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Friday, January 20, 2012

Making Money from Honesty, Consumer Reports for Scientific Consumers

What if you didn't have to make anyone happy with your research? What if you ran a small laboratory with about 10 really smart scientists who conduct research according to a well defined philosophy of science? That means no long winded narratives about your awesome pipeline. You are developing a biotechnology company that sells a service. Research! I am not talking about a CRO here. I am talking about a company that has no bias other than to tell the truth. Who needs such a company?

Those who are embarrassed by the scandals taking place at their organization.
Those who have to retract papers when their chosen peers are led astray.
Those who want to invest in a company but are only getting the input of the people trying to get their money.

How do you make money from a company trying to sell unbiased evaluations? Sell your service. Finance auditing services make money. Why couldn't a science auditing company make money? If it is true that one trillion dollars, (274 million dollars a day) was lost in the past decade on research then we have a business model. One of our original American entrepreneurs, Ben Franklin, told us that a penny saved is a penny earned. We could have earned a whole lot of pennies from that past decade. Of course that money wasn't really lost. It was earned by people who would love to see us continue down the path we are on. David Sinclair is an example. What about those who lost money, such as Roche did with Sinclair? Would they do anything different if they could?

Unlike computer science, engineering or physics, the life sciences do not always have clearly defined tests that lead to predictable outcomes. Medical science is at best soft. At its worst it is a bunch of misleading sciency nonsense that looks for the suckers who are born every minute. The old logic is that the nonsense is snuffed out by wise investors or a team of high powered scientists and lawyers working on the due diligence for a new partnership. That hasn't worked. The product/service of our business model must focus here. Why can't those who are suppose to catch the nonsense do so? How can we succeed where they fail? We will replace faith based methods such as peer review and return to empiricism. The scientific method will be a guiding light.

No matter how good you are in businessman, you can't be an honest success selling broken mouse traps. You can be a dishonest success but those are the guys who profited from the $Trillion dollar loss of others peoples money in the past decade. We are working against them. They have been winning. As of late however we are starting to see new weapons against the Cargo Cults of research. Original online creations like Retraction Watch are pulling the curtain back on the secretive world of research Wizards of Oz. There is a changing attitude towards science. It is fallible. However there is a possibility that Retraction Watch will run it's course and become boring without a greater cause. Abnormal Science blog will start to appear as repetitive because science will always have a dishonest population. The good must also be pointed out as well as the bad, just as it is in the automobile consumer reports. Pointing out that the Honda Accord has bad breaks, for example, is considered useful among car buyers. That doesn't mean that the Honda Accord isn't a nice car, it is. The same may go for a particular field of research or a drug candidate. There may be a highly effective antibody drug available for partnership but it comes with manufacturing issues such as low expression. These are issues that management, investors and future scientists and engineers of the project should know about prior to joining the effort.

Instead of forming an antibody company or an RNAi company, start a research company. Before putting anything on the market, develop the product/service. Like any biotech company, that means spending time establishing the company structure, mission, and financials. Methods must be put in place so that evidence or data isn't accepted without sound basis. Personal relationships must be healthy. Checks and balances can trump supervisors and annual reviews. Ultimately, there must be tests. That means a separate group will offer up several cases each year that should come up as nonsense (a negative control). A positive control will also be required. Each group must specialize in the ways of Cargo Cults.

Human beings have been trying to distinguish shit from shinola. since the dawn of time. We are all consumers of science whether we know it or not. We need better stewards of the information that is out there. Can those stewards be a for-profit organization?

Wednesday, January 18, 2012

Risperdal and Tamiflu Hidden Data

Tamiflu: A new review of the influenza drug oseltamivir (Tamiflu) has raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts.

We looked into our own thoughts on Tamiflu. We talked about it here on our very second post on the CCS.

Risperdal: Johnson & Johnson officials hid three studies showing some patients using Risperdal developed diabetes while claiming the antipsychotic drug didn’t cause the disease, a witness testified.

I'm starting to think there may be some systemic dishonesty in the Cargo Cults.

Type I error and Type II error are precise technical terms used in statistics to describe particular flaws in a testing process, where a null hypothesis that should have been accepted was rejected (Type I error) or where that hypothesis should have been rejected, but was accepted (Type II error).

