Our Method

Descartes "Rules For The Direction of The Mind" can help the Cargo Cults understand "what is missing", why there is no "wealth in their system".

Rule 5 holds that complicated problems should be reduced to their simplest parts. We then apply our “intuition” to the simplest parts and work our way back to the larger problem. 

For our purposes here today, let's re-create a failed drug research project that most biotechnology companies in the past 30 years have attempted. The project is to make a drug against TNF apha.

Planning:

The norm is that the executive staff and the board select a drug target based on profit potential and the probability of success. This involves faith in the sound decisions of the board of directors, advised by the scientific advisory board. The target is TNF alpha.  

Descartes: Rule 3 states that we should study objects that we ourselves can clearly deduce and refrain from conjecture and reliance on the work of others.

While others had proven TNF alpha to be a target that can bring the cargo, most TNF alpha projects failed. The notion that TNF alpha projects have a high probability of success is false. What the leaders tend to do, when selecting drug targets, is disguise conjecture as a scientific method.

Execution:

Have the lab staff find a molecule that interacts with the target selected in step one. For our purposes we will generate an anti-TNF antibody.

Descartes: Rule 5 holds that complicated problems should be reduced to their simplest parts. We then apply our “intuition” to the simplest parts and work our way back to the larger problem.

The larger problem is getting the molecule to validate the conjecture and assumptions of management. The simple part is good biotechnology. We know how to make the antibody. Although this knowledge fades as we go higher into the ranks of leadership, it is a very solid foundation that gives the biotech credence. Where we begin to fall apart is when we move from the known technology into the unknown outcome of drug testing.

Analysis:

Descartes: Rule 2 holds that we should only study objects about which we can obtain “certain and evident cognition.” It is better not to study at all than to attempt a study when we can’t tell what’s right or wrong, true or false. 


In my experience scientists at higher levels do not participate at this level. Each company has different methods, for example, on testing the binding affinity of their antibody. Some use biacore. I've been told to do the same complicated calculations from ELISA assays. The higher ranking scientists need only have a vague idea as to how a drug is being tested at the early stages. Those who required me to obtain a binding constant from an ELISA assay, had a vague idea of how things work in the lab. In order to know whether or not the test will lead to "certain and evident cognition" much more attention would be required of the higher ranking scientists. This is a critical moment in the process that is soft. If the data comes back saying, for example, that the antibody had a weak binding affinity to TNF, the laboratory staff must explain why they think that to be the case. In other words, the lab staff must convince the scientists what the truth is. The scientists have positioned themselves only to judge the methods employed by the laboratory class rather than participate in establishing that an assay will provide certain and evident cognition. 

I've simplified the process down to its basic components. Where Descartes had rules for the direction of the mind, we have a very different set of rules. For each Descartes rule, we have a very specific unwritten rule of our own that does not match.

Rule 4 proposes that the mind requires a fixed method to discover truth. A method is defined as a set of reliable and simple rules. The goal of study through the method is to attain knowledge of all things. The human mind begins life in a pure state, and from the moment learning starts, the mind grows clouded. The method’s purpose is to return the mind to that pure state so that we can be certain of knowledge we attain.


As I've stated, there are no written methods for the larger problem. The simpler problems, (cloning, purifying, etc) have detailed written methods, SOPs. The laboratory staff must also write down specifics in a lab notebook, which often comes with a set of rules the lab staff must follow. Date each page, initial cross-outs... The scientists at the higher level have no method, no rules and no police other than themselves. Their commitment is to the illusion of success. Even if your biotech company fails, you now have experience running a biotech company. A publication is a publication, reproducible or not. Is this what Descartes outlined? 


We have a random method of discovery. It's a broken system. Reproducibility, to ensure that we are dealing with the truth, is not a part of our system. What would our rules be if we were forced to write them out in an attempt to explain how we spent so many billions on failed TNF projects? Failed Amyloid beta projects? Regardless of the target, the company, the technology, we would find a pattern. There is no set of reliable and simple rules. When you look into the laboratories, you will find that the minds have grown cloudy. If you look into the offices, you will find that the minds have grown corrupt. We need a method to return our collective mind to that pure state that led us to certainty in the past. 

A Wealthy System

Is Science the same system it once was? Feynman said:

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.

We know that even the most productive scientists cheated at times. In order to stay on top a person has to continue producing. That just isn't in our nature. We grow old and we get lazy. There is probably a productive time in our lives where our minds operate best in the abstract concept of science. Therefore we need a method. We need to participate in a system that keeps us honest and productive.

Wikipedia says:

Science (from Latin scientia, meaning "knowledge") is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe.^[1] In an older and closely related meaning (found, for example, in Aristotle), "science" refers to the body of reliable knowledge itself, of the type that can be logically and rationally explained (see History and philosophy below).^[2] Since classical antiquity science as a type of knowledge was closely linked to philosophy. In the early modern era the words "science" and "philosophy" were sometimes used interchangeably in the English language. By the 17th century, natural philosophy (which is today called "natural science") was considered a separate branch of philosophy.^[3] However, "science" continued to be used in a broad sense denoting reliable knowledge about a topic, in the same way it is still used in modern terms such as library science or political science.


Even the definition of science is subject to evolution. The system changes. Currently it seems to have devolved into a religion. Is "science" the same systematic enterprise it was when Einstein was publishing papers in the early 1900s? What about when Descartes was working on his text books?

In Descartes day it was admirable to establish a body of work, not just a large quantity of publications. Not only did you set forth ideas, you used them to set up the next set of experiments. To go even deeper he wrote "Rules For The Direction Of The Mind". Rule 1 states that whatever we study should direct our minds to make “true and sound judgments” about experience. The various sciences are not independent of one another but are all facets of “human wisdom.” Possession of any kind of knowledge—if it is true—will only lead to more knowledge.

Does that resemble the system we are currently in? Once again, The Amgen Study:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies.

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."

