Harry Perry

I want to take a break from trying to figure out the Cargo Cult world and think about something that has worked. This is Harry. He began playing guitar and singing songs for people down on Venice Beach back in 1973. Some people think of him as strange. But if you were to look at his life on paper you would find a stable successful American businessman. He's had the same job since 1973, he leads a healthy lifestyle and he shows up to work everyday. He has no boss, just the hassles of everyday busking on the beach.

As a philosopher, I don't pass judgment on whether or not Harry is an odd fellow. Personally, I like to think about Harry happily blading up and down the boardwalk while I suffer through days of bad science and endless meaningless meetings at multimillion dollar mistakes with sciency names. I do judge cargo cults. Harry is not participating in a cargo cult. He plays you a song and asks you to buy a CD, a shirt or both. Twenty bucks for both. While he plays you can take as many pictures as you like. He has branded himself. He brings his product right to you and you can take it or leave it.

As a biotech employee I have never actually worked at a company that has sold a product. We've brought in millions of dollars but we've never turned that money into a profitable company or product. The only remaining company that I've worked for that hasn't folded is one that makes the claim (among many odd claims) of growing their drug in a more efficient way than the rest of the industry. The claim is false. In fact I don't know of a group of people who know less about the actual manufacturing of such a drug. It seems to me that they took the truth and simply said the opposite. If my experience has taught me anything however, this company will fail. You can only BS for so long.

As I contemplate the future, mine and the cargo cult airports, I can't help but think of Harry. He's outlived 100 billion dollars in biotech waste and hundreds of companies staffed and ran by the brightest minds of our life science scholars. His music isn't the best. He just rolls up to people and plays them a song and asks them to buy a T-shirt. At night he goes for a jog up the coast of that beautiful beach as the sun sets over the hills of Malibu to the north. His future will be to keep on doing his thing til old age takes him out of the game. Our industry will try to get him to hand over some life savings for the pills we make for old people with two months to live, our primary target. But I think Harry will die quick with only a little pain and no regrets.

Everything Is Obvious

If I were to put together a college course on Cargo Cults it would be based on five books:

1) Innumeracy (John Allen Paulos)
2) A Drunkards Walk (Leonard Mlodinow)
3) How to Lie With Statistics (Darrel Huff)
4) Surely You're Joking Mr. Feynman (Richard Feynman
5) Everything Is Obvious, Once You Know the Answer (Duncan J. Watts)

All of the books describe a lot of what Feynman hopes we all get through the course of our educations:

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.

Book one asks us to evaluate our relationship to math. Book two is a hilarious view into our random lives. Book three is a classic on how statistics are used to tell any story imaginable. Book four is Feynman telling funny stories from the point of view rarely seen. Book five is new so I'll elaborate on why it's on the list.

The author has an education in physics and engineering. As a profession however, he chose Sociology. Although the field has done a poor job of applying the scientific method, the author believes things are turning around. In his book, Watts explores what we think we know (not just sciency subjects) and he asks us to question that reality. We use common sense to decide what to wear to work versus what to wear to the beach. We use common sense to tell us what to do and we don't really question why. In science we are suppose to ask why.

What this course will do is important. Many in the class will be in the process of preparing for the corporate world. Many of those people will pursue science degrees in their quest to start a biotech company or to climb the ladder at Pfizer. They are bullshitters. Science is going to help them sound sciency. The others in the class however will be nice normal people who just want to learn a little and go into the world where they can contribute, go home and live their lives. They all need to know what the tricks are so that the bullshitters are less confident in bullshitting. It may even put a few bullshitters on the straight and narrow path.

After the course, students may a new framework in which to think. In questioning pharmaceutical executives for example, they might find their thinking more in line with common sense. RNAi is a good example. A Nobel Prize was awarded for describing a process that common sense tells us would be the next big drug platform. Drugs interact with molecules that cause disorders. Eliminating those molecules will prevent the molecules from causing the disorder. It's sciency but it's not science. Science is proving the common sense notion of RNAi to be wrong.

In the field of economics we have common sense notions such as giving the wealthy more tax breaks will lead to more jobs. How is that working out for us? The common sense comment I've heard is, "I never got a job from a poor person." True, but by the same logic, we could make that poor person rich and then he would give you a job. The truth lies somewhere else most likely. Jobs are created... how? We don't know. As a leader in the field you must appeal to the majorities common sense to make them think you do have an answer. Tax breaks for the rich is the answer. It's a common sense solution and it hasn't solved the problem.

The term sciency, by the way, is used in the field of Bullshit. Sciency refers to things that seem scientific by virtue of what scientist is speaking and how scientific they appear to be. Bullshit doesn't rely on lies nor the truth. Bullshit relies on whatever needs to be said or done to achieve the goal. Common sense is the foundation of the process. It's just common sense to listen to scientists when they speak of science. If you don't know what you are talking about you can bullshit your way around by sounding sciency.

The Cargo Cult Science course would also go against the grain of common sense knowledge. The five books are about uncommon, yet learnable knowledge. It would be a science course that isn't very sciency. There would be math but it would come in the form of Innumeracy questions like, "how fast does hair grow in miles per hour?" There would be expert guest speakers. The tests would be to distinguish which ones were bullshitters and which ones were actually who they said they were. Unlike science courses, the CCS course would be fun and accessible to all students interested in looking at the world more objectively. It would prepare you for no occupation but it would help everyone do their job better. When the students leave class and go to the next one, maybe they'll raise their hands and ask more questions.

The Proverbial N-Ray Prism

In a story related to my last, comes the story of the mutated prion that wasn't. We all make mistakes. It is how science deals with them that the keeps us from the truth.

There was a young post-doc who began his career in a laboratory of a prominent scientist. The scientist, not the post-doc, had an idea that needed to be verified. The idea was that a single amino acid substitution could prevent the conformational change of a protein that allegedly led to a brain disorder. There was cloning to be done, assay development, and the usual gels and western blots. Not rocket science but the conclusion, if things worked as expected, would put the world on notice. This was to be a major stepping stone.

At the end of a year the data was in and it all looked kosher. It was time to write up the paper and get the news out. There was only one problem. No one had sequenced the DNA of the clone being used in the study. Prior to submitting their paper the clone was sequenced. The mutation in the amino acid sequence wasn't there. The research was done on a protein that was the same as the controls. A new question arose. How did the data fit the preconceived notion?

How did they see their N-Rays without the prism?

The young post-doc failed in his task. It wasn't his idea but he understood what was expected of him. If he was to make it in the business the results needed to come out a certain way. Like a Sherlock Holmes novel, the final outcome smooths out the leaps of faith and unwarranted assumptions. Science is about genius. At least that is what we think the world expects of us.

Imagine a P.I. testing his post docs by giving them a bias in the form of a protein that is suppose to do something. An assay is provided to give an output signal that will vary from run to run. The protein and its control are in fact the same protein. Will the post-doc point out the precision issues of the assay or will he run the assays until the desired story has been told? In other words, create an N-Ray story. Short, sweet, elegant and false. Provide the measuring tools and bias the outcome. Who uses science to tell the truth? Who uses the bias to tell the story they know will get them them ahead in life?

If you've ever been in a bad job and you needed to get out, you knew better than to tell the next potential employer you want out of a bad situation. You tell the employer that you are looking to advance your career or something along those lines. The truth is not well tolerated in many human endeavors. It is not tolerated in professional science. It is not tolerated in finance or government. We want certain things to be true. Whether or not the prism is there, we want to see N-Rays.

The Drunk Under the Streetlight

A policeman came across a drunk on a dark road scrounging around on the ground under a streetlight.

"What are you doing?"
"Looking for my wallet, I lost it in that ditch over there."
"Why are you looking for it here?"
"The lighting is better."

I'd like to go back to a phage display project because it encompasses the fundamental flaw of science as it is conducted in the biology, medical world. Unlike other sciences, we have a low standard. W are wrong most of the time. The unofficial measurement, wrong 90% of the time, did not raise much protest.

Dr. Nicklin is one of the scientists who worked on the GETRAPL project. The paper is titled:

Development of efficient viral vectors selective for vascular smooth muscle cells.

And it's findings are false. Here is why.

Nicklin et. al. performed phage display as instructed by the kit purchased from New England Biolabs and they came up with a list of peptide sequences. It was decided that a peptide of 7 amino acids would bind to and deliver their DNA to a specific cells type. Once the peptide was discovered it could be used to deliver the viral vector to the cell where the vector will then enter the cell and increase gene therapy activity.

Many assumptions have been made but we will focus on one thing, phage display. The following is the list of peptides the turned up when using the phage display kit.