Clearly Roche and J&J did not make an error. The came to the right conclusions and decided that no one should be allowed to come to the same conclusions. Johnson and Johnson was hit with a $158 million fine this week. Tamiflu and Roche seem to be getting away with their sins against science.

They made billions, for those who don't follow this Cargo Cults. They did not make an error. In the Cargo Cults, Risperdal and Tamiflu are success stories. And they created a lot of jobs in their legal departments.

Saturday, January 14, 2012

Western Blot / The Tool of Scoundrels

The Nobel Prize in Physics 2009 was divided, one half awarded to Charles Kuen Kao "for groundbreaking achievements concerning the transmission of light in fibers for optical communication", the other half jointly to Willard S. Boyle and George E. Smith "for the invention of an imaging semiconductor circuit – the CCD sensor".

The image from a CCD is black and white, but by placing a red, green or blue colored filter over the top of each pixel, color information can be read directly from each pixel — but only for one primary color per pixel. Subsequently, software can also extrapolate the color of adjacent pixels based on their brightness, so that each pixel winds up with its own red, green and blue values. A RAW file is the “raw” color data from the chip before any of the post-processing extrapolation has been done. Cameras usually do all of this processing for you and spit out the result as a JPEG. With the RAW file you actually have all the original sensor data, which is much more information-rich.

So far so good. Here we pack up the Allied forces airport and the Cargo Cult takes over. Next we introduce the western blot. Somewhere between running the western and generating the image of that western we enter the cult.

Post-processing extrapolation was my job for five years. I was a photographer. The original data that I used was a roll of film. I learned how to expose film using f-stops and shutter speed. I learned how to process and print black and white, color and slide film. Interesting things to know but digital technology now takes care of all the things I was doing manually. Post-processing image quality issues like color, contrast, and density are now automatic.

My first few years running western blots were done on film. Then one day we received our first AlphaImager. It is a box with a light table that fold down so you can take pictures of SDS PAGE gels. Fold the light table up and there is a UV light box for DNA gels. Shut off all light and you can take pictures of chemiluminescent western blots. A a RAW file is generated, with all the original sensor data, which is much more information-rich than a processed image.

The western blot has seen some method advancement. There are E-gels and I-blots which speed up the time to transfer the proteins onto the membranes. There are more sensitive reagents for developing the westerns so lower amounts of protein can be detected. Each change challenges the Cargo Cult tribesmen. If a transfer is sped up, they claim, you will get less protein transferring. "How do you know?", I would ask.
Using film, I was told, was superior to digital images when it came time to expose for weak signals. "Can I see the evidence?" I was respond. I wasn't getting a satisfactory answer. I developed a test. I loaded a gel with high to low amounts of protein. The low end concentrations dropped below the level of detection even at maximum exposure time (chemiluminescent probes lose their energy after about one hour). I prepare two identical westerns. One western was visualized by exposing it to film for one hour and the other was visualized using an AlphaImager CCD camera.

Test number one: Hold film in hand and use eyes to compare with digital image on computer screen. Oh the varying opinions! Based on ones bias, a subjective argument would break out. "The film is more sensitive!"

Test number two: Use ImageQuant software from GE Healthcare to quantitate sensitivity. The bias was still there but the data was irrefutable.

Science and technology wins the day.

Next I ran the same western blot and probed it with a fluorescent dye conjugated antibody. I used the CCD camera to capture the image. I also captured the image of the very same western on a lazer scanner. The fluorescent probe provided greater sensitivity measured by the signal from the lowest detectable amount of protein. The scanner produced cleaner data as measured by the correlation coefficient of the linear curve generated by the protein signals. I laid the western in a drawer and let it dry out. Every month for six months I scanned the western. The results did not change.

So I had determined empirically the best way to run one particular western blot. I'm not done yet however. If I am to get reproducible results from my western I must also account for the protein sample I am loading. Purity and stability, for example, must be known. In a proper research organization all of this is known by the QC group. The people who develop the methods take these factors into account. The people who then run the western blots must adhere to the standard operating procedure. They are tracked electronically so that deviations can be accounted for. For example, if a standard curve appears to be lacking in linearity or range, the protein standards can be identified to see if they were used beyond their stability window.