If in fact we had the same system that Descartes was participating in, what kind of text book would the anonymous scientist who told "the best story" intend to write? Is this a wealthy system?

We do have a system and people can learn that system and have long successful careers. It is not however, the science of antiquity. No one intends on writing a text book that will be examined by the best minds in the scientific community. Their work is not intended to be examined in the laboratory. It is sciency (pronounced - science-ee). You take the rules from Descartes, for example #3: we should study objects that we ourselves can clearly deduce and refrain from conjecture and reliance on the work of others. Now you have a method. Take the work of others, and rely upon it and get others to get the rest of the community to gravitate towards conjecture. Conjecture: a proposition that is unproven but is thought to be true and has not been disproven. Karl Popper pioneered the use of the term "conjecture" in scientific philosophy. Conjecture is contrasted by hypothesis (hence theory, axiom, principle), which is a testable statement based on accepted grounds. Our system is sciency. Work on conjecture; things that are thought to be true, such as RNAi. Don't design experiments that will jeopardize your conjecture. When an experiment does not prove your proposition, try try again.


Karl Popper was a philosopher who argued for a change in the system of science. He went deep. "Logically, no number of positive outcomes at the level of experimental testing can confirm a scientific theory, but a single counterexample is logically decisive: it shows the theory, from which the implication is derived, to be false." Where do we go from there after the Amgen study? The answer, in our current system, is to move forward ignoring the falsified studies. The 47 papers that were not reproducible shall remain anonymous because our system is not that of Karl Poppers. It is in fact, the opposite. The Amgen study matched up with the science of Dr. John Ioannidis. 90% bullshit is the current rate of scientific publications. In the labs of biotechnology the daily grind is much the same. The philosophy of yore is not a part of our system. We make money by doing what we are told. We have a very sciency life. Take this antibody or RNAi and bring me evidence that it reduces tumor size. Bring me evidence that it can be used to treat Alzheimers. I will use it in a slide presentation to extract money from investors.

That is our system. I imagine a system where the NIH opens a branch that randomly takes publicly funded research to the lab. The concept that we self-police should be abandoned. Someone needs to start policing the bullshitters. The scientist who receives public funds should be part of a system where they are randomly selected to come to Maryland and reproduce their work.

As Descartes suggests:

The human mind begins life in a pure state, and from the moment learning starts, the mind grows clouded. The method’s purpose is to return the mind to that pure state so that we can be certain of knowledge we attain.

Our system has grown cloudy. We have great minds of yore to help us out of this mess. The question is how do we get our leaders to follow the methods and philosophies that created this thing called science? It was once a very wealthy system. It is now dirt poor, ran by financially wealthy people.

The Comment Section

Some of the most interesting things I read online are not the articles but the comments people make. A few of my favorites:

I'm a productive postdoctoral researcher in the biomedical field; my work has brought about $5 million in grant money into the lab.  My career path is to transition from doing the thing that I wrote my thesis on, that I am the world expert on, to being a lab manager and writing grants.  It baffles me that the normal career progression in academic research is to take good researchers and turn them into bad managers.

That's a comment from this article written by Derek Lowe. I came across another comment from Dereks blog, "In the Pipeline" that lead me to another blog by the commenter. He discusses why we have so many layoffs in pharma R&D:

The longer answer is that we don’t understand what’s going on inside cells and organisms well enough to even know what we want a drug to target.

If you put the two comments together to try and solve the problems of drug discovery you have got something that no one wants to admit. We take the people we train to understand what's going on inside cells and organisms and we put them to work doing something their education can't help them do. The companies use the credentials of their scientific employees for purposes other than conducting science.

I enjoy reading Xconomy every day. Mostly I'm looking for stories of the Cargo Cults of Seattle not getting their cargo. When I conjure the image of the natives of a cargo cult gazing to the skies during their ceremonies, looking for the big metal birds carrying cargo inside, I think of Xconomy as the sky. Sadly they don't illicit many comments.  The lack of an active conversation indicates that people are not engaged.

One of the criticisms of the commenters is that they are often anonymous. Comments are little blurbs from self appointed "wise old sages" who have to get their words out. Why don't they tell us who they are? Some are picking a fight. Some are expressing their concern. Some are just trying to be witty. Not everyone accomplishes their goal but the anonymity makes the possibility of failure a risk they are willing to take. The anonymity can lead to troll behavior but it can also lead to insights we wouldn't not have had on our own with the article. Anonymity is what we see from many scientists. They are absent from the lab and the many failed experiments based on their ideas. If you were to look into the laboratory notebooks of the young people who conduct research inside the lab you will find no mention of who told them to do the work. There will be no introduction outlining the thinking of the actual thinkers. Anonymity is a tool we all use.

Some comments are interesting in their defense of Cargo Cult thinking. In a recent retraction from Gerold Schuler, one commenter came to his defense:

Unless I am mistaken, Dieckmann is the corresponding author on this paper, so some caution should be exercised when going after Schuler. 

The commenter is "going after" another commenter. Going after people is common in the comment section. Going after a big time scientist is not common. They are exalted leaders. We here on the CCS recognize the amount of bullshit being put forth by our exalted leaders and we see no reason to mitigate ones speech when commenting online about their bullshit. Another commenter adds to the conversation about Gerold:

As early as 1997 the investigations started on some of the german investigators. Here is an example:Nature 387, 750 (19 June 1997) | and in 2000Abbott A: German fraud inquiry casts a wider net of suspicion…Nature 405, 871-872 (22 June 2000) | doi:10.1038/35016207Few names included in this report are currently directors of institutes…

Machiavellian Leaders? Is this how they reach that level were "going after them" requires commenters to exercise some caution?

There is power in the comment sections that is beyond the power of prayer. In prayer you throw something out there and you hope change will come. In the new world of online conversations we speak to actual people which gives us the ability to heighten awareness. Here on the CCS we try to "go after" bullshit in the world of science. We don't like that the bullshit and the master bullshitters make a career steeped in honesty nearly impossible. Real science is "bend over backwards to prove yourself wrong" honest, as Feynman instructed. The Machiavellian competition makes life hard on those who have a heightened sense of fairness. The comment section is an outlet. It's a place to exchange ideas and challenge each other.

