Negative Results On-Q-ity

Bruce Booth has been an interesting blogger on the topic of biotechnology. He is the recovering scientist turned early stage VC. I've made the analogy that he is like the recovering gambler turned gambling advisor. You take the risks, I'll mitigate mine by using your money. Bruce wrote this post about a company he and his co-workers backed with other people's money. It failed and the post mortem was indeed the product of a most clever wordsmith.

Bruce's original thoughts on the investment opportunity:

• “Hot space at nexus of two exciting themes in cancer and personalized diagnostics”
• "Strong team with a track record in building diagnostic businesses"
• “Robust financials with attractive recapitalization” 
• “Very strong intellectual property”
• Perception of “multiple possible exit paths via either diagnostic or oncology-focused pharma M&A or possible IPO”

Sexy, sexy, sexy!!! This company had a hot space, strong team, robust financials, strong IP and an exit door. What would the Reproducibility Initiative have added to this assessment? What Bruce was buying with other peoples money was a service. The money maker was suppose to be a cancer diagnostic service. Where in the above analysis do we hear anything about the science?

We here at the CCS believe that the number one reason most companies fail, and most projects in any company (successful or not) also fail is due to Cargo Cult Science. Whatever the reasons behind practicing CC science, it will not pan out in the end. The cargo planes will not land. In spite of this fact, money can still be made. This is what motivates Bruce to get the hell out of science to become an investor. I don't blame him, I got out too. The only difference is that I wouldn't waste any money on any biotechnology unless the technology is based on sound science. From that point the technology must then work as advertised. From that point you can start to look into the hot spaces where a strong team and IP can... MAKE MONEY!

After all... it is a business. Here is an easier decision, one would hope. The Office of Research Integrity (ORI) ruled that Andrew Aprikyan committed scientific misconduct. He no longer works at UW. Where does he work? He works at Stemgenics Inc. Stemgenics Inc. has recieved $180,000 USD in the form of a small business loan titled, SBIR Phase I: Membrane-Permeable Nano-Materials for Cell Reprogramming Solutions. The likes of Bruce Booth would probably have to pass in Stemgenics Inc. but the NSF likes what they see. In time Andrew Aprikyan could pull the wool over the diligent eyes guarding VC capital, except for the strong management team. Having a founder who has been ruled against in a misconduct case at the ORI should be a red flag for a venture capitalist. You may be able to hide this fact, but is the scientific foundation equally as shaky as the founder?

Ultimately, you can analyze the founders and the company all you want and you can easily fail. A better analysis would be focused on the science. Rather than doing what Atlas Venture did, hire a team at The Reproducibility Initiative to look into the science behind the technology. Hire anyone who has a laboratory and the ability to test the theory. If you think venture capitalists have a scientific method for picking winners, you would be mistaken. Science often takes off on paths that lead nowhere. That is part of the fun. The question for investors is "When?" is a business plan ready, from the scientific perspective? Without reproducibility, you are going to do what Atlas Ventures and On-Q-ity did. You will spend millions and millions more having the new lab staff try and validate the science. Chances are they will fail and your money is gone. 

Positive Results

I'm obsessed with the Amgen Study. It is true that the results are what I expect thus my own bias is satisfied. I don't like the results, but they support my belief in this whole cargo cult idea. So I went to set up the link on a recent post and I spent the time to read some of the comments. The first comment I read mirrors my thoughts.

Publication bias is a problem in all fields of research. The results of a paper should actually receive zero weight in the evaluation of its quality, otherwise there is the motivation to cherry-pick the data that give the most impressive result. The measure of quality should be the way the results were obtained – size of sample, experimental procedure, endpoints used. Ideally the reviewers of a paper should not see its results at all, only the description of the experiment.

But then there are a number of comments highly critical of the paper. What did these people not like?

The claims presented here are pretty outlandish. Particularly relevant to "Hematology and Oncology" we now know that mice housed under different conditions with different microflora can have vastly different outcomes in any model, not just cancer. To suggest academic incompetence or outright unethical behavior is offensive, and is a particularly narrow view of why experiments are difficult to reproduce.

This commenter seems to be defending non-reproducible results. Scrolling down we get a comment on this comment.

Reproducibility is the crucial part of scientific method. If indeed "mice housed under different conditions with different microflora can have vastly different outcomes in any model" (quot. from one of the comments above) then I wonder if mice presents a useful model-study that can be used outside a particular lab and on which further investigations can be built upon outside that one lab. 

Perhaps the commenter critical of the Amgen Study does not have a firm grasp on what makes for good science. The natural urge to simply defend could come from the human condition of favoring positive outcomes. As the first commenter points out, results shouldn't matter. That is a very interesting concept that not everyone will understand.

But all of this leads me to the latest TED Talk from Ben Goldacre. He too brings up the Amgen Study. He talks about this idea of positive results and our tendency, as humans, to favor them even when negative results are the accurate results. Hiding them leads to trouble, scientifically speaking.




Again, Feynman CCS

One example of the principle is this: If you've made up your mind
to test a theory, or you want to explain some idea, you should
always decide to publish it whichever way it comes out. If we only
publish results of a certain kind, we can make the argument look
good. We must publish both kinds of results.
 
I say that's also important in giving certain types of government
advice. Supposing a senator asked you for advice about whether
drilling a hole should be done in his state; and you decide it
would be better in some other state. If you don't publish such a
result, it seems to me you're not giving scientific advice. You're
being used. If your answer happens to come out in the direction the
government or the politicians like, they can use it as an argument
in their favor; if it comes out the other way, they don't publish
it at all. That's not giving scientific advice.

Amylins Fire Burns Out

Amylin Pharmaceuticals was a superstar biotech in San Diego. By the time Bristol Meyer Squibb acquired them they had over 1200 employees. The decision to set most of them free is a typical end to such an acquisition of a biotechnology company. The few that actually produce a product usually get acquired.  Those at the top get rich and the workers who contributed to the success get their walking papers. 

