat has a major factor on how we feel and how we die. I realized that I work in a field that treats the side effects of the American diet/exercise/stress lifestyle. We have pills for stress, insomnia, obesity, diabetes, stiff joints, restless legs, diarrhea, head-aches, cancer and AIDS. In the case of the last two illnesses, I'm convinced that some of the treatments make the situation worse. Because we have a hopeless population, we've gotten away with it. We don't want people to get better. We want them to die taking our $100K+ pill regime.

The real treatment for what ails us is diet and exercise. In the film, Forks Over Knives, patients given two year death sentences by their doctors were still alive after five years. Diabetes patients were no longer in need of the pills, much to the chagrin of their doctors. An old Chinese gentleman diagnosed with cancer talked about how his sex drive returned as a side effect of treating cancer with proper diet and exercise. It worked better than Viagra! The side effects of treating one target with pills are usually things like diarrhea and vomiting. The side effects of proper diet and exercise treatments are erectile functioning!

In Forks Over Knives I saw the real Cargo planes landing. On the other side of the island where we weren't allowed to go was an airport with Allied forces still operating. They demonstrated that the real way to treat what ails us is to ingest proper food. They taught me how to get "wealth into the system". I learned how to get the Cargo planes to land. I saw the cancer patients remain alive and well. I saw the diabetic who no longer needed his pills. The pills come after the sugar chains and processed boxed cereals, mashed potatoes and macaroni and cheese powder. The pills are the greasy eggs and sausage used to treat a hangover. When I see my older relatives, obese, suffering from heart disease and diabetes, I know I can help them. But they live on the Cargo Cult side of the island. They want the pills. Pills are hope. Pills are Cargo.

I've been angry about many things. I'm not the good obedient worker that George Carlin depicts in American Dream. I wanted to avoid the cubicle and the endless meetings. In the lab I found a place where being clever was a measurable quantity. If I clone a gene, grow it up, purify the protein, and run a binding test, I can watch my progress. I've seen people do that much work in two weeks. I've seen others flail away at such a project for years. I've seen the good and the bad and I know that they are aware of each other. The Allied forces airport workers know that the natives are on the other side of the island trying to emulate their airport. The contract manufacturing organization who requested that our director not attend the process development meetings was such a situation. Our small biotech company was not aware of the terms upstream and downstream process development so we labeled our director, "Scientist". Later it became director of target biology. He was the proverbial old lady with the wire wrapped around her (Cargo Cult radio) so our chief (CSO) could speak to the gods. When he met with what our cult thought were his real airport counterparts, they cut him out of the process. Happily he went back to the cult to prepare the next ceremony. He dealt with natives, not allied forces. He made me angry, as did the followers who adored him. The five people who left the part of the cult, including me, left shaking our heads. We represented nearly fifty percent of the Cargo Cult process development group. The first to leave came directly from the Allied side of the island. He left a note one day that read only, "Beam me up Scottie, no signs of intelligent life".

I don't know where to go now. It's hard to explain a career of working in this Nobel Prize winning lab, two failed teeny tiny southern California biotechs, one failed Seattle biotech and a final biotech hasn't failed yet, but is the most bizarre of them all. The Prusiner lab taught me that even a Nobel Laureate has a hard time interpreting a simple western blot. The antibody company in East LA sold themselves to a bigger company that failed clinical trials (phase III) in 2005 and called it quits after 20 years and half a billion dollars. The bio-informatics company folded up shop 9 months after I started after losing a battle with Rosetta to become a subsidiary of Merck. Rosetta was shut down last year. The nasal spray company fired the staff and replaced the CEO and CSO with RNAi successes from SIRNA. SIRNA was shut down a couple months ago. The RNAi company fired the CSO but kept the CEO. They are now on life support. And the most bizarre company of all have not made any news lately. Such an uncomfortable silence from a company that sells promises is usually a sign that they are ready to give up the scam and take their profits. What I know is that they have not taken a serious run at a second drug development candidate. The first candidate in the pipeline was successfully partnered up but it will never become a viable product due to a profound manufacturing incompetence. The other two candidates announced just last year will never be partnered up because they were announced to break the silence of a four year lack of productivity. The leaders of this Cargo Cult led a previous group of 90 that was shut down for their... lack of productivity.

For those who are not angry, you're not paying attention. I'm a concerned scientist who sees an industry ran by greed and other forces that destroy scientific integrity. The failure of so many projects and companies, compared to the success of Forks Over Knives, has led me to my belated decision to move along. My final experiment will be to continue on the Forks Over Knives path and live to be 100.