Peptide Frequency Peptide Frequency Peptide Frequency
AAPMQVT 1 KVTTTRV 1 TARQDSI 1
AKPSPFP 1 LAKHPDS 1 TGHHIFY 1
ALQBKPI 1 LERGPYG 1 THLSRTP 1
AMPYAPR 1 LVPPSGT 1 TLSNYSQ 1
ANMSLLT 1 MGPPSTP 1 TNGLRTA 1
ANSKLSP 1 MPPGYPH 1 TPPQSTG 1
APATSIG 1 NALKFSA 1 TPTIHKT 1
APQPWLM 1 NPFYSLR 1 TPVQQVA 1
ASTQQPT 1 QLTMFPS 1 TQEYRSA 1
DLRIAAS 1 QPNNHAH 1 TQMRQPP 1
EGLPANP 1 QQQHPFK 1 TQPPIRT 1
EYHHYNK 2 SAPERFS 1 TSPIPPK 1
EYTHTPY 1 SFGENSI 1 TTPRFIL 1
FPGKQTT 1 SGSPPSV 1 TTTLRPS 1
GETRAPL 5 SLPDPIH 1 TYATDRR 1
GHSHSHS 1 SLRPSID 1 TYSQSMT 1
GPGPNIS 1 SMPKLIN 1 VKPBTGA 1
GPNQVEW 1 SNAQSMR 1 VLPRASY 1
GSTQPPW 1 SNMAQHR 1 VNPVNTH 1
HLHTIGR 1 SPIRHVH 1 VSAQTRQ 1
HPFILKP 1 SPQLPQL 1 WAPPPAG 1
HPPBVSS 1 SQSPFFP 1 WNLQPPQ 1
HSFPHAP 1 SSHGSLS 1 WPNTYRL 1
HVLWTPP 1 SSQYAHL 1 YHPMSSL 1
IRPPSII 1 SWLPHNA 1 YLKPPGP 1
KLVASNP 1 SYMYKPQ 1

The two peptides of interest recur twice (EYY) and five times (GET). Had the New England Biolabs provided a database of sequences from other panning experiments, Nicklin would have known these sequences are contaminants from the NEB library. The observance of these sequences is to be expected. They are an annoyance and not the holy grail of DNA delivery for gene therapy. What we have here is a limited data set, kit science, and a hope that something shows up. The kits cost $300 dollars each and thus they provide the streetlight that can be used to search for the wallet in the ditch.

The peptide sequences that were "discovered" in this project are the proverbial prism in this modern day N-Ray story.

Once you have "something" the leadership can get to work. You now have a solution and the corrective measure that can be organized and managed. Leadership knows how to organize and manage. They hire team leaders and project managers and directors and even a few white lab coat kids to run the assays in the lab. And they are kids. They will take that useless phage contaminant and make the assays tell the predetermined story. The only question they ever had was how far the bars on their charts would be separated.

Management has found a nice comfortable streetlight. But the wallet is over in the ditch, under water behind a patch of thick weeds 3 feet high. It is hidden in a big way. 20 yards away the leadership stands with their hands in their pockets directing low paid grunts to look harder. Failure in this system is a guarantee. In order to not face failure, hope is put in its place. Hope keeps the project lumbering on and costing countless wasted man-hours and plenty of money.

A recent comment on the state of medical research from Roy Mankovitz.

I have a background­, and publicatio­ns, in the field of rocket science, having designed control systems for planetary landers and deep space probes. As most folks know, we have had a phenomenal record of getting it mostly right.

Well, with respect to science, research is research, but when I finally starting poking around in the area of medical research, spending decades reading and analyzing thousands of studies, I was horrified. It seems they get it mostly wrong.

We do and this is one example. I worked in a different part of the world but I did the same project. The NEB libraries were the same, the cell target was different, the peptide sequences were the same (we found EYHHYNK)and we made the same charts. We used the streetlight approach because it was within our understanding (so we thought) and we found what we wanted. We found the same peptides Nicklin did. Our bosses were satisfied for the time being and kept our project aimlessly moving forward. We too eventually gave up and found new jobs.

Never Confuse Movement With Action

In the book 'Science Business' Gary Pisano begins with the premise that biotechnology has not lived up to its promise. He has ideas and research and conclusions.

I argue that the performance of a science based business, like biotechnology, hinges on how well the sector is organized and managed to deal with the fundamental business problems created by science.

I argue that organizing and managing a cargo cult airport differently results in another cargo cult airport. The science hasn't produced enough drugs so they must shift the science work to someone else. It appears that science is a word that everyone thinks has one meaning. Medical "science", physical "science" cargo cult "science". It's the equivalent of assuming that "God" is understood by all and thus you start a church in Jerusalem with a Catholic priest. It's a good business model. It's a very religious town. You should make a lot of money in the old collection plate over there.

Gary Pisano does a little scientific research himself in his book. Academia and industry claim that industry scientists are the problem. The solution is to sack the staff and shift funding to university and biotech scientists. Gary points out however, that big pharma was no less successful at R&D than small biotech firms or academia.

Universities clearly began to see their science as a buiness. They aggressively patented and sought licensing deals, collaborated with venture capitalists to launch firms, and even began to mve downstream into drug development. Both private enterprises and universities were in the business of science.

So academia has been in the business for quite some time. If industry and academia were to conduct research into finding the successful formula for drug development, they would find that success is random. But then, they need an excuse and a corrective action. Randomness is not an option. Not succeeding is. In fact, it's the most likely outcome, but it is an unsatisfactory answer. No one is going to get at the big pharma money if they tell the leadership that there is no formula for success.

The current theme in industry and academia is to blame the structure of the old ways. Think, cargo cult airport structures such as the man in the watch tower with coconuts over his ears.

A businessman sitting in a room full of other businessmen makes the claim that the in-house science project aren't working. (The cargo planes aren't landing) He claims that this is a cancer and it must be cut out. The anatomy of this real life scenario can be followed by clicking here, then here. The scientists didn't have the freedom to pursue ideas like those in academia do!

A professor at a University sits in a room full of his peers and makes the claim that he is good at science projects that work. Regis Kelly director of the California Institute for Quantitative Biological Research

Academics like myself are great at discovery but are frequently embarrassingly ignorant of the useful applications of our discoveries.

Ahh, arrogance tempered with a dose of humility. He's a genius, but no one knows what to do about it. This is the premise of the alliance. Adacemia = genius Industry = know how. It's a winning formula. The plan is not random. The old ways were flawed, the problem has been identified, and the solution is in place.

Prof. Mark Pepys at the Royal Free and University College Medical School in London, commenting on an alliance with Gilead

We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else.

Ahh, arrogance tempered with presumptuousness.

So where are we now? Industry believes that there might be some creative restrictions in the corporate world that have hindered "scientists" from innovation. The academia scientists believe that they are good at innovation but they require industries money and "know-how" to translate their genius into drugs. And they are doing it for the good of mankind. Again, Regis Kelly

Alliances with Pharma can bring the knowledge of society needs that we lack. ...it was NOT about the money.

The businessmen are busy forming alliances with old white bearded professors. A call to action or just movement?

The American/Scientists Dream

What is the American Dream? This is what George Carlin has to say about it.

George Carlin and The American Dream

The owners want obedient workers who are just smart enough to run the machines and do the paperwork... It's a big club, and you aint in it!

Let's replace "American" with "Scientists" dream. The concept of obedient workers in science seems to fit. I'm only going to focus on the fate of early stage researchers here because they do the grunt work to create the foundation of the cargo cults.

The leadership will identify what drug targets can be pursued. Each decision is the starting point to a possible billion dollar bet. Ten years might pass between this decision and FDA approval. Think of it as a linear time line, Point A; zero dollars, day one. Point B; one billion dollars, year ten. During this time many things will occur that are classified as work. If you could create a chart of the work and how it is all related you would see how complex it really is. For example, deciding how much drug will be needed for a phase one clinical trial is related to expression level measurements from early stage R&D. This is real work. Somewhere in the chart however, is cargo cult science. This is the area where the billion dollar bet is most vulnerable.

Rather than admit the pitfalls of cargo cult science in the path to a successful drug development, the industry has switched the location of cargo cult work and the financing of this work. Big pharma is getting rid of their in house workers and farming out the early stage work that tells the higher ranking leaders what billion dollar bets they should make. Smaller biotech firms and academia will be taking over that role. Gilead and Yale, for example have a research alliance that will bring corporate sums of profit to the school. The workers now are state university employees or low paid entry level college graduates working at small biotech firms. Big pharma still requires the same obedience and science that conforms to their ten year plan, only it will cost them less. Our scientific dream is now regulated by for-profit pharmaceutical companies.

The employees of the airport must remain obedient workers just smart enough to run the machines do the paperwork. The science that goes into target selection is done by lower ranking people. Final decisions on the billion dollar bet are made by higher ranking people who must also consider making their investors a profit. Once the bet is made, lower ranking people must make the data fit in spite of the rigors of the scientific method. Avenues may open up that could shut a project down. This will effect whether or not you will continue having a job. Cargo cult leaders do not wish to be embarrassed by experiments that point out the foolish premise of their billion dollar bets. Scientists working before and after the billion dollar bet is placed must practice their expertise with diplomacy.