In the case of Amylin we have an interesting product. According to Consumer News:

If you take Byetta or Januvia to control your blood sugar levels, you might have a small, but increased risk for a condition marked by stomach pain and nausea. Not only are the drugs more expensive and no more effective than our Best Buy Drug picks for diabetes, they're associated with an increased risk for pancreatitis, or an inflamed pancreas, according to a new study in JAMA Internal Medicine. We recommend asking your doctor if you shouldn't be taking another drug in the first place.

There is, of course, a difference of opinion among the executives of BMS and Amylin. BMS paid billions for Amylin because Exendin was a sexy new alternative to the usual type II diabetes drugs. The disease itself can be easily reversed by a change in diet and proper exercise. The pharmaceutical industry has long been making bets that sick Americans would prefer a pill, and its side effects, to changing what they eat and how much exercise the get. Even if the pill doesn't offer improved results from cheaper drugs, they still have a sales force and lazy greedy doctors to offset the shortcomings.

Amylin certainly had its experts in the area of type II diabetes drug development. Imagine a court of law where there is a case known as Type II diabetes drugs vs Diet and Exercise. The case would demonstrate that pharmaceutical experts do not actually study the disease. They study the disease endpoints that they set out to alter for a more tolerable existence for those who choose to remain ill. The diet and exercise experts would offer their evidence that the disease state is caused by bad decisions. After an individual makes poor diet decisions  and get themself into the disease state, the pharmaceutical industry keeps them there. They also provide new problems. The pharmaceutical experts have also been caught hiding data from the FDA about hearts risks from Byetta and stalling the agency's efforts to learn more about the risk.

The hundreds of people who will be laid off as a result of BMS's decision to shut down the San Diego operation are mostly tribesmen. They did their job, looked to the sky and lo and behold something appeared. It needed help coming across as cargo but the leaders convinced the government that it was cargo. Once the cargo was given the official seal of approval, the cargo cult was made legitimate. It was sold, the cargo was secured, and the tribesmen are free to go find new cults.

“It’s not companies that matter, it’s people that matter,” said Walshok, associate vice chancellor for public programs and dean of UCSD Extension. “San Diego’s strength is in the talent that is resident here.”

If only BMS felt the same. The people who matter will spend a lot of time on unemployment. Some will switch careers. The expertise in type II diabetes research? Did it ever exist?

Award Winning Excellence

When we want more than we can actually obtain, we find substitute solutions just like the Cargo Cults. We have religion to help us deal with our existence and mortality. We have exalted leaders to give us a sense of order. We have corporations to keep us employed. And yet, the limits of these human constructs continue to let us down. The cargo doesn't always come. Only the laws of science seem to be constant.

At the Oscars, when a celebrity has to step out for a smoke or a bathroom break, their are people who take their seats so as to mask the stars absence. When we have an area of life that lacks a scientific explanation, we have seat fillers. In the world of professional scientists (I didn't say science), the truth is not coming to us as fast as our publications are being churned out. The area between science and what we want to believe is where we can put ourselves on the right or wrong path. It's the area where we went from assuming a god created us to beginning to understand genes and the structure of DNA. It's also the area where Alchemy exists. There is a fork in that road where scientific leadership is suppose to lead us. When the leaders decide that RNA interference, for example, is the right road we end up with years research and billions of research dollars wasted. We wanted our scientists to provide us with a tool to make future research easier. We got it.

Here is an example of what I am talking about, taken from the world of education. We as human beings want our leaders to make us smarter. We have ignored our limitations and we've given the leaders an impossible job. What do they do with their task? They succeed!

Three Dozen Indicted in Atlanta Cheating Scandal!

...the teacher came around offering information and asking the students to rewrite their answers. Juwanna rejected the help. According to Howard, Juwanna said that when she declined her teacher's offer, the teacher responded that she was just trying to help her students. Her class ended up getting some of the highest scores in the school and won a trophy for their work. Juwanna felt guilty but didn't tell anyone about her class' cheating because she was afraid of retaliation and feared her teacher would lose her job.

We wanted so badly to see the students get better grades that we created leaders to get the job done. Failure was not an option. We handed out medals for success and pink slips for failure. Then we had to face reality. We had exceeded the limits of human capabilities. The humans had to cheat or try their best and hope that things turn out in their favor. When your livelihood is riding on the outcome it is not out the question for otherwise honest people to cheat. We must also assume that the most dishonest among us will do the best. Juwannas teacher certainly did well. She won a trophy. Dr. Beverly Hall, the schools superintendent appears to have won a Nobel Prize! Just look at that medal.

In education we have a flawed system to begin with. We begin with the assumption of perfection, 100% or 4.0. Each time a student fails to tell us what we told them to think, we dock points from their perfect grade. The educators indicted in Atlanta took were suppose to bring their students average closer to perfection. They found a way.

We have to be careful what we ask our leaders to do for us. There is no shortage of highly skilled people willing to tell us what we want to hear.

Replacing the Journal

When we look back, as Feynman did in the CCS speech, we too question the minds of our predecessors. How could the Salem Witch Trials have occurred? It's now considered a cautionary tale on the dangers of isolationism, religious extremism, false accusations and lapses in due process. The Cargo Cults of pharma can be analyzed on each account. They isolate themselves via confidentiality agreements and they don't share raw data with anyone not sympathetic to their cause. They view science as a religion. They rely on, for example, the 51 papers cited in the Amgen study. Even after it is known that 90% of those seminal papers are not reproducible, they keep the faith. Once they have placed their labs atop the bad basic science foundations, they falsely accuse their in-house science staff of being the reason their pipelines are drying up. The due process they practice is to cut and slash jobs. They burn the witches.