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, 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.

Multiple Intelligence

Every day in life we experience education. You learn something new every day. There are several concepts here that I think need to be explored in order to understand yourself and those around you.

If you were an A student, the chances are you have what Howard Gardner calls law professor intelligence. You have linguistic and logical intelligence. Think Naom Chomsky. If you are heavy on logic and weak on personal intelligence you are more like Ted Kazinski. Both obtained PhDs and found employment in highly regarded universities. Both went on to international fame. Both might be considered misanthropic with regards to some segment of our society. What was the intelligence that prevented Naom from falling into the same hole as Kazinski? As Naom pointed out on the video I posted last week, he put up with stupidity in order to reach the next level. Naom Chomsky believed the end justified the means. Kazinsky believed the means ruined the end. He saw the means as a filter that separated the good from the bad and the bad was what was left at the end.

Education is a filter. We have "weeding out" courses in science. Freshman chemistry can be a tough course for some and many will drop out. The first day of class there are 400 students. By the final exam you are at less than 100. Simply by looking at the percentage of drop-outs in a weed out class, we can get an idea who excels in logical intelligence. Where do the drop-outs go and do they then excel at their new class? Maybe they switch to English and get an A. They are word smart. How would Oscar Wilde have succeeded as a chemist?

We have many examples of extraordinary genius in logical intelligence. Autistic humans have an uncanny ability to do math, to see numbers as colors and shapes that comes together quickly for a logical conclusion. They may also be able to play Beethovens Moonlight Sonata after hearing it only one time. These are forms of intelligence we try to teach students. I think of it as intelligence chromatography. We have a resin that captures certain kinds of intelligence. We pass through the entire student body. Those that pass through we give Bs, Cs, Ds, and Fs. Those who get As stick to the resin. We can then pass them on to other resins. The linguistic and personal intelligence resin shows that our logical intelligent autistic A student is not fit for society. They move on to all Fs.

Who succeeds as A students in all forms of intelligence? The law professor! Lucky for the law professor we don't require that they get an A in gym. It is our society that puts together the list of intelligence to which one must demonstrate a stickiness. As we pass through the education system we must go through numerous intelligence chromatography columns. After education comes employment. Now is where biotechnology comes in.

Most biotechnology workers are of average intelligence. The average laboratory worker is content to remain in the lab cloning, purifying and running the assays. They would have been successful farmers or mill workers in an alternate era. They passed through the intelligence filters with a smattering of As Bs and Cs. The leadership excel in linguistic but not business logic. Their intelligence filters come from PhD programs in science. They lack the ability to translate good science into scientifically developed products. They would have been snake oil salesmen in an alternate era. The support industries, companies like GE Healthcare or Stratos Product Development, provide equipment that automate things like DNA sequencing, cell culture, and protein purification. They would have worked for GE in an alternate era.

I often wonder what would happen if you could get a small child from a modern day cult. How would they succeed in our society. Could they become biotech professionals? As they say, it's not how smart you are, it's how are you smart? I think they would do well. Show them the ritual to purifying DNA. Let them know when the ritual is to begin. They wouldn't aspire for more. They would look too the leaders and hope they get to share in some of the cargo. When it never comes they just keep performing their part of the ceremony meant to bring the cargo. When sent from the tribe they go and find another. They hope the ritual performance is equal to that of their would-be new tribe. The tribe, suspicious of other tribes probes them on their understanding of the cargo rituals. If they possess the proper intelligence they will be allowed in to perform their understanding of the ceremony.

Rice Fields

Once again Malcolm Gladwell has stopped me dead in my tracks and forced me to rush back to this ridiculous blog. The topic is rice fields. In Outliers Malcolm discusses Chinese peasants who meticulously set up their rice paddies. They have a clay bottom with mud and fertilizer base for the seeds. They are then flooded with water and tended to every day. There is a balance that is maintained by hand, not automation. What the peasants know is hard work and an exact science.

Conversely there are the peasants in Russia. They plant their seeds and hope for rain. Their form of farming relies on luck. The Russians believe that God will provide.

So what is the culture of biotechnology? On October 24, a meeting with the "leaders" in the field of sequencing genomes will convene. They believe that this is the future for medicine. Why? If you step back and take a different angle, you will see sequencing a genome as a research tool. One probability is that the future will be same as Retrogen or Qiagen. The people excited about it should have already done the kind of thinking that would make this tool desirable and not just another sequencing service for researchers. It is a tool. What to do with it?