The cargo cults are changing their ways. The scientific dream remains as allusive as the American dream. The man in the watch tower with coconuts over his ears has been moved to the local campus. Universities officials will now look to their natural science colleges as a revenue generating machine on par with the football team. Superstars will arise and move on to high paying jobs in the industry. Both industry and academia run cargo cults so it won't matter much where the superstars take their desk job. It is the lower ranking tribesmen and women who will find it harder and harder to earn a living. The biggest casualty however will be the science that makes some people dream of exciting careers. There will be a lazer like focus on your research. The new science must identify drugable targets and pathways that, when disrupted, lead to the cargo planes landing on the airport owned by your corporate sponsor. Cargo cults dream of the cargo first. They still haven't figured out a way to get it. They've just came up with ways of reducing the cost of running their airports.

Biotech is Back Revisisted

Last year I posted a few times about the 'Biotech is Back' forum here in Seattle.

Seattle’s life sciences industry has been on life support for a few years, but now, for the first time in a long time, biotech has started to show some legit signs of rebirth.

The organizer of this event, Luke Timmerman, posted a very interesting article this week. The title:

Considering a Career in Biotech? How About Trying Computer Science Instead

The comments were also interesting. In them, we get to hear from some of the employees in the field.

As someone who is currently in the biotech industry and have been doing lab work for 10 years, I would not recommend anyone going into biology or life science period. The risk and reward is not worth it and yes, the ladder of success is extremely tough. I agree with this article, change major if you are still in school.

Given the training required and average payout for skills achieved, life sciences / bioengineering is a long, long row to hoe. It is slow, it is expensive, it is glass ceilinged to anyone without a PhD (this includes nearest neighbor industries where PhD’s have fled their serfdom), and it is dominated by a relatively older generation of scientists who do not provide a healthy work structure for young employees. Life Science is an extremely dangerous career path for bright young people, and I encourage them to avoid the field and it’s ever-thirsty vampires.

...be mindful of tailoring your experience to be too protocol specific, in this field having immunohistochemistry experience will only help you get a job doing more immunohistochemistry.

Ironically, on the same webpage, there is a piece by Ken Stuart entitled, "An Investment Opportunity: Training in Biosciences". One reader commented:

I thought it should be noted that the people in positions of leadership in biotech, ala Ken Stuart, can seem detached from the economic reality of what’s happening on the ground. I have to question the sanity of a pushing an training continuum that currently lasts over 12 years, fails to achieve an average pay above 50k at any point, and whose target field is experiencing large funding cuts. That isn’t even taking into account the trainwreck/vacuum of PhD management. In light of the problems already facing life science, Mr. Stuart’s suggestion of starting even earlier seems ludicrous.

We focus on the cargo cult science of biotechnology and hold it accountable for the woes of the field. The leadership can have meetings all day long on how to make more money so they can provide a life long career for young aspiring scientists. Until they understand the concepts explored in CCS and start to weed it out, they will not be successful.

Funny Stories

Lately, the Xconomy folk have been having a hard time coming up with stories to write about the local biotech scene here in Seattle. Since I'm not making a living at it I'd like to share a few stories I've encountered over the years that I think may have something to do with our troubles

There once was a lady who had just receiveed her PhD. During the course of her education she had worked in a lab but she had never dialyzed a protein. We showed her the cassettes and the flotation sponges. The next day we showed up and to our amazement, she had managed to balance the cassettes on top of the sponge, exposed only to the air. The dialysis cassette had not touched the buffer.

Our fermentation scientist (not a PhD) had six 3 liter fermentors. Every two weeks she would set up six runs, usually testing six different methods. When we asked her why she didn't do anything in duplicate she said that it was because she could get more tests done that way. "Ya, but how do you know if the data is reproducible?" "Trust me, it is," she barked at us as she stomped off. Then one day she needed to test only 3 pHs during a particular step. DO EACH ONE TWICE! we begged of her. She did. pH 4 gave very different results, pH 5 both died, and one of the pH 6s gave the best expression. The other pH 6 run died. Conclusion; pH 6 is the best condition but pH 4 could be used in a pinch. pH 5 is lethal.

PS: The six reactors were named after six of the seven dwarfs. Actual conversation: "Which pH 6 run died?" "I think it was Sleepy."

Related story: We had six fifteen liter fermentors. The original process development scientist on the larger fermentors was perusing the fermentation scientists "pH 6" method. The fermentation scientist entered the lab. "What are you doing?" "We're going to try this method at the 15 liter scale." The fermentation scientist snatched the method out of the hands of the process development scientist and stomped out of the room. The process development scientist had to get the method from someone else.

PS: The six 15 liter reactors were named 1, 2... 6.
PSS: The process development scientist was later fired and replaced with an even more experienced scientist. The fermentation scientist was to be a member of his staff. Within the first week of his arrival the he wanted to fire the fermenation scientist. It wasn't allowed. He later left a note reading "Beam me up Scotty, no signs of intelligent life." We never saw him again.

In a Nobel Prize winning lab, they decided to generate antibodies against infectious prions (and not the normal confirmation protein) by denaturing the protein with guanidinium and using phage display technology. As a result of the denaturation, it was impossible to fish out antibodies that adhered to our hopes and dreams. The phage display was done at the Scripps Institute in San Diego. Without testing they sent up numerous samples for western blot analysis. After 3 months it was determined that I (the cargo cult scientist) was incapable of running a proper western blot. In spite of my examples of almost daily western blots using proper antibodies, the job was turned over to another person. They retested my most recent lot. Same result. After a long meeting, my replacement returned to the lab. "How'd it go?" I asked. "You know the step where you boil your sample for 5 minutes prior to running the gel? Well I only boiled for 4 minutes." I responded that I had done that many times and it doesn't really matter. My replacement repeated the work with the 5 minute sample boiling and still obtained the same results. The supervisor was none to happy. She gave us both a dirty look when she saw the same results for the third time.

The ForteBio is a machine that will measure your binding affinity between two proteins. Our ForteBio people tested ten antibodies, 3 times each. In their presentation they listed the 30 results from strongest to weakest binding. A couple of us asked why they had not made a bar chart with the average of each antibody binding affinity and an error bar to show us the deviation of the measurement. The director then took a different tack. On the spot he created an excel spreadsheet and they began using the excel functions to list the 30 antibodies in as many ways as they could think of. Never an average with a deviation measurement. From the strongest to weakest list they selected the one with the first, fifth and 12th strongest binding affinity. It was the best.

AstraZeneca Destroys Their Airports

AstraZeneca has lost faith in R&D. The rituals have not brought them the cargo they hoped for. The airports are being destroyed.

R&D does not lead to profit. Scientists do not add value to Pharmaceutical companies and they won't be invited back!

Crime on the other hand...

The investment by AstraZeneca in scientists and their laboratories did not pay off. The whole point of this blog is to make the claim that what has taken place throughout the entire industry has largely been a cargo cult science. The scientists and their laboratories have been employing real science, such as the cloning of genes, expressing of proteins, and demonstrating various qualities of the products. But careerism takes over and the science quickly turns cargo cult. As Feynman would say:

they follow all the apparent precepts and forms of scientific investigation, but they're missing something essential. 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.

How do you arrange the good science and technology to get some wealth into the system? AstraZeneca is not giving up on science, just their scientists. Someone else can now do the early stage research and AstraZeneca will take over at a later stage. Their businessmen will make the decisions as to what is good science and they will invest accordingly. The gamble now is whether or not the businessmen will make the right decisions. On the surface it seems reasonable. The expensive laboratories will cease to exist and the entire world of science becomes an open field to explore. Small biotech companies can present their work to the AstraZeneca businessmen and those who are at the proper stage of development will be partnered up. The businessmen know how to arrange partnerships. They know how to attend meetings. Do they know how to spot a scientific endeavor that has wealth built into the system?

Science vs. Scientists

Imagine I am the Csar of Science and I am tired of the culture that places scientists on a pedestal but ignores science. I, as a high ranking government official, have the ability to conduct experiments with 100 NIH funded scientists. There is no hidden agenda here. They are told that it is their ability to uncover the truth that is being studied.

I express a protein in CHO cells. It will be a human antibody against TNF alpha, one of the most popular biotech drug projects. It will be purified to 99% purity and be in PBS. All I tell the labs is that it is a pure protein in PBS. The information that they send back is entirely up to them. What I am looking for is clarity, simplicity, and accuracy. Science shouldn't be any harder than it needs to be. I am looking for a response that identifies human IgG.

This will be stage one. Hopefully they will pay a CRO 500 bucks to perform amino acid sequencing and do a BLAST search. Expense is also a factor in my experiment. Who is the most efficient in simple tasks?

Next I reveal what the protein is. I tell the first 50 to provide physical details such as molecular weight, glycosylation, binding constant... I tell the other 50 to do the same but I throw in that we (the government) want to market the antibody to compete with the others. Once again, I do not tell the scientists exactly what to do. Even the format of the report is up to them.