The real challenge for a website is to get visitors. Facebook has demonstrated the power of online traffic. Huffington Post also made a fortune by getting people talking. The comments online are different than the comments you make at a cocktail party. They are different than the comments made at a cancer conference. They are more honest. Less intelligent in general but more honest. Perhaps the science community needs to purposely "go after" the illusion of intelligence and open the doors to the "back and forth" one sees in the comment sections. We might get a little more honesty, thus wealth, into our system.

Investments Gone Bad

Ipierian is now an Antibody company!

Ipierian, founded in July of 2009, is the combination of two companies, Pierian and iZumi Bio. Pierian was co-founded by George Daley, Doug Melton and Lee Rubin, from the Harvard Stem Cell Institute. iZumi Bio came with the leadership of Corey Goodman, chairman, and John Walker, CEO. John Walker served as a Director at Cargo Cult favorite, Geron.

iPierian’s has had four CEOs John Walker, Mike Venuti, Peter Van Vlasselaer and now Nancy Stagliano. The chief technical officer, Berta Strulovici, exited the company shortly before Venuti. The heads of finance, business development, and legal/intellectual property left shortly after Venuti. A few weeks later Corey Goodman resigned his position as chairman of the board and Doug Melton, gave up his role as a scientific advisor.

Originally the business plan was to use their stem cell technology as a tool for screening new drug candidates, and selling their services to Big Pharma. The company’s technology is used to coax ordinary adult cells into a stem-cell like state. The cells are known as induced pluripotent stem cells (iPSCs). After an iPSC line has been differentiated into the cell types of interest, a disease phenotype is investigated, revealing a disease-relevant difference between the patient-derived cells and those from healthy controls. From this disease phenotype, cell-based assays are developed to enable the discovery and validation of novel targets and molecules.

Enabling the discovery and validation of novel targets and molecules was the Cargo. The company was the airport. The Cargo never came. There was no wealth in the system. The airport has undergone several shake-ups in management and some remodeling of the runway. Since Big Pharma didn't buy into the airport, iPierian has no choice but to develop the drugs they were hoping big pharma would. We still have to wonder if underlying technology real or is it another fantastic narrative?

The big name scientists told a good story. The problems came when the narrative failed to fit the reality being faced in the laboratory. Without the promise coming true the executives began to fight. The company is now an antibody company with a stem cell twist. The new CEO, Nancy Stagliano is a neuroscientist by training. Her last startup (South San Francisco-based CytomX Therapeutics) is an antibody drug developer. 

The only thing that matters is the ability of the technology to "enable the discovery and validation of novel targets and molecules". Management is secondary in the long term of this company.

iPierian has spent $50 million dollars to reach this point:

iPierian used its stem cell technology in recent months which has given it new insights about targets to go after on the Tau protein and in the Complement pathway.  

- Nancy Stagliano 

Recent months? I guess the first few years were spent firing CEOs. The latest CEO was busy on her startup CytomX Therapeutics.

Our novel platform represents a transformational drug discovery and development approach.

That sounds familiar. The chairman of the board is also the chairman of Geron! Why did Nancy leave CytomX? Why did the iPierian leaders abandon their ship? Who is suppose to solve the problems created by the others? I don't have much hope that iPierian is not Cargo Cult. All of the signs are there. The founders are gone. The new leaders are doing what they did at their last job. Everyone at the top seems to have worked with each other before. That wouldn't be a bad thing if this were a more successful industry. Lots of money has been wasted and people are trying to get some of it back. Think gambling. The most difficult problems facing the company is in drug discovery. All of the PhDs from the best schools are out trying to get money from investors. The laboratory staff have been handed an exact path that they must take to success. If they fail, they lose their jobs. Money is running out so they had all better start succeeding.

Look to the sky. Hope the planes come.

Books

I've been reading a book written by the silent movie actor Douglas Fairbanks. It's called "Laugh and Live". It's written in a style that must have been popular back in the 20s and 30s. Very positive and nothing but self help advice from one of the most successful guys of that era. Fairbanks must have felt loved and he was giving back. I'm on a chapter now where he talks about good books.

Books by such men as Marden and Hubbard are great generators of the electricity of doing things. They have put into words those innermost emotions which are the instruments of success. They point out a way we may safely follow. They loan us inspiration which causes us to act for ourselves. They give us thoughts that are useful and practical which we never would have gained by virtue of our own reasoning power. 

It is the corniest book ever written but I love it.  I'm probably the most negative guy that ever blogged. I know that I am a nattering nabob of negativity and that people are turned off by that energy. That is why I read Douglas Fairbanks and Dale Carnegie. I, more than most, need to be reminded that reality is what we perceive. Science is not just what we perceive but pointing out how everyone is wrong all the time is a bummer.

Still, some of my favorite books seem to point to fallacy of reasoning. A Drunkards Walk, Wrong, How We Know What Isn't So, On Bullshit and Everything Is Obvious Once You Know the Answer, are just a few of the books that have inspired me to become a more critical thinker and disregard fears of turning people off of my message. Den of Thieves, The Big Short, and 13 Bankers are some of my favorite books on people who succeed while simultaneously driving their industry into the ground. I read biographies like "I Fatty" about the rise and fall of Roscoe "Fatty" Arbuckle. Somehow his tragedy is more interesting than the mundane existence of a biotech guy destined to live an unexamined life. I'm a devout atheist but I don't care to read the latest books on the subject. It is uninteresting because I don't need any reasoning to help me clear up any thoughts on supernatural beings. I read James Randis Flim Flam and I think it's a book that should be mandatory reading at every college in the U.S. He touches on how people believe and why they fight like hell to believe in things they want to believe in, in spite of the facts. I like Malcolm Gladwell even though, as one reader informed me, is a bit of a Cargo Cult social scientist himself. Nonetheless, he has interesting notions and it makes you think. He led me to The Checklist Manifesto. Imagine the complexity of building a skyscraper or running a busy restaurant. Why is biotech so simple and such a failure? I like reading about old Hollywood. Flapper, I Fatty, Minutes of the Last Meeting, Good Night Sweet Prince, Hollywoods Hellfire Club, were all good. These people also led interesting lives and in the end they grew old and came back down to earth. They were human beings that we held up as people we want to be. In examining their lives we get an idea of who we are. Imperfect human beings who have to get up and go to work.