Think of it this way. A prion is a mis-folded form of the PrP protein. The theory goes that the mis-folded protein causes the formation of plaques in the brain and eventually a horrific death. We now have a few end points to look for if we could just find a way of preventing the proteins from becoming mis-folded. We need a tool. That tool could be an antibody that only recognizes the mis-folded protein, not the normal PrP protein. The antibody will bind to the mis-folded protein and prevent its theoretical action of causing other PrP proteins to become mis-folded and joining hands to become a plaque. To be honest, I worked on such a project. Such an antibody is hard to find. We never found it nor has anyone else.

From the above paragraph the average sophmore should be able to create a list of projects one could embark on if they were magically handed the prion antibody. For example, coat 2 ELISA plates with 95 normal brain samples and 1 scrapie infected hamster. Test one plate with the anti-PrP antibody and the other with the new tool antibody. One plate will light up in all wells. The other plate will have only one well light up. Eureka! Next you move on to in vivo studies. You create analytical methods.

This type of research in fact takes place every day. We select targets, make antibodies and run them through our tests. Going back to the genome sequencing, we don't have a plan. Both situations are similar to the concept of planting seeds and hoping the Gods will provide. The board and the executives plant the seed and they leave the field work to the peasants. If the seed is strong and there is plenty of sunlight and rain, success will be certain.

Now back to the Chinese rice farmers. They do not take chances. They are extremely poor and failure is not an option. This is akin to what engineers do. If you make a car, everything must work. If the brakes go out or even if they squeak, you will have to go back to the drawing board. Therefore, each new version of car is built upon the history of making cars. Engineers develop the cars. Engineers develop the way in which a car is assembled. Engineers develop the assembly line!

Biotechnology executives however, have to hold public chat sessions where they discuss what can be done with the latest tool. They have given the problem some thought and are now ready to talk about it in public. In public speaking is what they are good at. Knowing what to do with new tools is not what they are good at. They are not like rice farmers or engineers. They are like Russian farmers who have planted a seed. A dust-bowl season will ruin the crop. That season is akin to a small handful of genetic researchers being the main customers of the $1000 human genome sequencing companies. The ideas that come from the stage of the upcoming meeting must inspire. They must convince the world that science is going to be turned upside down by this technology.

But we've heard this before. The human genome project created so many patents they had to end the practice of patenting genes. Where were the guys who knew what they were going to do with the genome sequence? Where are they now? The executives of the old companies got rich but what did we learn about our genome? Is it a useful tool? The new companies are like the old. They are hoping for someone, something to take a hold of their seeds and nurture them into a rich harvest for themselves. Whoever solves that problem won't be the ones up on the stage next October.

I've spoken about practical intelligence. A clever fellow with a high I.Q. can solve difficult math problems but he cannot necessarily become a successful human being. The rice farmers are peasants who live with little money. We on the other hand are successful humans with lots of money and comfortable lives. We rarely succeed. But facing the future of the human genome, who will solve the problem of "what to do with it?" It won't be the executives on the stage. It will be that guy with below average practical intelligence but above average problem solving skills. If biotechnology really wants to figure out what to do now, they have to put an end to the cheer leading, the mitigated speech and the low opinion of the peasants.

They'll Know It When They See It

Stewart Lyman from Xconomy gives a nice summary of how a drug can act within the body.

Drugs can directly stimulate (e.g. morphine) or block (HIV protease inhibitors) enzymes. They can bind to and sequester molecules (TNF blockers for rheumatoid arthritis). Drugs can replace missing molecules (insulin, hemophilia) and alter the rate of movement of molecules into or out of cells (anti-arrhythmics like sodium channel blockers). Some drugs stimulate the immune system (Provenge, Yervoy), change the pH balance in the body (sodium bicarbonate for acidosis), or interfere with the assembly or function of intracellular structures (anti-cancer drugs like taxanes). Drugs can stimulate the release of stored molecules (epinephrine), or interfere with DNA synthesis (sulfa antibiotics). Drugs can perturb cell membranes (anesthetics), and effect the modification of proteins, thereby altering their function (histone deacetylase inhibitors). In gene therapy, the drug is often a replacement gene; anti-sense drugs block the formation of proteins by binding up specific mRNAs.