How does the added information (compete against marketed drugs) affect that reporting on physical properties of the antibody?

Why do I consider this a good science experiment? To begin with, I do not have a bias towards any particular outcome. Next, I have not formatted the scientists thoughts on how to report their findings. We are all blinded as to what the information will be. I am testing the scientists, not the science. I know that the science and technology is available to get the right answers. The known unknown is the antibody. We know what it is. Can the scientists make it a known known? Next is the unknown unknown. I don't know what the group of scientists will do. Will 100% pass step 1 and name that protein? Finally, what affect will the added information (compete against marketed drugs) have on the analysis? Higher binding affinities? Will the government antibody successfully compete against marketed drugs as opposed to simply being fairly compared to them?

My experiment is about bias and science. Are there ways that leaders can prevent bias from affecting science or do the leaders want to bias research? Are there ways of measuring the affects of bias? Here at the CCS we naturally assume that any group of humans will be lead by those most adamant to obtain the desired outcomes. It is science, not scientists, that has no such bias.

Blind Clinical Trials

Last week the Seattle Genetics manager of clinical programming accused of insider trading committed suicide.

One can't help thinking about the leadership of the cults once again. They all seem to know how their trials are going. They design their trials in a manner that allows them to manipulate the data. Dr. Aubrey Blumsohn had this to say about working with a drug company in the analysis of clinical trial data:

It’s hard to encourage anyone to speak out about poor practice in the current environment. This case sums up what has gone wrong with systems set in place to ensure safety and integrity in scientific medicine. It would help if regulators put as much effort into responding to serious critics and whistleblowers as they do producing glossy brochures and yet more guidance.

Dr. Fan committed the crime of using inside information to turn a nice profit for himself and his family. Sam Waksal did the same thing. Aubrey Blumsohn did something a little different. He didn't focus on helping the biotech company tell their story. He tried to tell the story that science would dictate.

What does it mean to have a blinded clinical trial? Who can we trust? Are we blinding the trials to ensure integrity?

When to Retract

Retraction Watch posted a piece on why people/groups retract papers. The reasons people give all point in the direction that what was stated may not be true. What about the papers that are not retracted? Where is the line scientists cross that leads them to correct their mistakes officially?

Previously I've written about the peptide sequence GETRAPL. GETRAPL is the peptide sequence despayed on a contaminating bacteria phage that is found in New England Biolabs phage display kits. If you don't believe me, and you care, you have a few options. A) you can search and search for information on the sequence. B) you can call New England Biolabs and ask them if this is so. C) you can purchase a kit and use it until you start seeing white plaques in the presence of beta galactasidase. You will find GETRAPL!

That is the curious thing about modern science and our near religious faith regarding peer reviewed papers. Rather than going into a lab and reporting your results, people would prefer to find information from others. This is not uncommon. We went to war on faulty CIA information regarding weapons of mass destruction. We didn't retract Colin Powells speech at the U.N. We were wrong, but the war was just. Right? This is akin to the retraction of a paper. We can be wrong but that is not what gets a paper retracted. If you are a scientist who has spent the last 10 years studying the amazing effects of GETRAPL you are not about to retract all of your papers. You would rather just let the subject fade away while you find a way of burying the inaccurate information.

PubMed published an article on a peptide database that came across the GETRAPL confusion.

We suggest that one of the utilities for PepBank is to search the peptide sequences of interest to the user with BLAST or Smith-Waterman algorithms to find any important similarities to the known peptides collected in our database. In this example, the search can be used to remove a relatively nonspecific binder GETRAPL.

Even the last sentence is misleading. The reason GETRAPL ends up on your radar is because the phage displaying the peptide grows faster than the other phage. It has nothing to do with specificity. The sequence has been published and patented and beaten to death by cargo cult scientists. They needed to find something and they did.

So the question is simple: Do they have to retract? The Cargo Cult Scientist studies the ways in which errors occur in the minds of individuals highly educated in the ways of science. Where do they go wrong? Do their peers really get a chance to investigate and add to the story?

GETRAPL is a minor, insignificant story in terms of its impact on curing AIDS or targeting specific cells. It is however a modern day N-Ray story to the Cargo Cult Scientist. After all of the papers about GETRAPL, I have only one conclusion when I see the sequence. The authors used New England Biolabs phage display 7mer kits. That's all I can be sure of. Back in 2009, two years after the PepBank exposed GETRAPL we still have papers like the following:

Recognition of Patterned Molecular Ink with Phage Displayed Peptides
Yue Cui, Anupama Pattabiraman, Bozhena Lisko, Samantha C. Collins, and Michael C. McAlpine*
Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey 08544
Received October 2, 2009; E-mail: mcm@princeton.edu
Published on Web 01/06/2010

An aliquot of phage display library
(New England BioLabs, Ph.D. 7) (Figure 1a) was incubated with
a C8-functionalized Si surface (Figure 1b) and then eluted from
this surface to collect the bound phage (Figure 1c).First, fluorescent characterization for the binding of this phage to
C8 and Si substrates was investigated. This was accomplished by
exposing the substrates sequentially to (1) amplified single-colony

Eureka! I've done it! I've proved that New England Biolab libraries contain GETRAPL.

Education cannot teach people to Google GETRAPL. It is not considered science. Yet it is information. Education cannot teach people to design experiments. It will always be a subjective pursuit. Should Cui et. al. retract "Recognition of Patterned Molecular Ink with Phage Displayed Peptides"? They are wrong. They may have higher degrees in Aeronautical Engineering and work at an Ivy League school, but they have made a mathematical mistake. The data set was too small. The information from other scientists was ignored. They failed to consider alternative explanations. They are wrong. The research, even if correct, wouldn't be all that important. It is the fact that they erroneously attached such significance to their honest mistake that makes it a Cargo Cult Science paper.

Living Up to Our Promise

I've come across a book that acknowledges the lack of productivity from biotechnology. It's called 'Science Business', written by Harvard business professor Gary Pisano.

Why has the biotechnology industry fallen so short of expectations - despite its grand promise?

At the Cargo Cult Scientist world headquarters here in Seattle, we are very excited to hear someone come right out and say this. Earlier this year the leaders of the Seattle Cargo Cults held a conference called, "Biotech is Back". The title was a clear indication that the biotechnology industry does not employ scientific reasoning. The industry continues to suffer from business as usual.

According to Pisano, the problem is the relationship between business and science. Science deals with unknowns. When something becomes known (scientific advancement) we attempt to use it (technological advancement). The scientists know how hard science can be so they chose to become businessmen. They work in offices and adopt business logic. This is where Feynman hopes we do not end up.

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.

It's clear that not everyone gets into science because they feel the same passion as Feynman. A degree in BioPhysics will earn you more money than a degree in Theology. When the money started pouring into biotechnology, the wrong people started showing up. They created places where the Feynman version of integrity was not welcome... biotech places.

The book, Science Business, analyzes the industry and its performance over the past 25 years. One of the current assumptions about biotechnology is that smaller biotech firms are better at innovation. Big pharma is tied down with bureaucracy and corporate BS. What they found out in the course of their research was that there was no discernable difference in the R&D productivity of biotech and big pharma. The notion that there is a difference is one that biotechnology is using as a selling point. Executives at big pharma buy into this idea as well, hoping to partner up their next big drug rather than making harder decisions on in house development projects. In the book the author has done the research that those in the industry have ignored. The question was asked, "Who is best at R&D?" The data showed that no one wins.

The book 'Science Business' is on my reading list and I'm sure will generate more posts. We seek to find out why something so promising can turn out like it has. The hypothesis we have is that biotechnology is not doing well. We are not alone.

Retraction Watch, Omeros, and Confounding Factors

Retraction Watch is a scientific gift. Those who value the truth now have a source to help them through the minefield of scientific publications.

Our own blog here, The CCS, follows the retraction of scientific ideas. The ideas manifest themselves as biotech companies. We think of each company as a torch that illuminates a cargo cult airport. The airport I speak of most often is Seattle Biotech since I live here. Our cargo is a drug approval.

Today we report on Omeros. The torch has grown dim.

Omeros (NASDAQ: OMER) said today that its most advanced program in clinical trials, a combination of generic drugs designed to reduce pain and swelling in patients undergoing arthroscopic knee surgery, has failed. There was nothing to sugarcoat here—the drug, OMS103HP, failed to meet its goals in the third and final stage of clinical trials.

Of course we don't just sit back and judge a company based on whether or not they succeed. That is what investors do. We want to know why they failed. Due to the secrecy of modern day science, we don't get the full story. But we do get some hints as to what they think may have gone wrong.

Omeros blamed confounding factors in the studies, which means that if patients improved, it could have been caused by some other reason than the Omeros drug.

Sounds like they made their mistakes before the trials began way back in 2004. Statistics was the problem? How can this be?