In the future we will have better, faster, more intelligent machines and computer software to eliminate the faulty thinking described above. We currently have leaders who do not have to face the cold hard world of the scientific method. I predict a future where the hard copy journals will become more and more obsolete, like the pager or the land line telephone. In their place will be online depictions of the natural world using video (youtube) and words (blogs). Feedback will be immediate and hopefully ongoing. Eliminated will be the isolationism of the chosen leaders and their 'anti-scientific method' peer reviews. By pulling the curtain back on our Wizards of Oz, we will begin to view science in a less religious way. The new process will involve a true community, not a monarchy. I think of a future where truth trumps pretense. Where nonsense from Harvard will take a back seat to the truth from South Dakota State University.

For example, they could examine the latest paper from David Sinclair. Here is where the curtain of Oz is pulled back. The experiments themselves are filmed. Raw data is provided. We are talking about maximizing transparency. What is left to the viewer is only to compare their interpretations with Sinclairs. Imagine each experiment being set up with animations and explanations that your mother would understand. Discuss the system, the cell culture, the method of analysis, the background, the assumptions and so on. Hide nothing. After all, on this webpage you are studying the study, measuring the measurements.

AstraZenecas latest mistake, their partnership with Moderna Therapeutics would be a fun subject to study as well. The foundation of their science is to use mRNA to "trigger production of protein drugs in the body".

They have already provided some video to work with. You provide background, you design experiments, you show the results and allow for an online discussion. Provide a final analysis and leave room for future adjustments. In fact, revisit whenever important information lends credence or detracts from the story. It is, after all, a narrative at this stage. AstraZeneca shelled out money as if they were buying science. They bought a story. 

The time will come when the stories being told will face more and more scrutiny. Retraction Watch was the first to hold up a mirror to the journals and simply let them know that we, the commoners, are watching. We want more than sexy stories. We want tools to build new technologies. Therefore more methods of providing transparency need to become available. I can do without another David Sinclair paper from the journal Science. I can start the countdown to the day AZ pulls the plug on Moderna. What will impact science more than anything is a serious effort to replace the hard copy journals with real time online communications. 

Pfizer Demolishes Cargo Cult Airport

AstraZeneca did it in 2011. Now it's Pfizers turn. When the cargo does not come, tear down the airport!

Just take a look at what future generations of archeologists will not find in their search for the ancient research centers. Here

It is a nice little campus. Imagine the butterflies potential employees must have felt walking up the steps to this big pharma research center. This was the big leagues. Good pay, good name on the resume, and a nice location for a cozy east coast waspy lifestyle. Those who were hired did not provide enough value. Some were part of the problem, some were put in an impossible situation. Cargo Cult tribesmen can't bring the cargo by dutifully standing in the watch tower with their coconut headphones.

The fires continue to burn out. This one is a doozy. I'm not convinced of the sincerity of the "bone fide developer" who was going to save the day.

Sources identified the developer as Stu Lichter, president and senior managing partner of California-based Industrial Realty Group, which specializes in bringing empty buildings back to life.

Lichter, in a phone interview Wednesday, said he appreciated the governor and other state officials going to bat for him after he initially approached Pfizer about a deal. He added that Pfizer's decision to back out cost the region at least one major new employer that he had lined up as his first tenant, a bioscience company that would have added between 100 to 200 jobs with an average salary of about $100,000.

A pharmaceutical research site, even after its death, continues to attract bullshitters.

Kumare

I highly recommend the documentary Kumare (Koo-Mar-Aay). In this documentary an Indian man who grew up in New Jersey decides to make himself out to be a spiritual guru. He travels to India to study the mannerisms of gurus and guru followers. He returns to Arizona where he feels no on will recognize him and there will be plenty of would-be followers. He is a fake guru looking for people to believe he is real.



Long ago James Randi ran a similar experiment.



It is this kind of thinking that is at the root of all Cargo Cults. To make people believe in complete nonsense, you need to have a specific skill set. Kumare and Randi demonstrated how it's done. It's interesting how many similarities there are between these two scams and modern/science. Charismatic leaders from exalted institutions convince us that they have life extending elixirs and cancer curing pills.  

Our gurus wear suits and ties, white lab coats when the cameras are on. They have no intention of revealing the scam.  As someone who has friends and family currently dealing with cancer, I think we have to take our guru problem seriously. Let the foolish pharma people continue their quest for wealth. What we have to do is keep thinking, keep asking questions, and keep believing that science is indeed the belief in the ignorance of experts. It's okay not to believe the leaders.

AstraZenecas Solution

AstraZeneca is laying off 5050 human beings. Five thousand and fifty people who came in to work each day to do what they were hired to do, can all stay home now. The board says these people weren't providing value. What can we say about the board?

The board has decided to write a check for $240 million dollars for mRNA drugs. There will now be an unknown amount of human beings showing up to work each day doing what they were hired to do. Their job will be to make the case that Moderna Therapeutics has value.

The AZ board gathered with their investors to discuss their plans for the future. They will be:

Dramatically simplifying the business, improving productivity and building a culture that supports long-term success.

The biggest killer of real science within the industry is the need for scientists to be productive. There needs to be a laboratory of professionals who only provide science. People with job security and long term value. The production of scientific evaluation is different than R&D drug development production. Let the long term scientific lab employees offer up their opinions with no external pressures.

Why will Moderna not bring value to the investors in AZ? Because no one will be testing the validity of this small biotechs claims. No one will question the boards decision to pay $240 million dollars without any scientific verification of the claims made by the biotech company and the due diligence committee at AZ. They will fail. RNA anything will fail. We have zero appreciation of the subtle existence of this nucleic acid and how it is regulated. We think we can improve on DNA and RNA function? Without knowing how it works? We are arrogant and we have to pay the price for our misunderstanding of our limits.