Once you imagine a drug development project, what is the process? The target, where the action takes place, needs to be reached by the drug. Delivery becomes a new research project. How do you make the drug? Process development becomes a new project. The list goes on. What part of the puzzle is the role of a small biotechnology company? What is the responsibility of Big Pharma who is looking for a partnership to beef up their pipeline? What about the CROs, CMOs and the clinical trial branches of the process?

We assume that everyone knows their role. It begins with education. We set up a hierarchy. Responsibility of innovation falls upon the highest ranking members. The lower ranks must bring the innovation to fruition.

A better way to view the field of biotechnology drug development is to draw a straight line. On the X axis is time. On the Y axis is money. Assume ten years and 1 billion dollars. Where along that line are you searching for investment money? Where are you spending the most on clinical trials? Where along that line are you making the critical decision on the drug candidate?

Currently there is no graduate degree where you go through the entire process, without the spending of 1 billion dollars and ten years. We just hope the leaders will react to each situation in the proper way. A graduate degree would speed up the process by building a base of understanding what is coming down the pike. Base the courses on real life situations, such as the pricing mistakes of Dendreon. Maybe throw in a course on the history of financing so the students can have that trajectory in the back of their minds while they think about staying in business.

Undergraduate degrees can become more focused. Biochemistry, microbiology, molecular biology are all degrees that have become nothing more than vocational degrees for low level biotech lab jobs. Instead, focus all of the relevant information into the various areas of early stage research, process development, analytical development and so on. The graduate degree holders will know how to structure a company and thus they will know who to hire based on the education.

Overall, we need an end to the "we'll know it when we see it" process in biotechnology business strategy. You won't know it. It is not an ad hoc process to be ruled over individuals who feel they possess a special understanding of science. At this point it is fair to say that they are not very good at "knowing it when they see it". The weakest point along our line from 0 to ten years ($0 to $1 billion) comes in the early stages. What to do and what to select as the drug candidate is a very "know it when you see it" moment, and thus the weakest moment. It will make or break everything that happens along the line of progress. The rest of the work however is where we can focus education. You should not stumble in process development. It is not a "know it when you'll see it" process. It is not ad hoc. You take on the work, make a plan and you finish the job. The same goes for a clinical trial. Make a plan, execute and analyze. Need money? You have experts in that area.

Currently, Big Pharma is leaving that critical early stage "know it when we see it" up to small biotech. Big Pharma is setting themselves up for even greater failure than we are already experiencing. As Warren Buffet says, you don't ask the barber if you need a haircut. The education we require will not come from the current experts. They are experts in a failed experiment. In the process of getting smarter the cost of that drug development will go down. The time line will be reduced. Imagine a gant chart instead of the single line. Each line, each function along the way to approval becomes separate and can thus be analyzed and improved. Step one is to step back and look at where we are. Look at what we do. The real skill that is missing is not "knowing IT when we see IT". The skill is knowing how to get to "IT".

Mitigated Speech

Every case of scientific misconduct involves a powerful scientist and dishonest or disgruntled underlings. In the case of Silvia Bulfone-Paus, two rogue post docs were assigned the blame for fraud. In the Baltimore Case a disgruntled post doc outed her P.I. Speaking truth to power is never easy, even when the powerful are scientists. They expect certain outcomes. If the truth differs from the expected outcome, you have a choice. Do you stick with the truth or do you tell the leader what they want to hear?

Telling the truth will require mitigated speech. You have to decide how to tell the powerful scientist something they don't want to hear. In a recent post I talked about a situation where the CEO of a biotechnology company would tell the white lab coat scientists what they were suppose to do in order to find drug delivering molecules. Point A, (do this) did not lead to point B (and you will have a drug delivering molecule). What was doable was point A. We could make a peptide library. Point B was scientific analysis of point A. To this date, no one has said to the leaders of the biotech company, "this isn't going to work".

The first question that really needed to be addressed was the logic behind the drug delivering holy grail research. The leadership had decided how the holy grail would be found. A peptide or protein would bind to certain cellular proteins and the binding would lead to all sorts of wonderful effects. But how did they know? We hadn't found the molecules that bind yet. Do you ask questions or do you do what you can and hope that things will work out? How do you deal with the research when you find a molecule that binds to it's intended target but the desired effect does not happen?