It's clear that I don't read much fiction. Just what I read in the science journals. Wa wa wah! Debbie Downer. What Fairbanks had to say about books is very true. They inspire us and give us thoughts that we wouldn't have on our own. That is what eats at me with modern day science. There are too many intuitive thoughts that need to be proven. Upon examination you find out that those thoughts were too simple. That is when my mind starts to search for explanations. That is also the time I'm sent back into the lab to get the data to fit the preconceived notions. The narratives of the scientists that I've worked for was fiction. Reality is so much more interesting. Without coming to an understanding of the human mind and why we believe such nonsense, why so many people get away with bullshit and rise to the top is hard to fathom. If it's hard to fathom, I'm right there, ready to take notes.

The world is full of diversions that are known to be fiction. Movies, sit coms, and books. Other things are bullshit passed off as reality such as John Edward talking to dead people. I don't mind it because I can avoid it if I don't find it amusing. What I mind is the Flim Flam that has seeped into the world where I go to get away from fiction. I want my reality to be challenging. I want to struggle to understand until one day it all hits me like a ton of bricks and I'm blown away by the amazing world that I live in. I'm not just a negative guy. I'm truly interested in this world and how it works.

The Amgen Study

Why were 47 out of 53 landmark oncology papers studied by Amgen scientists found to be non-reproducible?

Six of the papers, 11.3% were reproducible. The assumption we should all have at this point is that around 90% of published papers are not reproducible. The Amgen study should have expected these results. The recent AACR annual meeting should have contained 90% non-reproducible information.
Each new issue of Nature, Cell and Science should have 90% non-reproducible information. The ten percent that can be used to develop a technology or advance human understanding, is science. The 90% is cargo cult, fraud, bullshit, honest mistakes, accidental or some form of fooling ourselves.

This blog is about both sides, but mostly about studying the 90%. I chose the analogy of Cargo Cults because it requires a religious type of mind to participate in the 90%. I talk about bullshit, in a serious way (ala Harry G. Franfurt, philosophy professor at Princeton), because I believe that is what the leaders are up to. The whole blog boils down to understanding the way in which we participate in non-reproducible "scientific" research and why so many defend the practice.

We begin with a narrative. Ideas get kicked around. A certain percent of those ideas get put to the test in the laboratory. The scientists (creators of the narrative) do not go into the lab and verify the research they are building upon. They do not go into the lab at any point. They send in younger weaker minds to retrieve specific results. Once the data is in it is applied to the narrative and used for writing a paper. Once published the idea must be advanced, preferably by others, to validate the mind (and career) of the person who came up with the idea.

I'd like to recount the journey of one idea and how it landed in the 90% group. It's an old story that I've told in many ways on this blog but it haunts me.

My story is about a small biotech. The company was in existence to sell an antibody against denatured type IV collagen. The mechanism of action was based on an unproven theory, the idea.

A humanized, affinity-matured IgG1 and its parental murine IgM have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models. 

The, "and thereby" was the whole idea. As a tumor spreads it tears into the structural matrix of our bodies. Most of that matrix consists of collagen. Therefore, angiogenesis is working on or with the surface of that matrix and its collagen, right where the tumors are spreading. But that was just a nice narrative. They skipped past the science part of proving the theory, made an antibody and swung for a home run.

I participated in several mouse studies where it was proven to me that the antibody did not have an effect on tumor size or growth. When the mouse studies showed no effect on tumor size they simply re-measured. In their minds this was not dishonest. This is precisely the kind of research that the scientists at Amben would have been unable to reproduce. Our initial report to the scientists provided no reduction in tumor size, compared to the PBS group. A paper was later published with a 57% reduction. I'm not sure if they used the re-measured data but it was the same drug on the same mice and tumor cells.

The efficacy of this antibody was presented at AACR in 2006. Also in 2006 Micromet filed an IND.  There is no information on the fate of the antibody. It was last reported on in 2007. My own work on the drug took place in the early 2000s. It was a painful experience. We lost a few good men. Eventually we handed the whole kit and kaboodle over to a group of "scientists" who knew what the narrative needed from the lab.

The people who conducted this research were intelligent people. They knew how to make their presence known in a meeting. They had impressive resumes and advanced science degrees. Their papers were well thought out and they competed well for publication. All of the authors in the 53 landmark studies evaluated by Amgen were of the same breed. Back woods hillbillies wouldn't be able to do what these men and women do. There is a skill involved. There is a culture to fit into. The knowledge of antibody structure, humanization and so on are all complicated concepts that require a certain mental capacity. My bosses had it. The papers and the posters and all of the money are of little value now however. If the goal was ever to put a drug on the market and reduce the size of tumors in cancer patients, they did not have enough intelligence. That intelligence tells you that the truth is the only way to move forward without one day shutting down because you missed something. We were always missing something and we knew it. In the Amgen study, that something was discovered in 47 out of 53 papers. We were always publishing and telling people about things we knew were not reproducible. We were smart and we knew how to avoid having to go back over our work.

What then happened to the research papers from the Amgen study?

The Amgen scientists approached the papers' original authors to discuss findings and sometimes borrowed materials to repeat the experiments. In some cases, those authors required them to sign an agreement that they would not disclose their findings about specific papers. Begley and Ellis were therefore not free to identify the irreproducible papers — a fact that the Comment should have mentioned.