Form a science organization that functions outside of your R&D groups. Let them advise the leadership by using the scientific method to augment the corporate C level executive method. You will find that science is your friend.

Resveratrol, Greek Coffee and Alchemy

Resveratrol was back in the news recently. On a Friday the journal Science published another sexy science paper by David Sinclair. On the following Monday GSK shut down daily operations at Sirtris, a company for which they paid $720 million... to David Sinclair.

The magical elixir, the fountain of youth we call Resveratrol, has found a new rival, boiled Greek coffee. Two can play at that game. It's known as Alchemy. According to Wikipedia:

The defining objectives of alchemy are varied; these include the creation of the fabled philosopher's stone possessing powers including the capability of turning base metals into the noble metals gold or silver, as well as an elixir of life conferring youth and longevity. 

David Sinclair and Dipak Das  have both ran afoul of the research community while pushing the sensational story of Resveratrol. In this paper the technical details the marred Sinclairs narrative are covered. The lab work is really where the science is taking place. The sexy narrative is the specialty of Sinclair and Das. The real science however, is not in the experiments they design to prove their preconceived notions. The real science would be in the analysis of their processes and the verification of their results.

We all want a magic pill. Some of us don't put any thought into such a reality ever coming to fruition, but it would be nice. Some of us still want the promise of Alchemists without the stigma of believing in charlatans and magicians. When people want to take a pot shot at Newton, for example, they bring up his belief in Alchemy. In the cold hard world of business, GSK has put an end to Sirtris. The cargo did not come. The elixir wasn't panning out and they (GSK) had all of the data to confirm their fears. They had been had! The journal Science however keeps the sexy science of Resveratrol alive.

Boiled Greek coffee is the latest offering for a candidate for the magic elixir of life. Here at the Cargo Cult Scientist however, we believe we are witnessing Alchemy in action.

The common thread to longevity is actually known. Smoking, drinking, stress, bad food, bad genetics... These things are going to shorten your life. The pharmaceutical companies will never offer you a "get out of the coffin free card". In the game of life, you have to believe in diet an exercise. It's not so much what certain people put into their body that makes them live longer. It is what they don't put into their bodies. Sadly, we have yet to solve the mystery of making money off of getting people to consume less.

Angry Allozyne

When they shut down the Seattle PI on March 17, 2009 they put an end to a daily telling of the Seattle story. Good people, who were good at their jobs, were let go. It was indeed a sad day for the people and for the art and science of journalism.

The Xconomy came along to take over the news in the tech industry. It reports on how to get money, who is getting money, and why everyone should be giving money to the cargo cults. I don't hide my biases very well. Occasionally however, they do something I like. They let out a secret today about a Cargo Cult known as Allozyne. I ran afoul of one of their supporters last year when I had this to say about their company. I do not understand what these people could be doing in that little space just down the street from the famed floating houses of Seattle.

Thought I'd throw in a picture. It is a beautiful place.

Allozyne started off as a promising story. According to Xconomy, they still are promising.

Seattle-based Allozyne, one of the promising biotech drug developers to graduate from the venture-backed Accelerator, recently conducted a small round of employee furloughs.

They branched off from Accelerator with a fat bank account, fancy digs, pretty people to run the show, and some sexy technology from a couple CalTech brainiacs. They were promising, if you were into appearances. Somehow the rest of the world was not impressed. Since leaving Accelerator, the leadership of Allozyne has boasted of no major collaborations nor any meaningful successes. Enough time has passed to make those of us on the outside wonder what is going on. A news story finally breaks but it is not clear what is going on.

Allozyne made the latest round of reductions to its payroll a little more than a year after another round of job cuts that I reported here in January 2012. CEO Meenu Chhabra Karson said by e-mail, “We did not lay off anyone recently,” but declined to answer further questions. Three other sources close to the situation said staff reductions were made recently at Allozyne and described internally not as “layoffs” but as “furloughs,” which suggests the people affected may be called back. 

Did Meenu deny laying anyone off this time or is that a quote from last year? If her quote is a year old, the only information we have comes from Lukes three other sources close to the situation.  If it's new, why not speak to the rumors of furloughs? We all assume that they will run out of money someday. Are they so Cargo Cult that they don't want anyone to see them without their look of success?

The anger from the Xconomy commenters offers some information. It appears to come from within the walls of that little space down the street from the floating houses. Like this one from "industry exec":

Having worked directly with the company very recently, I've seen absolutely no evidence or impact of the alleged personnel management "reported" here - Allozyne has a solid team and is extremely well led, so hopefully this rather loose and speculative story won't needlessly create noise or disrupt the company's ability to operate and deliver on its technology (which is truly exciting!). I have to say, I seriously doubt the accuracy of this story and would think even Xconomy has a higher journalistic bar for what even qualifies as newsworthy...shame.

Oh, this guy has worked directly with the company very recently... from his office overlooking the houseboats! Then there is this one from JMM:

The Allozyne approach and the products they are generating are top-notch, as is the staff's commitment to their science. If allozyne is refocusing their efforts expect great things from these guys.

Top notch? Expect great things? We've been expecting great things since 2005! To be fair, Amgen took 20 years to really take off but this is not Amgen. Allozyne is a small company that appears to be on its last legs. They took 50M down to 1.1M then managed to put another 4M in the bank last year. 4M is not a lot of money for a company that has to pay Seattle rent, Seattle employee taxes (why not set up shop in Bothell?) and exorbitant salaries to arrogant angry managers. Which one of these commenters was Leroy Hood? Which one was Carl Weissman? Who said this:

we're conducting a paid study with Allozyne and haven't seen or heard any issues either - management team is extremely professional and scientists are hitting our goals. I'd be surprised if this were true.