The term 'mitigated speech' was recently popularized by Malcolm Gladwell in his book, Outliers. He defines mitigated speech as "any attempt to downplay or sugarcoat the meaning of what is being said". He continues with reference to Fischer and Orasanu, to describe 6 degrees of mitigation with which we make suggestions to authority:

1. Command – “Strategy X is going to be implemented”

2. Team Obligation Statement – “We need to try strategy X”

3. Team Suggestion – “Why don’t we try strategy X?”

4. Query – “Do you think strategy X would help us in this situation?”

5. Preference – “Perhaps we should take a look at one of these Y alternatives”

6. Hint – “I wonder if we could run into any roadblocks on our current course”

Gladwell brings up the concept in the context of how crews relate to each other in the cockpit of a commercial airliner, graphically illustrating the degree to which mitigated speech can be detrimental in high risk situations which require clear communication. Gladwell also talks about different cultures and how they use mitigated speech.

What then can we make of the culture of science? It has been shown to be, at times, the art of deception. It is self correcting, but those who possess power work against the self correcting, as exhibited in the Baltimore Case. It pits the P.I. against the underlings, the office versus the lab. There is no way to correct a superior when they are wrong, other than to hope they are open to such a discussion. When a paper needs to be retracted everyone, scientists and journal editors, are embarrassed. They mitigate the need for the retraction or worse, they brush it under the rug.

A new way of communicating science is needed, Does mitigated speech stifle innovation?

Practical Intelligence and Success

The biotechnology and pharmaceutical industry continues to try and figure out new ways to encourage innovation. As patents expire and streams of revenue dry up, they need the next big thing. It's not that they didn't plan on this contingency. They knew these days would come and they shelled out the money to get people working in the laboratory. What happened?

The lack of innovation can be linked to what is ailing all of science. In a recent discussion on scientific journal retractions from "OnTheMedia" I found two comments from people who have interesting and similar concepts.

Paul Charles Leddy

Science is social, and if a bunch of morons decide to do science, they'll create a world of moronic truths. Those of us who don't want to live in a world filled with these "truths" have to be careful not to let the morons say what is truth. I think the past 10 years have shown this over and over. Same goes for journalism, btw.
Sep. 06 2011 12:43 AM

The key point here is that science is conducted by human beings and we tend to form groups of like-minded cohorts. We create the truth. Those with practical intelligence who want to be a success will gear their work towards the truth of the group, not the truth of nature.

p.f.henshaw from way uptown

Brook and Jonah,
You seem to be seeing only the manageable tip of the problem of finding and correcting errors in science. The cases where right and wrong are simple to identify are not the problem. Science never had, and can't have, a way to "purify" its archives, other than the same way nature purifies her complex systems to remove useless branches, by experiment and evolution.

The deep problem of modern science is that "useless branches" of thinking become the basis of social structures and clung to relentlessly. You see it in how the different "silos" of reasoning form around different socially preferred ways to ask the same questions. One dominant paradigm of that kind is "science as computers" with the dazzling display of results conveying the image of powerful insight, but if tested against the subject addressed often represents no insight at all.

Theorists tend not to study nature at all, just data, their theoretical models, and their social status. The naturalists who actually study the complex naturally behaving subjects of such a study are unable to contribute to the process, at all... don't even get brought in for discussion, for the simple reason that nature does NOT behave at all like a computer (!!) and the questions a naturalist would ask upset the social status of someone representing their theory as nature! ;-) See the problem?

So the core of the problem is the social basis of the questions that each science and sub-science organizes itself around, not just our present self-defeating obsession with computers. As a battle between social cells science becomes as much as if some endless TEA Party argument. Your radio piece seemed to assume that scientists were engaged in scientific debate, but you can't do that when people all standing on different platforms.

I love the imagery of useless branches being the basis of social structures being clung to relentlessly. This takes place inside each company but also among all of science such as the case of RNAi. Where was the hint that Merck bailed out on RNAi because after an exhaustive study they came to the conclusion that it will not be useful as a drug? They bailed but they did not send out any dissenting opinion that would upset the social group who still cling to RNAi.

In order to be successful you have to know what the group wants to believe. That is the easy part. The hard part is maneuvering around empirical evidence to the contrary of the groups "truth". For that reason the most successful members of science do not work in laboratories. Those who do lack the practical intelligence that keeps one out of harms way.

What To Do With It

It was not a beautiful paper.

Next came the patents. The news that came out today is that the U.S. Patent and Trademark Office (USPTO) has issued a Notice of Allowance for our patent application.

A primary advantage of this patented peptide library is the ability to rapidly screen and identify novel peptides that exhibit cell specific targeting characteristics for directed delivery of nucleic acid therapeutics," said the Chief Scientific Officer. "Delivery remains a significant challenge in the nucleic acid therapeutic space, and peptides with high affinity and specificity are expected to be a fundamental component to developing delivery approaches to a wide spectrum of tissues and cell types. In addition, the library may also be exploited to screen for peptides that function as specific antagonists, agonists or generally exhibit drug like properties.