Nature, like most journals, requires authors of research papers to make their data available on request. In this less formal Comment, we chose not to enforce this requirement so that Begley and Ellis could abide by the legal agreements.

The scientists at Amgen could not have implemented their study had they reserved the right to reveal the outcome for individual papers. The Comment highlights important systemic problems in preclinical cancer research, which we felt appropriate to communicate to our readers, even though the authors could not disclose the studies in question.

Bullshit Man!

I'm reading the book "On Bullshit" by Harry G. Franfurt.

That is why she cannot be regarded as lying; for she does not presume that she knows the truth, and therefore she cannot be deliberately promulgating a proposition that she presumes to be false: Her statement is grounded neither in a belief that it is true nor, as a lie must be, in a belief that it is not true. It is just this lack of connection to a concern with truth - this indifference to how things really are - that I regard as of the essence of bullshit.

The business of science fails when they have that lack of connection to a concern with truth. What the many people whom I have highlighted on this blog have taught us is that the truth is not a necessary part of a successful scientific career in academia or industry. Life sciences are most successfully pursued by those with the best bullshitting skills. They do not start off on a journey to find the truth. At the same time they are not deliberately being dishonest. They see the success criteria for a Cargo Cult and they know it is within their skill set to reach the higher ranks.

In the Amgen paper regarding 53 landmark oncology papers we learned that one author published the results of one experiment that was tried 6 times. The author admitted that the reported results made for the best narrative. That was the reason he published his result. This is a lack of connection to a concern with truth.

We've hit some dark times but bullshit remains safely behind the wall of, "It's science".



Would BullshitMan help?

Biology Versus Chemistry

In a recent In The Pipeline post, Derek Lowe asked the question:

Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?

The difference between chemistry and biology is blurred in the pharmaceutical business. For example Derek goes on to say:

...most chemists don't (to me) seem to go to the level of detail that I often see from protein purification people...

Let's take a look at a few protein purification job descriptions and their education requirements.

1) BioForce Solutions:  Protein Purification Scientist - BS degree in Biochemisty, Biology, Chemistry, or Chemical Engineering.  
2) Astellas Pharma: Group Leader, Purification Process Development - Ph.D. in a scientific discipline (Biochemistry, Chemical Engineering, or Biochemical Engineering)
3) Sunrise Systems Inc: Research Associate - BS in Chemical Engineering preferred 
4) Laguna Source: Senior Scientist, Protein Purification - Ph.D. in Biochemical Engineering, Chemical Engineering or related Scientific/Engineering field.
5) R&D Partners: Scientist I II, Purification - BS/MS in Biochemistry, Biology or other relevant discipline 


Okay, we've grabbed five random protein purification job listings. They all involve the purification of proteins. Out of the five jobs how many required the following degrees?

Biology     Biochemistry     Chemistry     Chemical Engineering     Biochemical Engineering     Other
2           3                 1             4                       2                            3


In order to address the question that Derek asked we have to first define what a chemist is versus a biologist, in a biotech/pharma setting. According to Derek, chemists are not protein purification people. What the above information shows is that chemists can be protein purification people. 

Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?

What if a chemist gets a job as a protein purification method developer? Will he/she present his/her work with less detail than their biologist predecessor?

A trivial detail for sure. It's just a bloggers question to provoke thought. I agree that chemists give less method details but they use too many big words. Ultimately however, details matter. We should worry more about what is not being said.

The easiest way to explain this idea is to contrast it, for
example, with advertising. Last night I heard that Wesson oil
doesn't soak through food. Well, that's true. It's not dishonest;
but the thing I'm talking about is not just a matter of not being
dishonest, it's a matter of scientific integrity, which is another
level. The fact that should be added to that advertising statement
is that no oils soak through food, if operated at a certain
temperature. If operated at another temperature, they all will--
including Wesson oil. So it's the implication which has been
conveyed, not the fact, which is true, and the difference is what
we have to deal with.

Winning The Lottery

I once heard that your odds of winning the lottery are very close to your odds of finding a winning lottery ticket. Holy Shit.

Finder

Keeper

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The Information Scapegoat

Wise Old Sage:  Why hasn't the cargo shown up? Where are those big metal birds that brought food and medicine to the white man?

CEO of Cargo Cult:  We have information that can bring the cargo but everyone is hoarding it. If we could simply share our information using the "computers" we would get the cargo.

Enter Sage Bionetworks.  The Sage is now going to help the gatherers of information. The similarities between this information sharing and the Genome Project:

But a lot of what comes next will depend partly on what Sage does to clear the way, and what people in the biomedical research community choose to do with its platform. “Our mission is to develop flexible approaches that can be championed by others,” Friend says.

Championed by others?

Friend is Stephen Friend, a former VP at Merck who started a nonprofit with a bold vision to speed up drug discovery. He plans on offering the scientific community a common place online where scientists could pool their data and brainpower to speed up the pace of discovery and drug development. According to S. Friend, "biology has become far too complex for any lone researcher or Big Pharma company to keep tackling problems in isolation." 


Biology has gotten more complex?

Flash back to the days when biology was not too complex. It was so simple, we could still make progress without computers! Rene Descartes was a scientist who made many important contributions to the scientific community. He had a set of information that he thought had value.

 Meditations is by far Descartes's most popular work—though this would not have been the case in Descartes's day. This work is important to today's scholar for many reasons, not the least of which is its including as an attached text written objections from some of the best minds living in Paris. Mersenne sent the Meditations to philosophers and theologians for criticism. The list of critics includes: Caterus, Hobbes, Arnauld, Gassendi, and Mersenne himself, with several other unnamed readers who raised their objections through Mersenne. A later edition would include an objection from Bordin. Descartes replied to each critic, and the result was an appended text referred to as “The Objections and Replies.” The second edition contains seven sets in all.