This all leads to the quality control of a cargo cult. I consider a peer reviewed journal to be part of the cult. The tracking of source material, equipment, and technician is not something that a journal editor asks for. It is even rare for immediate supervisors to read over a laboratory notebook, especially when the results turn out in their favor. The cargo cults do not have quality control mechanisms. They rely on their intuition and intelligence. As a result, any questioning of the finalized data is frowned upon. Lower ranking members of the organization are then held accountable for any transgressions, since the scientist above them has such a high standard for their honesty.

If the JPEG or TIFF files were made available we wouldn't have to use our eyes to try and discover fraud. Variances in density, for example, could indicate cutting and pasting. That clear line that gets erased with density adjustment remains on the pre-processed image file. The pre-processed data is what we need, not the post-processed product offered up for publication. The post processing is where the scoundrel plies his/her understanding of imaging and ways of fooling the older generation of leaders. Fortunately, post-processing is tracked by the software. If post-processing takes place, that image must be saved as a new file. The family tree of an image is stored automatically. It all leads back to the pre-processed image.

This is a critical point in the Cargo Cults use of imagery in their ceremonies. The real wealth of the imaging systems comes from the pre-processed data. Office dwelling scientists don't publish relevant information on image enhancements. They offer up aesthetically pleasing images that support their narrative. Orthogonal methods should be required to back up the western analysis, such as the ForteBio.

Wednesday, January 04, 2012

Hanging From a Tree in a Forest In Belgrade

You hear about pharmaceutical companies bribing doctors, promoting off-label use of their drugs, cherry picking clinical trial data, ghost writing scientific papers, and all sorts of bad behavior. You rarely hear about the people who do this work for a living. When they get caught the Corporation steps up to the plate and takes the hit. The corporation loses lots of money. The public furls its brow and says, "Bad corporation!". Who are the people who do these bad things? Do they go on to more prosperous positions? Are they ultimately rewarded for their dedication to profits? Or do they succumb to ridicule and ostracism from an honest industry such as biotech/big pharma?

One such person, Nenad Borojevic, a former director of the Serbian Institute of Oncology and Radiology, was found hanging from a tree in a forest in Belgrade. He was charged with supplying drugmakers with information on the amount of cytostatic drugs needed and on public procurement plans. Nenad Borojevic and representatives from several pharmaceutical companies, including AstraZeneca and Roche, were indited on suspicion of accepting and giving bribes totaling about $1.4 million.

Who were the employees at AstraZeneca and Roche who worked with Nedad? According to reports, police also arrested the director of Roche pharmaceuticals office in Belgrade, Vojislav Petrović. Other suspects detained include Director of PharmaSwiss Oncology Sector Andrej Soretić and Predrag Marinković of AstraZeneca bio-pharmaceutical company. Who were their superiors?

How does this relate to a Cargo Cult? The drugs are already approved thus the cargo arrived. I tend to believe however that the drugs are of little interest scientifically to a certain sector of the industry. The drugs are merely widgets that generate profit. With a little help, those profits can go up considerably. The execs with the right credentials, who talk pretty are tasked with making the most money possible from the pills. They have to convince the world of medicine that they need to prescribe the pills. They have to educate. In the process they tend to stretch the truth. And the truth is what we are all about here.

The truth about the pills, in this case, was stretched to the point of criminal activity. One of these leaders was found hanging from a tree in a forest in Belgrade. How can an industry that relies on science employ leaders who have cumulatively created such a corrupt corporate culture? How can such leaders understand how scientific research is conducted? It is fairly easy to deceive ourselves and our fellow human beings. To do so purposely seems to be the skill that the leaders have in spades. Such leaders thrive in Cargo Cults. Sometimes they get caught.

Allozyne Layoffs and Sacrificial Lambs

The last post was about the fallout of a merger that went sour. The CEO and four board members from company A resigned. Company B has possibly laid a few of its 20 employees off but their CEO denies the claim. The details of the merger and the subsequent fallout would be good reading for those of us interested in the business of science. It is not however, what we want to do here on the CCS. What we do here is philosophy. An interesting technology came out of Caltech that enabled one to add a non-natural amino acid to a recombinant protein. That non-natural amino acid would allow for conjugation to other proteins or PEG chains that could add some pharmacokenetic advantages to a protein. Fantastic. What happens next is of interest to the CCS.