The only problem is that the library has no ability to do the things described above. It was a dud. The obedient workers did everything they could but they couldn't get the results that validate the statements of the Chief Scientific Officer quoted here.

The CSO didn't mention that the team who developed and tested the library were sacked. They needed to go out and find someone who could figure out what to do with that library.

There are very few people with the expertise and resources to perform this kind of science.

"What to do with it?" was always the question. There was no conversation about "what to do with it" other than use it to target this cell or that cell. But how? That was the scientific "wealth into the system" that Feynman speaks of. Everything else was what Kurt Vonnegut referred to as "Kit Science" in Cat's Cradle. We had molecular biology kits, phage display kits, and we did some cell culture work. We got our patents and paper. But what should we have done with the library?

A lot of scientists I've worked with believe that there is some clever thing we didn't think of. When we got the orders to test the library against specific cells there was no discussion about the possibility that it wouldn't work. We tested the random thoughts of the leaders, various methods of treating the cells, different buffers and so on. When about 100 random thoughts had been tested they told us to go home. It was a relief.

But it doesn't work. No airplanes land. So
I call these things cargo cult science, because they follow all the
apparent precepts and forms of scientific investigation, but
they're missing something essential, because the planes don't land.

Now it behooves me, of course, to tell you what they're missing.
But it would be just about as difficult to explain to the South Sea
Islanders how they have to arrange things so that they get some
wealth in their system. It is not something simple like telling
them how to improve the shapes of the earphones. But there is one
feature I notice that is generally missing in cargo cult science.
That is the idea that we all hope you have learned in studying
science in school--we never explicitly say what this is, but just
hope that you catch on by all the examples of scientific
investigation.

The CSO makes the claim that "peptides with high affinity and specificity are expected to be a fundamental component to developing delivery approaches to a wide spectrum of tissues and cell types". Why are they expected to contribute to this Holy Grail of RNAi technology? How will it work? Feynman also said:

You can know the name of a bird in all the languages of the world, but when you're finished, you'll know absolutely nothing whatever about the bird... So let's look at the bird and see what it's doing -- that's what counts.

I think of the peptide in this library as the name of a bird. They are looking for that name spelled out in amino acid letters. But even if they find it they will still know nothing about the peptide. They have to see what it's doing. How will they do that? Once again, "what to do with it?". Who will ask the question?

There is nothing wrong with not knowing something. That is why we do research. The problem comes when we want to believe something so much that we accept false answers. This library is just a library. It was not conceived of by someone who had any idea what to do with it. That person, and all of the others are gone now. The CSO quoted above inherited the library and he doesn't know what to do with it. Somehow he's figured out that it will be fundamental to solving the RNAi delivery problem. How will he know when they've found the magic RNAi delivery peptide? I guess they'll know it when they see it.

What Is Really Stifling Innovation

Profit

The Art of Deception

Magic is the only honest profession. The pricing of Seattle Genetics new drug is an example of dishonesty in the biotechnology industry. Clay Siegall, their CEO, is good at the art of deception. He holds a PhD and a large number of patents and publications. You might be lead to believe that he is a scientist. He is actually a businessman. He tells you his company is dedicated to unmet medical needs. That is the diversion. While we are patting them on the back for doing something to help mankind, they are plotting to charge us over 100K to have access to their drug.

The trick is not hard to do. The Invisible Gorilla is an example. In the invisible gorilla experiment there are people in white t-shirts and black t-shirts passing a basketball around. You are told to count the number of times the people in white t-shirts pass the ball to each other. While you are counting passes, someone in a gorilla suit walks through the scene. Most people seem to not see the gorilla because their attention has been diverted by the direction to count passes. You are tricked into not seeing something that is quite obvious once you know it is there.

This is how biotechnology operates, and much of the scientific community as well. Biotech CEOs and principal investigators do not wear white lab coats. They do not work in laboratories. They get noticed. They work very hard to gain a reputation that can be cashed in for money. Once the research grant or investment is in the bank, they go out and hire low paid obedient bachelor degreed servants to do the work. The only requirement is that the results must further the career of the leader.

We at the CCS are always looking for that gorilla walking past the screen. Go to the Seattle Genetics website and count white lab coats.