Descartes's letter to the “learned and distinguished men” of the Sorbonne, which is appended to the Meditations, suggests that he was trying to pitch the Meditations as a textbook for the university. Though the endorsement of the Learned Men would not have guaranteed that the Meditations would be accepted or used as a textbook, it could certainly be viewed as an important step to getting it accepted. Unlike today's notion of a textbook, in Descartes's day “textbooks” were intended mostly for teachers, not students. Typically, at the close of a teacher's career, his notes would be published for the benefit of those who would go on to teach such course material.

A text book for teachers who would go on to teach... What we have with Sage Bionetworks is a list of information. The difference is clear. Sage offers random information that the proprietors did not generate themselves. They hope to share the information with people who will turn it into technologies that make money. Cargo. Descartes had a set of information that he gathered himself. He offered it up to the teachers in a manner that would allow them to understand, in great detail, who, what, when, why and how this information came to be and what can be done with it. It wasn't a football to be handed off but a playbook on how to play the game.

Disassembled an old car. Lay the parts on the ground. Bring in an engineer and tell him to make the car run again. It won't work. Sage Bionetworks likewise, will not work.

One of the ways scientists used to get information was in the laboratory. The laboratory is where you ask nature a question. If you are clever and do so in the right way, nature will reveal itself to you. At the end of your career you might have a very interesting text book to write.

  

John Le Carre

At 9:37 of this video you hear a great description of what journalism should be. "Whatever we came upon, however offensive it was to those in power, we told it straight".



There is plenty to cull from this interview that pertains to our own predicament in science. I'm certain that what we experience when dealing with the elite has been dealt with by those in the past. The concept then of telling the truth, as Feynman described, comes with great opposition that has always existed. If the truth is something that benefits power then they will have you go back and make sure you are accurate. If it goes against their hopes and dreams it might just get squashed on the spot. You will end up marching your meager possessions out to your car in a cardboard box that day. This is true now, yesterday, in industry and in academia.

My work in a Nobel Prize winning laboratory seemed to have a strange relationship with the truth. I wasn't alone in my utter confusion at this my very first foray into big time science. My lowly supervisor however understood what it took to get her name on a Prusiner publication. She has spent her entire working life at this lab and by professional science standards, is successful. Yet if she were to be sent to any other lab, her work ethic and intelligence may not be sufficient to keep her around. She found her niche, and it required a special talent. It wasn't scientific.

David Cornwell, aka John Le Carre, spoke truth to power. Gary Taubes spoke truth to power. What we need more of are people like these. It is difficult however because we have no real science journalists. Science information is told to us by people who journalists should be writing about. When Taubes wrote about Prusiners very first Prion paper he mentioned something Prusiner left out.

The researcher who did Prusiner's lab work at the University of California at San Francisco quit over the publication of Prusiner's very first prion paper in 1982, arguing that Prusiner was overinterpreting the available data to push the prion hypothesis. 

Only a journalist would enter that information into the public domain. In discussing Prion research one might want to know who this man was and why, exactly, he quit. All we know is that he quit due to "overinterpreting the available data".

To some of us, science is not just the boring details offered to us by the authors of published papers. It's personalities, power, lies, cheats and the occasional flash of brilliance. The truth behind our daily lives conducting science and spending billions of dollars is a good story. Who is really telling that story. If you are lucky enough to work in this field, whatever we come upon, however offensive it is to those in power, tell it straight.

The DNA of Identical Twins, A Novel

Bill Clinton said that the Genome Project was going to be one of the major scientific discoveries of the 20th  century. Was the Genome Project a discovery? It was a project in which we laid out a simple plan. Sequence the DNA of five people.



Any one of us can sequence our DNA today. The details on how to do it are no more or less a mystery to us than it was to Clinton or any of the bigwigs on the project. Let someone else worry about it, and we'll take to the podium when the work is done.

I've taken up my own genome project. I have an identical twin brother so there will be two people sequenced and there will be two sequences for sale. That's right, for sale. This is a biotech business. The product I'm selling is not just a DNA sequence, but a genome of two clones that will be sequenced over and over as we progress through life and die. The genome project pieced together their sequence from five strangers from different parts of the world. I will be offering two separate genome sequences from identical twins who are very different people.

Unlike the genome project I am starting my project with a check list. What are our similarities and  differences, nature versus nurture? The sequences will be overlayed to find the differences and the similarities. I will look for correlations but make no claims to consequences (causation). Perhaps my smoking habit led to some damage. Then I throw in a twist. After all of the comparisons have been made I shell out another five grand and get another sequence done. What are the differences between me and myself? Could there be some human misunderstanding of how we humans go about DNA sequencing of a genome? We're still new at this.

I've seen the way in which humans interpret simple DNA sequences. A single read runs about 1000 nucleotides. In the beginning stretch there is usually some noise that must be thrown out. I've found explaining this to scientists is not easy because they don't want to hear about it. In explaining the little anomalies that come up when allowing Vector NTI to spit out your sequence from a FASTA file I have encountered opposition. I've engaged in adversarial conversations about who's fault it is that we have these little problems. In my own project I will address these issues.

Since 3 billion nucleotides 3X is a lot of letters to put down on paper, the sequences will be available online. The details of interest will be broken into chapters of a book where I lay out my naive view of DNA. Perhaps that will be of interest to the world outside of science. We have questions for the genetics community. How do they know, for example, that every cell in the human body has the same sequence. Surely they do not. A B-cell coding for different antibodies have shifted their DNA around. I should probably make a side project out of sequencing B-cells.

This is getting expensive!

It is also getting exciting, at least for me. According to the genome project logic, my brother and I should die on the same day from the same disease. But DNA as a predictor of health and happiness is a myth for now. We need to learn more before we can start making wild claims about future humans living to 150 years old. For now we need two clones, twins. But I promise to have this project done in the next five years. When I am done I will publish in book form, "The DNA of Identical Twins". Publish or perish is not a problem on this project. Along with cheap DNA sequencing, we now have the ability to publish books on our own. It will simply be a few DNA genome projects, of twins and a couple sequences of me alone, different times different cells. Online perusing of the sequences will be for sale. The book will be for sale and I will put forward my own naive ideas on what our DNA is there for. I couldn't do much worse than the leaders of the genome project. I am a free citizen. I have nothing to lose here but a little money. I don't predict any huge impact on the future of human health. I simply want to open up a window and see what is on the other side. Unlike the genome project folks, the philosophy here comes from Sgt. Joe Friday from Dragnet, "Just the facts ma'am."