He calls himself "insider". He doesn't always use capital letters to start his sentences. He must be a high ranking insider exec. He claims to be paying Allozyne. We can no sooner verify his claim than we can verify Lukes. At least we know where Luke works.

I don't have anything to add to the story here. I started the blog a year after Allozyne began. My premise was that most of these little companies were ran on smoke and mirrors. The "entrepreneurs" are mostly PhD or MD level people who have a sense of entitlement. They put millions of dollars in a pot and swish it around to collect what spills over. During the day they hold meetings on how to swish the pot around. When the companies run out of money their work is done. Very few succeed so why worry about the failure. You move on with a C-level pedigree. Good job! Meanwhile the layoffs are real. You just aren't going to hear that from the Cargo Cult leaders.

New Jerseys Plan To Help Biotech/Pharma Workers

Give a man the reputation of an early riser and he can sleep til noon.   - Mark Twain

New Jersey has come up with a plan to offer $14,000 to employers who hire unemployed biotech/pharma workers. The concept here is that New Jersey does not want to lose its highly educated and formerly highly paid people. They enjoyed a period of financial success and they want to keep the gravy train rolling.

The Mark Twain quote above sums up the rather absurd situation. Biotech/pharma had earned a reputation as a successful lucrative industry. Along came the burdens of capitalism. The industry is shedding jobs and the local economy is taking a hit. What remains is the reputation. The local government officials have conspired with the local biotech/pharma executives to force the people of New Jersey to shell out $14,000 every time this failing industry hires a new person.

The $14,000 per person is part of a $3.6 million federal emergency grant, which includes $1 million in on-the-job-training dollars that have to be spent by the September deadline.  

If every dime of the $1 million is spent, about 71 people will land jobs. The workers must have lost their jobs in 2010 or later from various locations of Bristol-Myers Squibb, Hoffmann-La Roche, Johnson & Johnson, Merck/Schering-Plough, and Pfizer.

3400 drug company jobs were lost in New Jersey between 2008 and 2010. The government is going to spend one million dollars to create 71 jobs. Who will get the money? 

The $14,000 grants will underwrite training for six months for up to 50 percent to 90 percent of the employee's salary - although jobs in the pharma sector typically paid much higher than that.

At 50 percent we are looking at an annual salary of 48K. At 90% we are looking at $31K per year. 

The most curious logic in this plan is the training. 

"Every company is going to train their new employees," Flatley said. "This allows us to pay a portion of that training."

What is it about former BMS, Roche, Merck, and Pfizer scientists that lead people to believe they need more education and a $14K dowry? Were they lacking value? Are they still lacking value? Does a Cargo Cult worker have anything to offer the next cult?

Douglas Prasher and Science Careers

One of the most perplexing thought experiments that I engage in here involves employment. You can't experience the joy and the power of science by working in a Cargo Cult. Real scientific thought involves that understanding illustrated in Feynmans CCS speech. You must appreciate Feynmans Wesson oil example. Wesson oil doesn't sink into food as advertised. But neither does any other brand of vegetable oil when applied to food above a certain temperature. A scientific mind will find such marketing tactics disdainful. The disdain towards this kind of dishonesty will lead you into a career in science. You discover that your personality is best suited for utter-bend-over-backwards honesty. Scientific progress will be your revenge on the higher paid marketing execs and the child molesting priests who wish to influence those around you. You have faith that you can succeed by harnessing that power and providing the world with new and better products or services. You've had an epiphany, that science is a way of thinking that leads to things that change our world.

Then comes earning a living in a world that has not had that science epiphany.

It ought to be remembered that there is nothing more difficult to take in hand, more perilous to conduct, or more uncertain in its success, than to take the lead in the introduction of a new order of things.  - Niccolo Machiavelli

In my last post I discussed the career of Gertrude Ellion.

"I would just go ahead and make the compounds, and then the question was, well what do we do with these compounds?" How do we find out if they really do anything?"

She had to take the lead in the introduction of a new order of things. What did that involve? She first had to succeed at making the molecules. She had to provide evidence that she had succeeded. Then she had to find out if they did anything.

That brings me up to modern times and the career of Douglas Prasher. Douglas Prasher cloned GFP. It is a great tool for conducting research. Like Gertrude Ellion, he just went ahead and completed the first step. Gertrude made her compounds through chemistry. Douglas cloned his genes through molecular biology. When it came time to find out what could be done with it, Douglas Prasher had a difficult time. He had envisioned that the gene could be inserted into the end of the hemoglobin gene. When hemoglobin was being made by the cell it would have a green glow. GFP was a small protein that could possible by expressed without disrupting the normal function of the gene into which it was cloned. Unfortunately, he ran out of funding before he could express his GFP clone in the manner he had envisioned.

Since then many others have taken the baton and sprinted on. GFP was a huge success. D. Prasher ended up driving a courtesy shuttle for a car dealership in Huntsville Alabama for $8.50 an hour.  Two of the scientists, Martin Chalfie and Roger Tsien, took the baton sprinted on to win the 2008 Nobel Prize in Chemistry. It's not their fault however that the Nobel committee left D. Prasher out. They were working outside of the Cargo Cult. Dr. Prashers enemies were inside.

Because the innovator has for enemies all those who have done well under the old conditions, and lukewarm defenders in those who may do well under the new. This coolness arises partly from fear of the opponents, who have the laws on their side, and partly from the incredulity of men, who do not readily believe in new things until they have had a long experience of them. 