The confounding factors in the Omeros clinical trials are what we want to know all about. Omeros is the victim of the confounding factors, and now their investors are as well. We believe that real science can prevent these things from happening. Like Retraction Watch, we believe there is value in negative results. The team at Omeros and their investors are hurting. They took a gamble and lost. Now they are going to put all of the negative behind them and forge ahead. Now is the time however for those in the negative sciences to start their research. If allowed, what would a couple of cub reporters for the Science of Negative Results turn up? The secrecy behind the trial data alone would merit a book. Imagine a series of scientific and business avenues all interlocked that led to the demise of the Omeros lead candidate. Which ones hurt the most? Who made the decisions. Did the molecule really act on its target as advertised? Did the statistical set up of the trials make sense? Many questions could be asked. The answers would serve the industry. Will they be asked? Should they be asked?

400 Million Dollars

I wanted to go with a more positive note today. Then I saw a report on a 400 million dollar planning experiment. In 1997 the Washington Department of Transportation set out to replace the 520 bridge that connects Seattle to the opposite side of Lake Washington. The old bridge remains in place. I couldn't go on with a positive attitude. A few gems from the research into the spending showed projections of starting construction in 2002 and 2004. Tolls were set and never put in place. Starting later this year (???) a toll system will be put in place with scanners and varying tolls based on the time of day. Out of towners will be billed (unbeknownst to them) by taking a photo of their license plate and sending them their bill for 5 dollars in the mail. I couldn't believe how badly local officials can do their job and get away with it. We are shutting schools down out here to save sums of money far less than 400 million dollars.

This is what a Cargo Cult does. They plan, they design, they talk and the use up resources with almost no regard to the actual goal. The cargo in this case is a bigger bridge that will ease congestion during peak travel times.

Allow me to digress and mention the "positive" story I was going to write about. It is related to the 400 million dollar bridge plan. I recently went to New England Biolabs (NEB) in Ipswich MA. NEB sells restriction enzymes for cloning DNA. They are a rare biotech company because they make money. They also use a portion of the money on environmental causes. For example, when planning to build their headquarters, they ran into the obstacle of three 200 year old Birch trees. They could have easily chopped them down. They spent over a million dollars extra to save the trees. The company is owned by one man, who at the age of 80 goes to work everyday in his own lab. The running of the company has been turned over to the younger generation. The old man conducts science in hopes of finding new ways of extracting energy from things like lobster shells.

The old man must have had a plan. He did not cash in and sell the company. As a result, the old man did not have to argue with investors over whether or not he could shell out the million plus to save three old trees. The employees could relax and do their jobs without fear of shutting down. Research tools were developed to help users use the products, free of charge. The plan was to make NEB synonymous with molecular biology while respecting employees/customers and our world.

What then can we say about the 400 million dollar bridge plan? There is a lot that can be learned from the investment. The problem however, is that the lessons are considered negative. We want to be positive. We want a bigger bridge. We don't want to sit around bickering about who wasted what and why we didn't stop them. Yet that is important to know.

It is the study of the Cargo Cult. The cargo in this case is a bigger bridge. After 13 years and 400 million dollars, we still have the same old bridge. But that is not all we have. We have 13 years of plans. You can research this. Surely something went wrong. It is not negative to want to find out why. The bridge planning leadership will accuse the Cargo Cult Scientists of seeking to judge and blame, but a science merely seeks the truth.

So I am left wondering two things: 1) Why did New England Biolabs succeed? 2) Why did WSDOT fail? There are concrete logical practices that could explain both.

BMS and California

Corporations don't commit crimes, their people do.

Bristol Meyer Squibb is full of criminals. They paid $515 million in 2007 to settle allegations by the federal government and other states that it used a kickback scheme to defraud the Medicare and Medicaid insurance programs. Now the state of California is going after them. Apparently it is illegal to bribe doctors to get them to prescribe your pills. The article makes the claim that BMS had paid out of 15,000 bribes in a six year period.

Let us not leave out the blame to be placed directly on the medical profession. Doctors don't want to sit down with their patients and explain the relationship between diet and exercise. They deal with the relationship between sickness and pills.

Cargo Cult Journals

I've come across a most interesting contributor to the idea that science is simply the pursuit of the truth. Bruce G. Charlton is a Professor of Theoretical Medicine, University of Buckingham, and was formerly the editor of the journal Medical Hypothesis. He was fired from his position after the journal was taken over by Elsevier and Dr. Charlton had decided to publish a paper from Peter Duesburg.

In their actions towards Medical Hypotheses, the publishers (Reed-Elsevier - who publish about 20 percent of the world scholarly journals, and a higher proportion of those journals with high impact in their fields) decided what went into the scholarly literature and what did not.

One of the great threats to science (the truth) comes from the demands of a large group of human beings. Many will engage in the competition to be in charge of the group. Elsevier executives must know what the corporate identity is and what they can do to preserve it. Mentioning Peter Duesburg is taboo within Elsevier so they had to remove Dr. Charlton from his position as editor. The next generation of scientists are also effected. They rely on being published by Elsevier journals. They too mustn't upset the non-living entity known as Elsevier. Their livelihoods depend upon understanding what is acceptable. The most successful will pursue what is not just acceptable, but what is favorable.

I'm going to explore some of the ideas (as I interpret them) presented by Dr. Charlton in greater detail later. The moral of todays post is that we are facing a monopoly in science. Executives at a large corporation are making decisions that should be left up to the talent. Elsevier took control of a journal and control of editorial decision making. Warren Buffet doesn't even operate this way. Buffet researches companies and buys the good ones. He leaves the management in place and lets them do their job. Science needs to learn this lesson. Smaller groups of humans means more groups of leadership. More groups of leadership assures a diversity of ideas. Since scientists are good at convincing people of both good and bad ideas, diversity is needed to get at the truth. When leadership is consolidated into one group we have lost a battle.

We here at the CCS dream of a journal of negative results. By asking scientists to write about things that did not work, we can get a fresh perspective on things like RNAi.

Another Dendreon Exec Departs

What is going on at Dendreon? Last year Dendreon lost a high ranking executive with no explanation. Varun Nanda, the Senior Vice President of Global Commercial Operations was said to be an arrogant egotistical a-hole but when did that ever work against an exec? Now they are losing the Chief Scientific Officer and co-founder of the company, David Urdal.

Anyone who has talked to me for more than two minutes knows that I have become bewitched, bewildered and bedazzled with the arrival of our first grandchild last April. The same month that the FDA brought us into a new era of cancer treatment with the approval of Provenge, my daughter brought the Urdal family into the next generation with the birth of my granddaughter – Ava. I look forward to seeing the world through her eyes and the eyes of the grandson we expect to see in June.”

“I am now in my sixteenth year with Dendreon and what an extraordinary journey it has been – the first autologous cellular immunotherapy approved by the FDA! What an achievement and what a pleasure it is to be a member of such a truly extraordinary team – the Dendreon team – as we won the high achievement of Provenge approval. We are just getting started.

Why would a high ranking member of Dendreon leave when they are just getting started? Because he wants to hang out with his grandkids? Do these types of people even take off work to watch their own kids grow up?

Something is wrong at Dendreon. They have a drug that has marginal efficacy. A lot of work has to go into bullshitting your way through life. Maybe he has grown tired of it and wants to take a rest.

Improving Early Stage Research

The NIH has a new one billion dollar plan to help the cargo cults get more airplanes to land on their runways. It seems that about 1 out of every 10,000 molecules selected to become drugs ever make it. And the biopharmaceutical research sector invested an estimated $65.3 billion to discover and develop new medicines in 2009. How does all of that money and brilliant science result in such failure?

The National Center for Advancing Translational Sciences has been created to fix the problem. According to NIH director Francis Collins, the goal is to develop old discarded drug development programs far enough to interest industry in finishing the job. The government is going to help the pharmaceutical industry get more drugs into the market. I guess they have some data that shows a correlation between the number of drug approvals with an improvement in the health of the American people.

To be fair, they are claiming to take on disease indications that are not profitable to big pharma. When the NIH scientists get to a certain stage, big pharma will take over. There will be a smooth tech transfer and drugs will be made available to help people.

It seems like the government is working for the drug companies. The new center will be in the same position as a small biotech company, offering up possible drug programs for pharmaceutical companies. How will this effect the claim of one molecule in ten thousand becoming a drug? Will government scientists improve early stage research or will they take the financial hit for some of the failures?

Me Talk Pretty One Day

After listening to a few panel discussions from this years WBBA Life Science Innovation Northwest, it became painfully obvious that an interest in science is of little use in the business of biotech. Ironically, neither is there much discussion on how to make investors money. The individuals speaking at the meetings were already making good livings off of other peoples money. Investors can make money in a number of ways, including betting against a public company. But the business of biotechnology has many different kinds of companies and business models. Innovation Northwest was a group of Cargo Cult leaders talking about ways in which to keep the gravy train rolling regardless of scientific progress.