Do it, publish the results, make a side project out of my own thoughts on the subject, and walk away.

"We Re-Measured" Honesty

In my study of the Cargo Cults of Biotech I have seen first hand the curious deceptions that humans employ to get around the rigors of the scientific method. We had a drug to prevent angiogenesis, for example, that was to stop tumor cells from growing. In a study using mice, the Rituxan control group stopped tumor growth entirely. The PBS group all sprouted various sized tumors. Some mice, with smaller tumors, had to be euthanized sooner than those with bigger tumors. The group of mice receiving our drug were no different than the PBS control group. Without any trickery, Rituxan was an obviously efficacious treatment for mice being injected with cancer cells. Our drug was not working.

We were sent back to the lab with a grad student who showed us how to "properly" measure the tumors. She got the desired results by squeezing the caliper a little tighter around our drug group, and less so around the PBS control group. When I handed her a mouse that she had already tested, she wanted to know what her first measurement was. I refused to tell her even what group the mouse was in. Should she measure tight or loose with the caliper?

Why not simply take out a new data sheet and change the numbers? Because that would be misconduct. By re-measuring the tumors we were being, by Cargo Cult standards, more honest. The ceremony of re-measuring made us feel better about fudging the data. It somehow took us out of the realm of flat out fraud.

This experience shaped my view of early stage cancer research. The measurements are meaningless because cancer doesn't work in a manner that would make our research easier. Tumor size is an end point that the human beings conducting research can handle. The reality of explaining the "leaves blowing in the wind" chaos of cancer cells in the body would be too hard to follow. Using the "Drunk Under the Streetlight" logic we now have a place to look for efficacy. Using the "Beer and Pizza Diet" we then have a way of dealing with the nonsense we find.

Our anti-angiogenesis drug used in the cancer study described above, was picked up by a company called Cancervax. Their product was an attenuated cancer cell that expressed 26 antigens on its surface. It failed clinical trials in 2005 and the drug development ended. The anti-angiogenesis drug faded away, last heard from in 2007. While these two anti-cancer products were discontinued, the methodology remains much the same. Cargo Cults may have many iterations of their airports but the thing that is missing is always missing.

Two news items came up this week to exemplify the Cargo Cult science as usual approach. Presage Biosciences make the claim that they can separate the winning compounds from the losers early in development. According to Xconomy, Presage has partners who, "are hoping to improve the odds of success in clinical trials, where only about one out of every 10 cancer drugs that enters clinical trials ever makes it through the hoops necessary to become an FDA-approved product." The leaders are right ten percent of the time? Well anyway, Presage will help them increase their hit rate. "One of the operative words in cancer research today is “combinations,” which Olson (Presage founder) said people are buzzing about this week at the American Association for Cancer Research meeting in Chicago. Companies are becoming more interested in finding those instances in which a single drug doesn’t work on its own, but can show a potent effect when given synergistically with another compound that works in a different way." 


In 2012 folks at the AACR are buzzing about combinations? Perhaps science needs historians to keep the research in a scientific perspective. In addition to CancerVax's 26 antigens, I think  the Anil Potti story is germaine to this company. The Presage approach assumes that maybe we are only off by a few targets. Instead of grandma taking one or two pills for her cancer, she might need ten. Twenty? A thousand? No, that couldn't be because we can't make grandma take that many pills. The bloggosphere is buzzing too. Here is a comment on the AACR from In the Pipeline:

Take a look at the 6000+ abstracts from the 2012 AACR national meeting last week. Wishful thinking is a mild description for that carnival sideshow. Maybe 3% of the work was worthwhile. Four darts and a genome map would provide a better chance of hitting a cancer response biomarker.

I added that because it cleanses the palette after Jim Olsons gung-ho attitude towards the AACR meeting. And it's funny. 

The second news item this week comes from Oncothyreon.  They are marching forward with a Beer and Pizza Diet approach to their original stinker. According to Xconomy:

There are some very interesting scientific and business reasons why Oncothyreon wants to test the second-generation product, called ONT-10. It is attached to a more potent immune-boosting compound than the original, and the new drug is designed to stimulate a sort of two-pronged immune response, instead of just the T-cell reaction sparked by the original.

Why not start with the more potent immune booster? Why did they need to improve something on which they had already placed a huge bet. The company and their investors have us thinking that the clinical trials of their original product won't be much to talk about. But the new and improved product... now that's... well it's just going to be better... that first thing we did wasn't well thought out and... is it getting hot in here?

My message is that we are not really changing the way in which we approach cancer research. At the end of the sciencey meetings and the millions of dollars, a low paid BS Biology major, in her early 20s will be given a caliper and told to go measure the tumors on the backs of nude mice. Whatever the method, whoever makes the measurement, some things will remain the same. All of the promises will be backed up by the same "we-remeasured" honesty. We have not worked out a method to prevent it. It is a human issue involving psychology, not a laboratory issue, business model or funding issue.

Of course we hope that Presage and Oncothyreon are telling the truth. We want to believe them. We want them to be honest and not just "we re-measured" honest.

The Quilt

At the "Reinventing Biotech's Business Model" meeting yesterday here in Seattle we saw an assembly of men and women who will lead us to prosperity. At least that was their purpose for getting together.

“When you’re building a team today, you need to have people with enough former company T-shirts to knit together a quilt in a nursing home,” quipped Bruce Montgomery, the founder and CEO of Seattle-based Cardeas Pharma. 

That’s one way of saying biotech startups now need teams of highly skilled, highly experienced people who can go a long way on a little bit of money. That was one of the main themes that came out yesterday at our big Xconomy event, “Reinventing Biotech’s Business Model.“

It's also another way of saying that we have created a multi-billion dollar quilt pieced together by failed biotechnology companies.