What happens next is a business plan is written up and submitted to a venture capital group, a biotech incubator, an angel investor, a rich relative, or whoever has the money that the inventors lack. In a classic "you've got the money, I've got the brains" situation, a relationship is formed. Trust and money is given to the inventors by the investors. A meeting takes place. Where are we going to set up shop? What should we pay for rent. Who do we need to hire? Who can we put on the board and advisory committees to attract other players in the industry? In all of this shuffle it would be easy to lose sight of the original excitement of being able to stick a couple antibodies together and see what happens.

This is of interest to the CCS because what usually happens ends in failure. We ask ourselves how so much interesting science and so much money result in failure? We believe that this is no ordinary business failure. We have recently given a number to the failures of drug research ventures. A trillion US dollars has been lost! That is veritable petri dish teaming with life for a philosopher such as the CCS. I want to put that petri dish under a microscope and watch the interactions and understand what is happening. In one petri dish I have a thousand little companies. 999 of those companies die but one lives. If I look real hard through the microscope I can see a little sign and it says Amgen! What did Amgen do to survive?

What happened at Allozyne is a microcosm of the Trillion Dollar Failure that is drug research. The inventors left the business up to the Cargo Cult Leaders of Seattle and went back to Caltech. One outsider, the CEO, came from the business side of Novartis. The rest of the crew, including the chief scientific officer were selected from the usual suspects of the Seattle Cargo Cult. The CEO and the board are now in charge of turning legitimate science into a profitable business model. They need those Powerpoint slides to tell a story. The story was told to Wall Street but Wall Street didn't bite. Allozyne and Poniard leaders failed. Poniard leadership accepted responsibility and fell on their knives. Allozyne sacked a couple low level techs and offered up soundbites like, "“The syndicate is extremely excited that we are on a Phase III trajectory in 2012” and that their pitch to Wall Street was, "very well received" and that “No one here is in fact at all disappointed. We are very much looking forward to 2012. We are invigorated about the challenge ahead.”

Allozyne began with an initial investment from the Accelerator Corporation. Accelerator usually ponies up around 1 to 2 million dollars. From there Allozyne received 50 million dollars and moved into some rather swanky digs a block away from the Accelerator building. As of June 2011 they were down to 1.4 million cash on hand, leaving 49.6 million to contribute to the lost trillion dollars. I've mentioned that Allozyne is a part of a microcosm. I've mentioned that the microcosm could be thought of as a petri dish teaming with life. 1000 entities begin life in that petri dish. Rather than studying that one Amgen life form that strives, we are looking at one life form that looks sickly. We know that we must add a certain concentration of money into our petri media to keep all of the companies in there alive for a few years. We don't have a good idea what is needed to make the Amgens emerge. In fact, if Amgen were put into a modern biotech microcosm petri dish... it wouldn't survive either. Is Allozyne like an early Amgen? Are they misunderstood yet poised to one day make their detractors very sorry? Or are they dying because the management team is Cargo Cult?

It is hard to study what is happening in our biotech petri dish. Allozyne is a secretive group. One or more people were laid off but according to management it was of no consequence. It was merely a ceremonial sacrifice. Part of the cult rituals is to seek out the members who wear white lab coats and give them pink slips and watch them march out the front door with a box of their meager belongings. These sacrifices take place towards the end of the process. It is believed that the laboratory workers are causing the airplanes to not land. By removing them the investors breathe easier which relieves stress among the managers. The white lab coat clad members of the cult are like lambs. They have no power over the direction of the research they conduct on behalf of their leaders. They do what they are told and they disappear without explanation. It does not however signal the end of another dot in our petri dish. It only signals trouble.

We would like to see a research class that emerges one day with the power to fight. A small biotech is not where that power will come from. It will come from outside of the lab. Slowly people will begin to speak up about the common mistakes that we make in trying to manage science as if it were a business. Firing lab workers is like firing an automobile assembly worker for making a Yugo or an Edsel. The real culpability lies in the minds of those who design the car. The reason the airplanes do not land in our airport is not because the man in the tower is doing his job improperly. It is because Cargo Cults are missing something. That something is unknown or is purposely being ignored by the management class. One thing the are missing is the knowledge that sacrificial lambs make for a dull and timid research staff.