Imagine if you will, the very first Innovation Northwest meeting 11 years ago. The individuals speaking at those meetings were all leaders of the field. They spoke of how to pursue an IPO, how to get initial funding, and all of the money ideas of the time. This years meeting was no different, only the ways of getting money have changed. It is much more difficult to get money because whatever they were talking about 11 years ago didn't go very well. One thing that the CCS takes great interest is in the ways people talk about things that aren't so. The tones of certainty that were used 11 years ago were probably the same as those used this year. It is a tone of certainty that makes you believe that what you are hearing is about progress. But is it?

James Randi spent his early career as a magician, tricking people into believing things that didn't seem to be real. He called it magic. If he were to be honest with the people he would take away the magic. For example, he would lay a pencil on a table and make it move with his mind. In reality he blew on the pencil to make it move. There was a misdirection involved where he appeared to be focusing really hard and thus causing he audience to focus on the pencil as well. While they started at the pencil his lips were free to pucker up and blow.

The tone of certainty is one such misdirection. While you sit and listen to the biotech leaders you get the sense of a pending success story. The same tone was in effect 11 years ago but we know something was amiss. People lost a great amount of money. However, had they listened closely 11 years ago, and this year as well, they would have heard the real story. The people speaking were speaking about making a company money, without making a product. They spoke of making partnerships. They spoke of being acquired. They did not speak of the tricks they intend to use to get the money. Making a product takes too long and costs too much. Seattle folk don't have the time, money nor expertise to do what is needed. They are selling something else. The question, is it real or is it bullshit?

The best way to sum up the concept of certainty, bullshit, and biotechnology is to take on the case of Sam Waksal. He wasn't an honest man. He didn't invent or discover Erbitux. He ran a biotech business. He got rich and went to jail long before Erbitux made its first sale. People lost money but Sammy made sure he and his friends and family weren't in that group. A few of them did some time and that is very sad. But what remains is Sams influence on the business. Sam does talk pretty and you have to when there is a book on your shameful career, yet you go on to found another biotech company.

How many speakers on the Innovation Northwest stage would shun the likes of Waksal. He speaks as they do. He knows the industry. People give him millions of dollars in spite of his history. Perhaps it is all about being a good magician. Get people writing checks and keep them from looking at the past. It's not a Cargo Cult, it's a shiny new biotech company and the future is looking bright. Trust us.

An Old Idea

The company is called NeuroPhage. The idea is one that I have personally worked on at several different companies. Bind something to amyloid beta (antibody, phage, peptide) and amyloid plaques will not form. The population of potential customers and their end of life spiral makes this disease indication enormously popular among biotechnology companies. You might call this one the holy grail of biotech.

The concept makes several assumptions. It is assumed that binding to amyloid beta in the laboratory will scale to binding amyloid beta inside the human brain. Scaling from a cell line in a petri dish, to an animal model, to a human being, is not something that bio-scientists can rely on.

It is assumed that preventing the formation of amyloid plaques will result a significant reduction in the symptoms of Alzheimers Disease.

It is assumed that phage will be more efficacious than using antibodies or small molecule approaches.

Having done this research I take great interest in the amyloid beta story. I watched others attempt to cure or treat this disease in Cargo Cult amazement. At the highest levels the amount of thought that seemed to go into the "research" was to hire people to find the binder. The executive view (and their investors) was to name the molecule and send in the lower ranking people to finish up the details... of curing Alzheimer's!

On NeuroPhages' website they offer up some evidence. They begin with the perfect world graphic arts version of the disease and how the drug will work. They then show two pictures. In one you see the plaques in a "vehicle control", which appears to be a brain slice. In the other picture there appears to be far less plaques. That is the drug working.

This is a red flag. Science is not done by selective photography. I've seen this trick used in many fields, especially RNAi. You show a knock-down by simply finding the highs and lows of a non-homogeneous system. In this case the system is a brain slice. As far as we know the pictures offered up could be from the same brain slice. We are left to trust the authors that they are not interested in pulling the wool over our eyes.

We're off to a bad start. Now comes the worst part. How do they propose the drug get into a humans brain? How do you measure phage floating around in a brain, breaking up plaques. The Alzheimer's patient is not officially diagnosed with the disease until after an autopsy. Where is the graphic art depiction of drug administration and finding of the target? There is an entire field of science that is not being addressed by the Cargo Cult here. It's called ADME. Tracking the phage on its journey into the body, to the plaques, breaking up the plaques and being cleared is not something that can be done. That frees up management to worry about other things like financing and perhaps adding information to one of the sparsest websites in the biz.

It won't work. I've seen it not work over and over. It's an idea that is taken to the point of, "what do we do next?" and left off to lower paid worker bees. In real science, this is the starting point. Did this really work? How did it work? Does it work every time? Will it work in a human being? The questions are instead left up to the white lab coat people who have only one option in reporting their findings, tell management it works and don't bother with the details that weren't ask for. Keep the story just as it is on the website. There is no turning back now. Look to the skies and wait for the delivery of the Cargo Airplane that carries the cure for Alzheimer's. Once it lands get your sales people together and get ready to make some money.

Delivering RNAi

I would be remiss if I were to not revisit the Cargo Cult of RNAi.

Last week we had a conference on the Cargo Cults of Seattle. RNAi was represented by PhaseRx. Since their inception they have had very little to report besides their 19 million dollar series A financing. They do however make very bold claims on their website.

RNAi therapeutics, also referred to as short interfering RNA or siRNA, have demonstrated broad applicability to many therapeutic areas, including cancer, inflammatory and autoimmune diseases, infectious disease and metabolic disorders.

These promising therapeutics are being held largely in check today by the lack of broadly applicable delivery technology. RNAi therapeutics generally cannot, on their own, penetrate the cell membrane and gain access to the cytoplasm where they can reach the drug targets.

The PhaseRx polymer system overcomes the central stumbling block in the field of RNAi therapeutics by delivering RNAi molecules into the cytoplasm where they can reach and inhibit the desired target of interest.

How do they have evidence of efficacy for the diseases if they've been held in check by delivery. Does their delivery include a ride straight to the cells of interest, avoiding a depletion of drug by being absorbed by other cells?

The problem is scalability. If you work as an engineer in a biopharmaceutical manufacturing facility you start small and scale up. There are certain relationships involved in scaling up that have been addressed by the industry, resulting in predictable outcomes. But with RNAi, they have predicted the outcomes without doing the research. The outcomes exist mostly on company websites. What do they now know that makes everything work where it failed in the past? As predicted by the CCS, the RNAi industry is not evolving.

Inside Information

When you think of disgruntled employees you think of crazy people. The kinds who come back to work with guns and mow down their old colleagues. But there are other kinds. Some people are good and the company management is lacking.

Here is what a high ranking former employee at a small biotech had to say about the management:

I thought they had some good technology..., however, the leaders had no clue how to develop ethical pharmaceuticals and they weren't folks that I could respect. It was really unfortunate as they hired good people but really didn't allow themselves success due to incompetence at the top.

Will those four clowns at the top every get rich like they want?

For the record, the leaders went on to make a rather lucrative deal with Big Pharma. The Big Pharma company wanted a large amount of the drug to start their own research. Little Biotech company had about 2% of what the Big Pharma company asked for. What they did have did not pass the bioburden test. So how did they get the positive data that attracted Big Pharma?

Overseas, third world country testing! Unethical? Yes. Could the leaders "develop" pharmaceuticals? No. They haven't made one molecule that could be used in the US or Europe. Did they get rich? Yes. The "clowns" at the top have multiple houses and new cars and all of the things a greedy person would cherish.

Could we blow the whistle on this company? I don't think so. Overseas testing is legal. Incompetence in medical research is subjective. Unethical conduct can be argued against by claiming ignorance to the rules. They could claim that they had to go outside the US and Europe because they are small and can't afford the rigorous process in the modern world. Once again medical science has designed in flaws that select for the bad guys.

But this is the kicker today. Our history is rotten to the core. Human beings can't be trusted. Testing dangerous drugs on human subjects is decidedly bad. Now we know better. Right?

The new test subjects have to take "medicine" that would not pass muster in the US or Europe. Once again, we've lowered our standards and found people whom we have less fear of. They are not protected as Americans and Europeans. The prisoners and mentally ill were not protected either. How far have we come in our humanitarian ways?

The "clowns" at the top of this little biotech are not evil. They are greedy and they want to be powerful players in the business. They are a small and dangerously desperate company.

Biotech Inc.

I took my latest lab tour after a 2 hour interview for a 5 week temp job. It was a small space with all of the usual things. Hoods, gel apparatus's, incubators, shakers, PCR machines... It was merely a satellite branch of Biotech Inc. Sometimes I think biotech is all one big secret corporation (Biotech Inc.) whose mission is to collect money from gamblers (biotech investors). Each branch has a twist to the usual story. They cure disease with big brain ideas that no one really understands. The idea needs money to work. In reality, Biotech Inc. needs money. Invitrogen, GE Healthcare, BioRad, Pall, Millipore and companies like these have made a fortune off selling to Biotech Inc. As a result each lab looks the same. The tour I took yesterday was short. I'd seen it all before.