Quip:  A witty or funny observation or response usually made on the spur of the moment.


The main theme seems to be that failure is no big deal. Make a quilt and move on using the same people. Perhaps to reinvent biotech we should replace certain people. If you have made a fortune in the process of losing a fortune... you need to be replaced. 


We should think about making another quilt in ten years. This quilt will be built from success. 

Avi Biopharmas Major Advance

Over at Dendreon they have a mechanism of action that can't be confirmed. Rather they go with the survival data as evidence that their MOA, as depicted in cartoon form on their website, is accurate. Avi Biopharm this week has shown a different approach. Their product did what the cartoon depiction advertised.

The study, which randomly assigned 12 boys to a couple different doses of the AVI drug or a placebo, showed the boys were able to produce about 22.5 percent of normal dystrophin levels after 24 weeks on the therapy, while there was no increase on the placebo. No serious adverse events were reported in patients on the experimental treatment, and no patients dropped out of the study, AVI said.

On the downside, their was no improvement with the higher dose and worst of all, the boost in dystrophin had no clinical benefit. Researchers saw no difference in patients’ walking ability in a standard 6-minute walk test.  

The study’s lead investigator hailed the finding as a “major advance”. 

Opposite of Dendreon, Avi has evidence that they can make the body do something very specific. Dendreon made the claim that they could elicit an immune response resulting in tumor cell death, yet they could not provide evidence of that MOA. Avi made the claim that they could make the body produce dystrophin and they provided information claiming that they did. Yet Dendreon provided a clinical benefit to their unsubstantiated MOA. Avi could not provide evidence of clinical benefit to their substantiated MOA.

From a scientific standpoint it is indeed interesting that a piece of RNA can accomplish this result. Eteplirsen is the therapeutic candidate for DMD and uses their core PMO chemistry applied as a splice switching oligomer (SSO). The drug is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter – but still functional – form of dystrophin. From this point one would think that the scientific community would begin conducting research into skipping exons to restore or improve gene function. What we do in biotech is swing for a home run however. In this case I don't think we have much of a chance. Are we altering our DNA or are we throwing nucleic acids at the body and hoping the DNA will know what to do with it?  


The investor community gave the major advance a thumbs down. The stock went down as much as dystrophin went up, 25%. This could help investors understand such claims of 25% changes. If the stock were worth $100 they would have lost $25 per share. Instead, after a 25% loss, the stock was worth $1.16, a loss of 38 cents. In terms of what matters, the percentage of change is less important than the consequences of change.


When dealing with our DNA, we are dealing with evolution. Can we change millions of years of selection that has produced human beings destined to live short difficult lives? Of course we should be trying. But is this the best way? A for profit effort hell bent on surviving one month to the next? The desperation in the careers of the Avi scientific staff leads to certain outcomes that ignore the sad results of this trial. In a fair world the science would be handed over to an academic lab to learn more about what happened. The expense of moving on with more clinical trials, the suffering of the patients through this invasive research on their muscles is not warranted. It is time to get back to learning about our DNA and to move away from trying to make it stop doing something evolution has somehow allowed.  

The Provenge Trials

The comment left yesterday directed me to this website created by Marie Huber about the Provenge Trials. A one woman crusade against a Cargo Cult is too good to be true. She has alliances with prominent scientists, a website, evidence, and she is clearly passionate about this company and what they did to get their product on the market. Will we see her on 60 Minutes one day? It is modern day "Emperors New Clothes" story. Have we all played along because we have to believe the FDA and the multi-billion dollar biotech?

I will let her tell her story so please go to her website and read all about Provenge and Dendreon.

   

Immunity to a Cancer in Progress

As Science Tsar of the World, I hereby assign Group A to study the Dendreon science and their vaccine for prostrate cancer. What I want Group A to study is the concept of a cancer vaccine, what they did to prove the mechanism of action, and how they conducted the statistical analysis of the clinical data.

Why is a hedge fund analyst more skeptical than the scientific community? Who is Marie Huber and what is her motivation?

If I, the Science Tsar of the World, want to know more about the Dendreon story I will need to know more about the psychology of the players. I know Dendreons vaccine story and it is bizzarre.

Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man's arm in a three-to-four hour procedure called leukapheresis.

The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a "fusion protein:" One protein that stimulates the cells' growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells' surfaces.

Dendreon says the patients' white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.

Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.

In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.

I set the scientists down with the piles of data to sort through. That becomes one piece of the puzzle. I now set my sights on Marie Huber.

She argues that the main reason Provenge seemed to extend survival - a crucial factor in the FDA's decision - was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.

She raises the possibility the "placebo" they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.

My scientists are working on the placebo logic / clinical trial design. But Marie... who are you?

In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said. Instead, she says she is motivated to help "vulnerable and desperate patients" - so much so that she gave up her job, salary and health insurance. 

Why did she give up her job for this? Because she cares? How did she get so much traction to her side of the story? An unemployed hedge fund analyst takes on a former $5 billion dollar biotech and people listen? It could have something to do with the unforgiving logical nature of science:

"There is no efficacy in the younger patients, the primary group where you would expect it," said Huber.Since the immune system weakens with age, an immune-based therapy should work better in younger men. Some experts agree."If it was really a vaccine, you'd think younger men would show more response, since they are more immunocompetent," said NCI's Rosenberg.

Then there is the logic of Dendreon:

"We have a lot of data that supports the idea that the product works the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief medical officer. "We're seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor."

There is support but no verification. Marie Huber has just as much fire power scientifically. Applying Occams Razor, a principle urging one to select among competing hypotheses that which makes the fewest assumptions and thereby offers the simplest explanation of the effect, who should we believe? Do we even need to know who Marie is and what her motivations are? Scientifically, no. Cargo Cult Scientifically we would love to know more about her and why she is so into this issue.