Did you see the businessmen deciding on the price of the drugs and the size of their bonuses?

Magic is the only honest profession.

Ideas Not Preached from the Pews

The discussion of ideas is necessary for them to catch on. Watching TV or reading a book can be enjoyable but the best shows and books lead to further discussions. You get to participate in the seed that was planted. Watching NOVA or reading a Malcolm Gladwell book may enhance your ability to hold an intelligent conversation. It's up to you to surround yourself with people who also enjoy discussing new ideas. If you enjoy science, you should have friends who have something to share about the latest findings in Science or Nature or any of the other journals. Beyond the mandatory presentations and seminars, you should discuss the latest ideas.

I've had an epiphany on this very subject. I have no friends who enjoy exploring the absurdity of science as it is currently practiced. No one I know has anything negative to say about the profession of science. It seems impolite to be so negative about something that has a positive effect on our society such as science. I believe that only a small percentage of the ideas put forth by scientists ever amount to any greater understanding of our world. And that small percentage is very powerful. The other 95% of our ideas are not going to be useful. They may even be harmful. That 95% of BS deserves greater discussion.

For example, there is a paper out in Nature this week entitled "Broad neutralization coverage of HIV by multiple highly potent antibodies". The title itself seems unscientific. Using words like "highly potent" should be qualified in the conclusions of your paper. But that is the conversation I can't have.

Upon hearing about the HIV paper in Nature, I asked a friend if it would be a good idea to test the authors ability to identify their antibodies by coding each one (A, B, C... Q). Using the techniques reported in Nature, could they retake those measurements to identify each antibody. My friend was shocked that I was nothing but excited about how far science has advanced in HIV research. I said that I would be very excited if I could believe it were true. I was told I was just a skeptic. We did not discuss the paper, just the benefits of believing versus non-belief.

Every Sunday you will find churches full of people listening to a person discuss some aspect of the bible. That one book is discussed in a one way conversation by the preacher to the congregation. Later that conversation is carried on amongst the congregation. The better the sermon the more it will be discussed. Where do scientists gather on a weekly basis to discuss the latest findings? Usually, in the U.S., we gather in rooms where the lowest ranking "scientists" present their data to the highest ranking scientists. The direction of the conversation is taught in graduate school where the wannabe PhD "defends" his/her work to their committee. The preaching among scientists, in other words, is done from the pews, not the pulpit. Subsequent conversations are usually held by disgruntled grad students back at the laboratory, well out of the hearing range of a college professor. It is here where the real scientific conversations take place. Ideas are put forth to squash the dumb ideas. All of the proper controls are thought up. But rarely will those ideas be taken seriously unless they support the ideas of the preacher from the pew.

The mainstream idea to improve our world through science is to increase funding. The idea that I have today is to increase the discussion of scientific work. How to do it? If you read the Huffington Post, you will see that certain articles illicit more comments than others. What if there were a Huffington Post-like science blog where people could discuss work such as the latest HIV/AIDS paper in Nature? As we do with the work of social/economic engineers (our elected leaders) we can discuss the ideas and the merits of the scientific community leaders. Thought leaders such as Andrew Fire and Craig Mello can offer up their thoughts on why RNAi has been such a bust. Throw in a some comments from RNAi biotech CEOs and CSOs and see what the rest of us who are very interested in the subject have to say. We'll get into arguments and have an old fashioned debate, rather than the usual Lead Zepplins found in the journals. Break a paper down to pieces such as the IC50 measurements used in the HIV/AIDS Nature paper. Try and illicit a discussion on the measurements, the use of statistics, and the conclusions that can realistically be drawn. Highlight vested interests and how they effect certain outcomes. Talk about the "sexiness" of the research and how it enhances careers but increases the amount of BS being put forth. Highlight seemingly boring observations and how they can make a big difference.

The preachers from the pews do not seem to inspire. They conspire to keep bad information in the published journals so as to not hurt their careers. They have created a situation where laboratory work is looked down upon. Their greatest sin however, is that they are boring. They do not want the lower ranking members of science to discuss their work. They want us to read about how successful they were and thank them. If we don't believe them or we question them we are nattering nabobs. It flies in the face of what science is all about. If we want to know what really happened in the laboratory, we are going to have to let the people who actually do the work have a say. Let the people who read the papers and try to use them have a say. By increasing the level of talk surrounding science we'll increase the honesty.

The Complexity Issue/Type III IV Errors

An idealist is one who, on noticing that a rose smells better than a cabbage, concludes that it will also make better soup.