- Niccolo Machiavelli

The enemies of innovation and lukewarm defenders are the many people one will meet along the way. Pursuing a career in science will not be a success if you only focus on the science. What we set out to accomplish is something new and in direct opposition to the goals of those who have done well under the old ways. Gertrude Ellion and Douglas Prasher both brought about new ways of conducting research. Only one however, succeeded in having a long career in science.  Both scientists had menial occupations mixed in with their science jobs. Gertrude was a secretary and a substitute teacher before taking an unpaid laboratory job. Dr. Prasher drove a shuttle bus. Gertrude is the success story. What did she do differently? It's hard to pinpoint. She lived in a different time and worked under different people. Did she have better Machiavellian skills? Perhaps she didn't need them. Perhaps there is a mixture of interpersonal skills and the need to apply them in your work environment. One thing is for sure, there is more to a successful career in science than simply being a good scientist.

From a Molecule to A Cure

Just to be fair, I want to talk about someone who worked on single target - single drug treatments. This person did her work in a manner that had some "wealth in the system". This was not my experience but I can appreciate that it can be done. I went to a speech given by Gertrude Belle Elion a few years before she died. She won the Nobel Prize in Medicine in 1988. Of all the seminars I attended, this one has stuck with me. At the end of her talk she was asked by one of our professors if she would have benefitted from the modern tools of biotechnology. I can't remember her exact response but her answer was NO! She made it clear that research was something that requires the human mind, not just applying a few technologies. She showed a map of discovery. It went from chemistry to microbiology to biochemistry with stops through physics and math. The process she described was similar to Feynmans view of science. The stuff our professors hoped we had picked up during our education under their watch.

12 December 2008 , published , doi: 10.1098/rsbm.2007.0051 54 2008 Biogr. Mems Fell. R. Soc. 

After receiving her bachelor’s degree in chemistry from 

Hunter College in 1937, Trudy realized that neither she nor her family had enough money for 

her to attend graduate school. She began to look for a job, and immediately ran into the prover- 

bial brick wall. ‘Nobody … took me seriously. They wondered why in the world I wanted to 

be a chemist when no women were doing that. The world was not waiting for me.’ Secretarial 

school followed, and then teaching at a hospital and a high school. She finally landed a posi- 

tion, albeit nonpaying, with a chemist, just to keep busy in her field; during this period she 

decided to pursue her master-of-science degree, which she received in 1941 from New York 

University. During her graduate studies, she started teaching high school chemistry and physics 

as a ‘permanent substitute’ for $7.50 a day. 

Her big break came when the United States entered World War II. Since there were few men 

around, women came to be seen as potential employees, and Trudy was hired as an analytical 

chemist; her job included the measurement of the acidity of pickles and the colour of mayon- 

naise. After a while she tired of those functions and a spell of testing the tensile strength of 

sutures, and sought more meaningful work. The most interesting opening was at Burroughs 

Wellcome, where biochemist George Hitchings (ForMemRS 1974) was trying to make antago- 

nists to nucleic acid derivatives. Hitchings, who would later become a member of the National 

Academy of Sciences, ‘talked about purines and pyrimidines, which I must confess I’d never 

even heard of up to that point, and it was really to attack a whole variety of diseases by interfer- 

ing with DNA synthesis. This sounded very exciting.’ She accepted the position of biochemist 

in 1944 and spent the next 39 years at Burroughs Wellcome, becoming head of the Department 

of Experimental Therapy in 1967. 

Let Trudy explain how she started out making compounds and ended up eventually with the 

first effective drug that induced remission in childhood leukaemia. 

At the beginning … it was my job to find out how to make (compounds). So I’d go to the library, 

look up the old literature to see if I could figure out how to do it. … I would just go ahead and 

make the compounds, and then the question was, well what do we do with these compounds? 

How do we find out if they really do anything?

She attracted many associates who became known as 

a research dream team, some of whom invented azidothymidine (AZT), a mainstay drug for 

treatment of HIV (human immunodeficiency virus) infection. 

Trudy was awarded the Nobel Prize in physiology or medicine in 1988 for her discovery 

of important principles for drug treatment. 

What were those principles for drug treatment? Gertrude and George Hitchens demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria and virus. On the basis of these differences they developed drugs that blocked nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells.

How does the biotech/pharma industry hire people? How do they use the new buzz word search technology to sort through resumes and end up with someone like Gertrude? Someone who can use the literature to make the molecules AND "find out if they really do anything?"

The executives may be concerned about whether or not they can find these people in the future. Gertrude came from the secretarial pool. She was a substitute high school teacher. Would Gertrude Elion have succeeded, sans PhD as she was, at Pfizer or Merck? What did she have that so many are missing today? What did she and George Hitchens do that the drug developers are not doing today? With all of our modern technology we are missing something. 

Implications of Missing The Complex

The paradigm of the single causative agent - single receptor antagonist, is one possible reality in the quest for new drugs. If so, this is a complicated system. The journey from complicated to complex:

• Complicated, in which the relationship between cause and effect requires analysis or some other form of investigation and/or the application of expert knowledge.
• Complex, in which the relationship between cause and effect can only be perceived in retrospect, but not in advance.

In a clinical trial, we are studying the relationship between cause and effect in retrospect. However, we have blurred the lines between complicated and complex. We begin pharma research by creating a cause, linking protein X to disease state Y. We have reduced our research to a complicated project. We hire experts to conduct the analysis that validates our cause and effect assumption. Our scientists know that their career aspirations lie on providing evidence that the drug intervenes on the cause and alters the effect, the disease. 

Look at health in a different way. Look at it in a complex way. In many disease states, it has been shown that diet and exercise works much better than the pharmaceutical interventions. In the documentary "Forks Over Knives" several very sick people were restored to health. The intervention was not simply that protein X causes disease Y. Some combination of the wrong food at the wrong quantities was causing a disease state. Changing diet and exercise habits brought about real change. But what was the cause, on the molecular level? A single target protein that was attacked by a barrage of vegetables? 