Rumor has it that this particular company is looking to sell itself off for a quick profit for investors. I was interviewing for a 5 week job at the bottom, once again. I was informed of the temporary status of the job half way through the interview. During the lab tour I knew I was looking at an entire group of temps. They had more benefits and longer contracts than an admitted temp, but they didn't have long to go. The company is looking to be sold. If they can't pull it off they will shut it down. Either way, the laboratory staff had short futures with a small company.

Big Pharma has tired of wasting their time and energy trying to develop drugs. Big Pharma has made the claim that the small biotechs will become their feeding ground. They will let the innovation take place on someone elses dime and snatch up the winners. The Biotech Inc. lab space that previously had taken up real estate in Pfizer and Merck is fading away. The Biotech Inc. space moved to small dangerously desperate companies. Like a dishonest post-doc who needs data to fall in his/her favor in order to advance his/her career, the desperate small biotech gets the kind of results that go over well in a meeting. Easily understandable stories that put dollar signs in wealthy peoples eyes are what people want.

A fair amount of money had to be spent on the company work space. Besides the Biotech Inc. lab, there was a nice reception/office/cubicle space. All of the colors matched on the carpet, walls and tile. It was a nice theme. The management comes from The University. They have higher degrees in science than the lab staff so they get to spend some time developing color schemes and picking out carpet. This job could not be done by people earning the same as the lab staff. The difference in salary is an indication in importance of daily work. Although The University tends to teach things that would be most useful in the lab, the money from the investment pool can be used to hire the best biotech architects and interior design experts. In the end it looks as though the high ranking members of Biotech Inc. have really done a good job. You can look at the end result.

The end result of the laboratory work is a different story. The laboratory looks the same before and after major accomplishments. Each worker has the same white lab coat supplied by the same white lab coat company. Their Invitrogen DNA preparation kits look the same stacked up in their Thermo 4 degree refrigerator. Their Eppendorf pipettes look the same. The chemical cabinet, the hood, the tips, the gel boxes all look the same. But these tools of the trade are powerful when used properly. The laboratory staff can create molecules. They can alter a molecules shape, size and chemistry. But ultimately, it is the decisions of those who pick out the carpet and wall colors who decide what to do with the products created in the laboratory.

Biotech Inc. is not just a collection of Cargo Cults. There are many useful people in the corporation. You have to break it down to components and people are the indivisible component that separates the Cults from the companies.

The People

In 2001 I was working at a little biotech company in East Los Angeles. The founders were two professors at the USC Med School. The company had a pipeline of 4 antibodies against "denatured" collagen. The idea behind them was that they would prevent blood vessels from forming around tumors and thus kill them. The company was funded by an angel investor. The goal was for us to obtain some data that could be used to sell the company off and make our investor some money.

The experiment consisted of three groups of bald mice. Each group had 10 mice. There was a positive control group, treated with Rituxan. Rituxan is a monoclonal antibody that binds to VEGF. There was a negative control group, treated with PBS. There was an unknown group, treated with one of our antibodies. Day one we injected cancer cells subcutaneously on the backs of the mice. Each day the mice were injected with a large dose of the drug or PBS shot into their belly. In a couple days tumors began to grow, which we measured with a caliper.

It was extremely inhumane because no one had a painless way of doing this. The mice were horrified when the lights came on. I tagged along to write down the readings. I watched as each mouse was held upside down and a large needle was injected into a non-distinct region of their underbelly.

The experiments were done over and over. That is because we had to get the set of data that our superiors wanted. The investor had decided that the antibodies were a great idea and he sank millions into making a profit from them. The lab people needed to get the results. The problem was that we our antibodies didn't work. The Rituxan worked great. No tumors. The other two groups were statistically the same. But this would not do. We were sent back to have a graduate student from one of the founders lab show us how to "properly" use the caliper to make the measurements. She spoke as she measured, instructing us. As she instructed she was clearly favoring the hoped for measurements. Using a caliper is not a skill. When she had finished getting the data to look "better" and she ended her lesson on measuring tumors.

I had just one question. I handed her a mouse that she had already measured. She asked, "what is this?".

Me: It's a mouse with a tumor. Can you measure this one?

Her: Didn't we measure it?

Me: Yes, if you are measuring accurately you should get the same tumor size.

She measured again and was off by 30%. This number of course was not written down. It was for my own assessment. That was my N-Rays moment. I knew in my heart that they had been playing these games. The new measurement didn't count. I knew I was in a Cargo Cult.

The graduate student and the boss needed to show a reduction in tumor size. Somehow by measuring the mice again, they did not feel that they were simply fabricating data. After all, they had performed the measurements. To me, this was fraud. To the boss and the grad student, this was survival. They needed the data as much as anyone else.

My entire biotech career is littered with this ilk. They are good people until the data doesn't go their way. They convince themselves that these things are simply little white lies. They don't matter. In the big picture they know their drugs work and they'll be vindicated later. The little experiments where data is cherry picked is no big deal. It's one or two slides in a presentation that tells a much more interesting story. And the story is what sells. Investors open their pocket books and bigger companies start listening.

Oh Pfizer Again

Good thing they have lots of money. Pfizer is once again shelling out hundreds of millions to pay for covering up the danger of their drugs.

I posted last week about Pfizer being sued for 142 million for promoting their drug off label knowing it was potentially dangerous.

Paying out money is a lot better than going to jail. But actual human beings made these bad decisions. They are allowed to hide behind the corporate logo?

Who Likes Bad Science?

I used to joke with my friends in the physics community that if you want to cleanse your discipline of the worst scientists in it, every three or four years, you should have someone publish a bogus paper claiming to make some remarkable new discovery — infinite free energy or ESP, or something suitably cosmic like that. Then you have it published in a legitimate journal ; it shows up on the front page of the New York Times, and within two months, every bad scientist in the field will be working on it.

Gary Taubes

The quote brings self doubt into the mind of the CCS. Are the people in the laboratories attracted to bad science? Is it just easier to get a degree in a bio science than a harder science such as chemistry or physics? Would it behoove the Biotechnology industry to insist on stronger math skills?

Let's look at a couple jobs and their requirements for the industry:

Entry level research associate: Education; A B.S. or B.A. in Molecular Biology, Biochemistry or Chemistry or an Associate’s Degree in Biotechnology.

A bachelors degree in Chemistry = an associates degree in Biotechnology?

A protein science temp job: QUALIFICATIONS; Ph.D. or equivalent industry experience.

A PhD? A PhD in what?

And these come from Craigslist. Would an executive recruiting company use craigslist? Why are biotech scientists subjected to a craigslist ad?

Bad businessmen and bad scientists are attracted to bad science. They hire their scientists from Craigslist ads. Critical positions that can cost the company millions in delays getting a drug through the approval process are left up to temps. The businessmen and those applying for the jobs don't know or they don't care. They are in it for the short term.

In The Big Short there was a Cargo Cult Science taking place in the financial industry. A handful of people became aware of it and they bet that the sh*t was going to hit the fan. They found the way to make money off of it. The biotech professionals who have bet their careers can do the same. Be aware of bad science and stay away. There are places to go where the science is real. Seek out good science. It won't be as easy as you think. If you find yourself in the pool of bad scientists who Gary Taubes described above, get out. Leave that RNAi company. Don't apply to that PhD temp job. Work harder and get where you need to be. The Cargo Cult Airports are very tempting. They pay the same and they look the same. But they are not long term winners. Career professionals need to work for the longterm. A resume of short term bets will not be very satisfying.

And so I don't think that working in biotechnology is just a bunch of bad scientists who are attracted to bad science. There are good places, even inside bad companies. Seek them out. Look for long term options that make sense.

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.

Feynman

Huge Airport Shutting Down

This isn't like shutting down that quaint little coffee shop you thought would be a good idea to buy so you quit your job and sank your life savings into and ended up staying up late at night counting up your daily losses until finally you had to file for bankruptcy... Whew! I'm just saying... that would be a bad idea.

Pfizer and Merck won't be facing an end to their dominance in the drug pushing business. But they have different ways of facing their future. Pfizer sees their massive R&D campus as a Cargo Cult Airport and they are tired of not getting the cargo.
Merck maintains their faith in their airport.

Since we at the CCS believe that most drug success stories are random events it will be interesting to see how these two companies fare. Does it matter if a major drug company shuts down a major scientific research center?

Oh Pfizer

I've spoke of the truth spectrum. On one end you can miss the truth by making an honest mistake. On the other end you have committed a fraud that you hope to benefit from. In between you can be in a place where you don't care what the truth is as long as it supports your story. That is called BS. Many professional scientists have been exposed as BS artists and gone on to have successful careers. It takes a corporation to be able to get caught at the far end of the spectrum and still survive. It takes money and power to get past violating federal racketeering laws.