H. L. Mencken

Thought experiment: Executive Bill believes that siRNA can be used to knock out TNF alpha and reduce swelling in joints in rats and thus it will do the same in human beings.

Think of Executive Bill as a Martian who has come to the conclusion that humans will prefer rose soup over cabbage soup. He sends his little Martians out to prove him right.

By setting up such a complex hypothesis Bill has failed to acknowledge that the siRNA may not even be the proper molecule that mimics a naturally occurring small piece of RNA that will reduce gene expression. Smell alone may not predict food preference.We fool ourselves all through the hypothesis testing and reach the end point (where Executive Bill demands a full report in his office) with the false assumption that a human being should see a reduction in joint swelling. Executive Bill wants to know one thing, did the human see a reduction in joint swelling? Did the humans prefer rose soup?If the human sees an improvement, Executive Bill is vindicated. If there is no improvement, Executive Bill sends the scientists back into the lab to tweak the system.

In colloquial usage type I error might be called "failing to believe the truth". In biotechnology this is a common error when desired results do not match actual outcomes. Executive Bill will reject the truth (siRNA against TNA alpha has no effect on joint swelling) and send the scientists back to the lab to get the desired results. The Martian leader will send the little Martians back to earth to get them to prefer Rose Soup.

Type II error is "believing the falsehood". This would be the case if the data showed a reduction in joint swelling from the siRNA treatment when the siRNA had nothing to do with the reduction. Executive Bill would eagerly accept this type of error.

The Martian leader would eagerly accept any data that showed humans preferring Rose Soup. Let's say that the problem came from a mislabeling of the soups or fraud was committed by an ambitious little Martian. The desired results were obtained. They were false. They were accepted. Executive Bill and the Martian leader accept what they are being told.

In these two examples, siRNA and Rose Soup, we (the Cargo Cult Scientist) are saying that the non-erroneous outcome would be that siRNA has no effect on TNF alpha or anything in the human body, and that human beings will not eat Rose Soup. Our antagonists, Executive Bill and the Martian leaders' desired outcomes should be proven false. No matter what the outcome, they will only be accepting validation of their hypothesis. The easiest path to success, as defined by Bill and the Martian, is a type II error. Type I errors will be made until a type II can be arranged.

Now let's enter a superior being I will refer to as God. It is the Cargo Cult God and he needs to keep his subjects ignorant for amusement purposes. He delights in the folly of the minds who keep themselves fooled at all times. The Cargo Cult God wants to explain how Executive Bill and the Martian leader reach their status in their respective groups and how they maintain their positions. First, they are bullshitters and thus would use the truth if they could get to it. But getting to the truth would be a random act since they do not know how to conduct research. They begin from ignorance, either type I or type II errors or they are randomly yet unknowingly correct. They then select a desired outcome and draw a line from A) type I or II error or random correct assumption, to B) desired outcome. The desired outcome however cannot be attributed to the path of reasoning that is depicted by the line from A to B.

In 1974, Ian Mitroff and Tom Featheringham argued that "one of the most important determinants of a problem's solution is how that problem has been represented or formulated in the first place".

They defined type III errors as either the error of having solved the wrong problem when one should have solved the right problem or the error of choosing the wrong problem representation when one should have chosen the right problem representation.

In other words, Executive Bill set out to solve the problem of how to make siRNA into an anti-RA drug where he should have tried to solve the problem of determining the possibility of using siRNA as a drug in the first place. Maybe siRNA cannot survive in the human body.

Likewise, the Martian leader wanted to prove that Rose Soup would be preferable to Cabbage Soup. He should have conducted research on the relationship between the human senses of smell and taste.

In 2009, 'Dirty Rotten Strategies' by Ian I. Mitroff and Abraham Silvers was published regarding type III and type IV errors providing many examples of both developing good answers to the wrong questions (III) and deliberately selecting the wrong questions for intensive and skilled investigation (IV). Most of the examples have nothing to do with statistics, many being problems of public policy or business decisions.

The human body is complex. Biotechnology has yet to accept this fact. The study of type III and IV errors has been handed a gift in the form of medical research. How did we get to the point where we are today? 90% inaccuracy in our scientific journals? Publication retractions on the rise for unknown reasons.

The desired (i.e., non-erroneous) outcomes of a test are called true positive meaning "rejecting null hypothesis, when it is false" and true negative meaning "not rejecting null hypothesis, when it is true". What is the case when the desired outcome is not defined as non-erroneous?