Let's replace the Forks Over Knives success stories with the curse of baldness. Have we ever changed a diet and exercise routine to reverse baldness? If we had, men all over the world would make the change. They do it to sculpt their bodies. Why wouldn't they take the advice seriously to stop losing their hair? What is it then that prevents people and scientists from learning more about the complexity of the human body and the relationship to diet and exercise? Is is because it is too hard, too complex? The madness of Resveratrol comes to mind. Someone noticed that the French had longer life spans than the rest of Europe. They focused in on red wine. They wanted to find one single molecule that they could make into a pill. A few years later Resveratrol. N-Rays in a capsule. Once again, a single agent that provides a key to long life. But it didn't work. 

So we really ought to look into theories that don't work, and
science that isn't science.

Covx, The Cult of Barbas

The last posts title was, 150,000 Jobs Lost Since 2009. Add another 100 or so losses from the ranks of Pfizer. Covx is going away. Started in 2002, Covx used phage display to make peptide-antibodies. Improving on natures invention of the antibody, Covx selected peptides that bound to target proteins (like an antibody) then they attached the peptides to a stealth antibody. The antibody protein is there only to stabilize the peptide and increase its bioavailability.

No one will talk about the demise of Covx like the Cargo Cult Scientist. The question we have is, and always has been, regarding the sustainability of the single target - single drug paradigm. We humans have thrown billions and billions into the paradigm and we haven't come up with much. Humans can still get rich in our current health/sick care system investing in this drug development approach. But are we really making any progress in treating disease? Do we understand how one protein can make us sick? How does one protein spin out of control, unregulated by the controls built into our DNA over billions of years, then suddenly become properly regulated by a single molecule that humans design in a few years tested at a few dosages? It seems highly unlikely that this actually works.

The CCS once worked with the laboratory that spun out Covx. Their phage displayed antibodies were sent to us in vials of various consistencies of goop. Our job was to take the goop and run western blots to verify binding to our target. Down in San Diego that merely had their technicians select candidate based on an arbitrarily selected ELISA signal. Anything above X was sent up to us at UCSF. Every single ding blasted frigg'n candidate was selected due to high background. We learned that they were panning their phage against completely denatured proteins. No structure! The day they started using non-denatured proteins to pan against was the day they started getting actual target binding antibodies. Those of us running the western blots were put through a humiliating few months of heavy criticism on our western blot skills.

Covx however was no different than most. They begin with the single target - single drug molecule paradigm. They have a technology to obtain the single drug molecule. A technology is a practical application of a science. That technology was not theirs originally. Phage display was developed by Dr.
George P. Smith at the University of Missouri. The folks at Scripps got ahold of a sexy new technology and ran with it. They made the Herculean leap from phage display technology to medical science. My personal knowledge that comes from experience indicated to me that they were lacking wealth in their technology system. How might they fare in the upper realms of science?

How can a group like this go on to form a multi-million dollar partnership? Some say the founder was awarded a couple hundred million dollars from Pfizer. Well of course the founder and a few at the top were the winners. The laboratory people are the ones who are suppose to  add those pesky details like having an actual test for target interactions. The leaders offer up the sexy narrative that attracts the investments. In our case, we were attracted to them by the narrative of getting antibodies quickly and for less money. In the end, we received ordinary antibodies that anyone with phage display skills could have provided. Ordinary...

Was Covx an ordinary phage display group that had an influential leader, Carlos Barbas, who excelled at the narrative? According to Pfizer, upon the acquisition of Covx:

CovX’s biotherapeutic platform is a technology that links therapeutic peptides to an antibody“scaffold”. The peptide targets the disease while the antibody scaffold allows the peptide to remain in the body long enough to achieve therapeutic benefit. The technology thereby allows half-life extension and bioavailability to support optimal dosing regimens for peptide therapeutics.

As validation of this technology, CovX has generated three early- stage compounds, one diabetes and two oncology compounds, that are expected to further strengthen Pfizer’s biologic pipeline portfolio.

Is it fair to say then, that "as validation" that this technology is just phage display, smoke and mirrors, Pfizer is sacking the entire staff of Covx? 

"We are pleased to transition the CovX technology to Pfizer's Biotherapeutic and Bioinnovation group and are confident they have the vision and resources to scale the platform and realize the opportunity to make efficacious drugs which will make a difference in peoples' lives," stated Shehan Dissanayake, Chairman of CovX and CEO of Tavistock Life Sciences.

I talked about a former gambler who decided it would be best to sell his picks rather than bet on them. For a fee he would let the gambler in on who he thought would be covering the spread that day. In a sense this is what Jeff Kindler and Corey Goodman did back in 2007 when they acquired Covx:

“The acquisition of CovX is a further step in Pfizer’s strategy to acquire and identify new product candidates that we can put into development, leveraging both Pfizer’s expertise and that of world-class scientists charged with discovering and bringing in new compounds,” said Jeffrey Kindler, chairman and chief executive officer of Pfizer. “With this deal, we are building on our recent announcement of a new Biotherapeutic and Bioinnovation Center based in California and led by Dr. Corey Goodman. We are looking for the best science wherever we can find it, with a special focus in our priority areas, such as biotherapeutics.”

 The ceremonial beginnings of Cargo Cult projects are always followed up by the rather unceremonious  announcement of their demise. It is sad to see so many people out of work. But we have to wonder if they were actually doing work, or were they focusing on the narrative offered by their leadership.

My friends you are getting tired of hearing it from me, but the cargo didn't come. Covx did not fail because the guys with the white lab coats were no good at phage display. They failed because the narrative was cargo cult. Phage display is real. We can select peptides that bind to targets. We can't make the binding lead to the outcomes described in the narratives.

Farewell Covx. Good luck to those who invested years of their professional lives on the Covx promise.