Pfizer was ordered to pay $142.1 million to Kaiser Foundation Health Plan and Kaiser Foundation Hospitals for illegally promoting Neurontin for unapproved uses.

Before I go on I must comment on Kaisers responsibility when handing out drugs. Corporate for profit medicine is not a bunch of doctors who get together to discuss what works and what doesn't. They seem to assess symptoms, google them in their brain or some big pharma database and prescribe the magic pill. Problem solved. It reminds one of a scene from Anchorman with Will Ferrell. The main character, Ron Burgandy would read whatever was on the teleprompter. He did not think before he spoke. As a joke someone wrote something for him to say at the end of a broadcast. "I'm Ron Burgandy, that's the news, go fuck yourself San Diego". And that is how the broadcast ended. It wasn't Rons fault. Right?

Kaiser officials alleged they were duped into believing that migraines and bipolar disorder could be treated effectively with Neurontin, approved in 1993 by the U.S. Food and Drug Administration for epilepsy.

They were duped. There is a lot of duping in Cargo Cults. They don't think before they prescribe. It's not their fault.

There are over 300 lawsuits over off label prescribing of Neurontin. It is a dangerous thing according to the lawyers. The scientists and marketing department at Pfizer allegedly knew Neurontin was dangerous also. Where on the truth spectrum does this case really fall. How dangerous is this little pill and what group of people are most vulnerable? Did the scientists, clinical trials professionals, or doctors know that the marketing department was trying to sell the drug to the vulnerable people just for a profit? Did the marketing department really not care about the people they were hurting?

Sinning Against Science

The Sins of Science : A small compilation of people who know how to succeed in the Cargo Cult Airports. It's not as if anyone is ever going to go into the laboratory and check on their results. Right?

The article about scientific scams that you will not find is the one about a team of hard working laboratory professionals who can spot BS and quickly disprove it with empirical data. It is merely assumed that the review process weeds out the liars and cheaters. Why? Because at the highest level they are too sharp to be fooled. This is mandatory for a Cargo Cult. Leadership cannot be questioned. But what do they know of empirical data if they do not venture into the laboratories they rule over?

The word empirical denotes information gained by means of observation, experience, or experiment.[1] Empirical data is data that is produced by an experiment or observation.

A central concept in modern science and the scientific method is that all evidence must be empirical, or empirically based, that is, dependent on evidence or consequences that are observable by the senses. It is usually differentiated from the philosophic usage of empiricism by the use of the adjective empirical or the adverb empirically. The term refers to the use of working hypotheses that are testable using observation or experiment. In this sense of the word, scientific statements are subject to and derived from our experiences or observations.

Those who are charged with deciding if Silvia Bulfone-Paus engaged in scientific misconduct are not the ones who called attention to the BS in her publications. The judge and jury are like her. They left the laboratory long ago and never looked back. Laboratories are for prestige. You raise money for them and put little people in them to obtain results that prove you were correct. But what obligations does the PI have in verifying the results? What do you call second hand empirical data?

The story of N-Rays once again helps us describe modern day science. Long ago, scientists had a way of verifying puzzling results.

Nature magazine was skeptical of Blondlot's claims because laboratories in England and Germany had not been able to replicate the Frenchman's results. Nature sent American physicist Robert W. Wood of Johns Hopkins University to investigate Blondlot's discovery. Wood suspected that N-rays were a delusion. To demonstrate such, he removed the prism from the N-ray detection device, unbeknownst to Blondlot or his assistant. Without the prism, the machine couldn't work. Yet, when Blondlot's assistant conducted the next experiment he found N-rays. Wood then tried to surreptitiously replace the prism but the assistant saw him and thought he was removing the prism. The next time he tried the experiment, the assistant swore he could not see any N-rays. But he should have, since the equipment was in full working order.

What can one say about N-Rays and the multitude of scientists who publish papers on things they've never seen first hand? Self deception is one explanation. On the other end of the BS spectrum you find Dr. William Summerlin who coloured in the black patches of fur on white mice with permanent markers to prove his skin graft technique was a success. Bulfone-Paus' people coloured protein bands on western blots. Either way, they got what they wanted. By separating yourself from the collection of empirical evidence you will have an easier time climbing the ladder of successful scientists in todays world. By not entering that lab you will not have to fabricate data. You hire people to do that for you.

Questioning Favorable Results

Baltimore, Bulfone-Paus, and Daniel Klessig all had the wool pulled over their eyes by people telling them what they wanted to hear. It is not only easy to do this to some scientists, it seems to be the only way to get ahead in their world.

It's not always black and white. Baltimore wanted the data from Imanishi-Kari. Imanishi-Kari got the data from her lab staff. The data that was wanted was published. The data that contradicted the desired results was the cause of a whole lot of trouble.

Bulfone-Paus wanted the data from subordinates who worked in her laboratory. She got it and published. When did she decide that there was a problem?

Daniel Klessig wanted the data and he published. Trouble!

How does the Cult deal with the trouble?

Highest level:

A BTI investigation concluded there "was no conclusive evidence that Dr Chandok achieved the results reported" but also found "no conclusive evidence" that misconduct had occurred.

Publishing data that no conclusive evidence supports isn't scientific misconduct?

Principle Scientist Leadership level:

This was considered a significant discovery in the field of plant biology. Dr. Klessig and Dr. Chandok began work on a paper to publish the results. Dr. Klessig requested that Prof. Brian Crane, a researcher of animal NOS activity who was familiar to Dr. Klessig, attempt to confirm.

And it was confirmed! How?

Prof. Crane assigned the work to Mr. Pant, a doctoral student who was already performing similar work. Dr. Chandok worked with Mr. Pant to reproduce the results, which was reported as a success. At that time, Dr. Klessig seemed satisfied with this verification, and the paper he and Dr. Chandok completed was submitted to Cell for publication. The paper was published in the Spring of 2003.

Remember the degrees of separation? The fact that PHd scientists do not work in laboratories to confirm data? Dr. Klessig needed to keep building on this foundation of quick sand. He needed more proof. To the lab?

In 2003, Dr. Kim was hired and assigned to verify Dr. Chandok's work.

Were they not convinced yet? What was wrong? Whatever it was, Dr. Chandok wasn't about to go back into that damned laboratory to validate her work. Dr. Kim was not getting the same results as she did. She sued over the retractions of the papers.

Was it scientific misconduct? Bad science? Fraud? Error?

It was a Cargo Cult Science!

The Culture of the Cult

Western blot and ELISA are simple things. They are also what got David Baltimore and Silvia Bulfone-Paus into trouble. Both tests can give varying and ambiguous results. When you are on the margin of detecting a signal that proves your theory, you should bend over backwards to prove you did or didn't detect it. This, however, is a part of the culture of the cult.

As a cargo cult leader, you must set up what you perceive to be the truth. The bamboo antennas for example, may be reshaped time and time again. Each time you must have a reason for reshaping the antennas and a reason for the new shape. Therefore, there must be some truth that makes the old shape wrong and the new shape correct. That truth is the heart of the matter. If the makers of the antennas screw up, you can maintain, as a leader, that you are still the keeper of the truth. You are in charge and the others need to do their job better. In general, you must keep several degrees of separation between your "heart of the matter" and the incompetence of the others. They keep the planes from landing in spite of your brilliance.

How does this translate in the real world of science? You may think that scientists work in laboratories and maintain careful records of all they do. This is false. I once worked for a Nobel Prize winning scientist. He came into the lab once to have his picture taken for the award ceremony. He was loaned a white lab coat. He posed next to a hood where inside we had lit a bunson burner for a special "sciency" effect. Later that photograph was hung up inside the laboratory. The caption underneath the picture read, "this isn't like my piano at home". Rest assured, this would have made the Nobel Prize winning scientist very angry. There was little chance of him ever seeing it however. It was inside the lab.

It is not just Nobel Prize winning scientists who stay away from the plebeian confines of the laboratory. Almost all PHds stay away. The laboratory worker is the lowest member of any scientific project. Ironic? There are scientists, project managers, department heads and many more individuals, all of whom help create the degrees of separation. This is why Dr. Silvia Bulfone-Paus had the wool pulled over her eyes by her scientific misconductors. 12 papers now have to be retracted which will effect the other non-laboratory scientists. Their lab staff may have already tried to replicate the results that were a part of the misconduct. At this point it becomes a toss up between who is right, your lab tech or the published (un-retracted) paper. It's hard to use laboratory data to refute published data. Non-laboratory scientists prefer published data.

The quest for fame and funding create this culture. That is what this Cargo Cult Scientist believes. Toiling away in the lab for days only to find out your protein was misfolded or your reagents were at the wrong pH in step 27 is tough. It's also boring. You end up in an office with the non-laboratory scientists explaining what happened. If it is what they wanted to happen you will have an easy time. If it's not the mood turns dark and the relationship becomes more adversarial. But reality is best observed in the laboratory. That is where we need to go back to. Considering how much money has been lost in the industry, can we afford to keep the degrees of separation in place?