150,000 Jobs Lost Since 2009

According to PricewaterhouseCoopers, 51% of pharmaceutical execs are of the opinion that it's getting harder to find good help. As reported by Pharmalot:

...a slight majority of drugmakers complain that it has become increasingly difficult to find the right talent and most worry they will not have access to the people they need to hire.

If this abstract group of humans, the pharma executives, has such a good idea of who the right people are, why did they hire all of the wrong people in the last couple of decades?

Since we think that the Cargo Cult mentality is the hidden story behind this industry, we find the question of finding talent interesting for other reasons. The question we ponder is about the actual research conducted by PricewaterhouseCooper and the innumeracy that goes into considering the validity of their work.

Driving home this evening I heard an ad from a Las Vegas odds maker. If you want to gamble and win, you give him some money and he will let you in on a few sure bets. Of course, if you take his advice and lose, the money you bet plus the money you paid the expert is all gone. No refunds. Knowing the odds is what gambling is all about. Once you figure out how tough it is to make a living gambling you might just want to turn to a safer bet. Rather than laying down your own money on the Superbowl, have people give you money for your pick. Genius! Don't be the gambler.

That is what we have here with the PricewaterhouseCooper research team. They serve as the expert selling the unknown knowledge hidden to the common man. The bias we may all have, that massive layoffs lead to talent shortages is not even being quantitated. The experts in judging an industry merely asked the experts who run the industry for their opinion. Even if difficulty is encountered when hiring the talent, it could just be that the experts are not good at identifying talent. Simply because the executives feel uncomfortable is no indication that talent does not exist?  It's just a feeling, like our gambling friends feelings about the Lakers chances over the Bulls next week.

What was lost in the course of laying off 150,000 people since 2009. Only the executives know. They are like the seller of gambling secrets. They know something you don't. At least, that is what they are selling.

Did you know that the word gullible can't be found in the dictionary?

What are the odds that the pharma experts in this research know what they are doing? They have yet to come up with anything as powerful as a proper diet and daily exercise. They attack single targets with the usual suspects; small molecules, antibodies, RNAi... and they want us to believe that clinical data is solid. Just don't ask for the raw data. The industry has been propped up by the occasional useful product. Antibiotics, Insulin, the Polio vaccine are the kinds of breakthroughs we wish for. Drug products like Provenge are what we seem to get. It appears that the talent they seek is in finding people who are best at hammering square pegs through round holes. The status quo has a track record of not being able to predict the breakthroughs. Without predictable success in our pipelines, we select for corporate types who succeed where more honest types accept defeat. As a result, chances are we'll lose more jobs. Some of the jobs may just be currently held by someone who offered up their expert opinions to PWC.

51 percent of life science execs – which is the highest of 19 sectors examined – say that hiring is getting tough and only 28 percent are confident about finding the right candidates. This comes as roughly 60 percent of pharma execs plan to invest more heavily over the next three years to create a more skilled workforce and 72 percent intend to boost their R&D capacity over the next 12 months, PwC Health Research Institute reports.

The ex-gambler who now sells his knowledge is an expert. He knows the odds and the futility of placing the bets. He makes the picks, sells them, and lets the gamblers lose. Perhaps the biotech/pharma industry, after sacking 150,000 people, has become concentrated with similar experts. They know where the risks lie in a career path in the industry. In spite of all of the losses, they are still there selling their knowledge. Quantitating that knowledge is most likely not going to provide any insight on the future in the drug industry.

A Great Rant

I tend to enjoy what some refer to as "rants". I think this spirited dialogue posted on the "In the Pipeline" blog yesterday was most enjoyable.

I’m leaving bioinformatics to go work at a software company with more technically ept people and for a lot more money. This seems like an opportune time to set forth my accumulated wisdom and thoughts on bioinformatics.

My attitude towards the subject after all my work in it can probably be best summarized thus: “Fuck you, bioinformatics. Eat shit and die.”

 One commenter had this to say:

When someone finds fault with the way a field conducts itself, I would implore them to constructively influence that field. You might be surprised how many are actually sympathetic to your concerns. 

I'm not dismissing this author's concerns: to do that would really require knowing the molecular biology field (which is more than sequencing, it turns out). I do neuroscience right now, and programming can be a problem for some. But a constructive suggestion to change can have much more impact than a long rant.

This "long rant" was chock full of interesting ideas. The human genome project was not a science project, for example. Good science require an understanding of the limitations of ones tools. That is good stuff. This was a rant, devoid of mitigated speech. Notice how quickly the lack of mitigated speech became the topic of discussion for the commenter. He did not dismiss the author's concerns, nor did he have anything constructive to say about those concerns. What was at issue for the commenter was the rant.

Here at the CCS we feel that the rant was fun. It was real, written with obvious passion, and spot on. We too spent a short period of time at a bioinformatics company called Protein Pathways. Garbage in, garbage out. Our competitor, Rosetta, beat us to a buy-out from Merck. Neither Rosetta nor Protein Pathways are in business today. The cargo never came.

If you were an investor, you could easily discard such rants, my entire blog included. To some, we are not offering constructive criticisms. But read with a critical eye, vitriol in italics, big picture idea underlined.

All the molecular biologists, devoid of skills beyond those of a laboratory technician, cried out for the mathematicians and programmers to magically extract science from their mountain of shitty results.

The big picture idea here is straight out of the Cargo Cult Science speech from Feynman:

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.

"extract science from their mountain of shitty results"

"get some wealth in their system"

This is what it is all about. This blog and the numerous rants all focus on this area. Sure we are angry. We want to explain, using our education and experience at your Cargo Cults, what you are missing. We want to point out why there is no wealth in your system, nor your investors bank accounts. But it is as difficult as explaining to the South Sea Islanders how to arrange things.

Good job Fred Ross. You are an official ex-tribesman of the Cargo Cults of Biotechnology.