Tuesday, January 03, 2012


The Cargo: Allozyne
Biologic therapeutics represent the vanguard of innovation. By 2006 they had captured a $30 billion dollar market with forecasted growth to $60 billion by the end of 2010. Although the creation and adoption of biologics has been rapid, the markets that they serve are still burgeoning with unmet medical need. We, a privately held and clinical stage biopharmaceutical company, have rapidly developed a number of protein therapeutics product candidates through its next generation protein engineering technology in order to serve unmet medical need in various autoimmune diseases and cancer.

The Xconomy Headlines:

* Allozyne, Developer of Multiple Sclerosis Drug in Fewer Shots, Poised to Enter Clinical Trials 10/16/08

* Allozyne’s Next Drug, Made to Kill Two Birds With One Stone, Being Prepped for Clinic 11/16/10

* Allozyne Passes First Clinical Trial, Dreams Big About a Once-Monthly Multiple Sclerosis Drug 1/10/11

* Allozyne Acquires Poniard Pharmaceuticals, Finds Backdoor Route to NASDAQ 6/22/11

* Allozyne Looks to Rustle Up Interest on Wall Street With Backdoor IPO 7/13/11

* Allozyne, Poniard Scrap Plan to Merge Amid Investor Apathy 12/22/11

* Allozyne Raises More VC Cash, Looks to FDA Meeting After Poniard Deal Fizzles 12/23/11

One final headline by the Wall Street Journal: Poniard CEO, 4 Board Members Resign In Wake Of Merger Collapse

Xconomy missed that story.

The unfettered enthusiasm remains a mystery. The journalistic approach to the story is non-existent. A balance comes in the comment section of a few articles. A reader who goes by the moniker Nanostring added a few points on the Poniard deal that the article does not mention:

1. Based on today’s price of PARD, the merger values Allozyne @ ~$20 M ($11M*65/35).
That is: they took valuable technology from Caltech + $43M in investor money and ended up with $20M in value. You do the math.

2. Even that $20M may be too rich, considering that PARD got immediately hit by two lawsuits for agreeing to the terms of the merger.

3. As of now PARD shareholders have twice rejected the reverse stock-split, which is a prerequisite to the merger: (second graph)

Nanostring sounds like an interested party with ties closer to the money than the science. He was correct about the market value falling short. He is no fan of the Xconomy cheerleading.
Will this FAIL be covered at Xconomy? What happens next? Will we hear again from OVP’s Carl on how proud he is with Allozyne, now that PARD shareholders have flipped a middle finger to this merger? Why are comments disabled on the other Xconomy article?

Unfortunately, (as I have complained to Luke and Buderi on numerous occasions), Xconomy again wants to be more of a PR shop for the local VCs rather than a real news-reporting blog with journalistic integrity…

Keeping the positive spin on the disastrous management of Allozyne is worthy of journalistic coverage all by itself. Meena Chhabra is very attractive. Yet she was unable to attract the kind of attention needed among the geniuses of Wall Street. While she continues to go unscathed in Xconomy and among her local peers, her counterparts at Poniard suffered a different fate.

Will Allozyne survive? With plans to skip phase II trials and sign up only 700 people in a phase III, funded by Allozyne alone, all carried out by a management team that orchestrated the Poniard fiasco... we think this plane won't land. And all of this for the hope of a longer lasting form of a drug already on the market.

Will Xconomy cheer leading continue, leaving in the good and leaving out the bad? Unfortunately we think they will. They are a part of this Cargo Cult.

Sunday, January 01, 2012

Friend or Foe

Retraction Watch estimates close to 400 papers were retracted in 2011. A couple comments came up with retraction numbers below 100 for the year:

Thanks so much for providing this valuable service. Of interest, a PubMed search for “Retracted Publication” or “Retraction of Publication” for 2011 yields only 35 papers. So if you and your colleagues weren’t on the job, we’d be missing out on ~1 in 12 of these papers!

Pat French

“Retraction notice” gives 63 hits. Still, the problem is exactly that it is not clear how to retrieve all the retractions, which may well be in the PubMed database. There should be a standard tag!

Jon Beckmann

We think that retractions are important pieces of scientific information. Unlike a Friday night bar conversation where you make the claim that the Buffalo Bills won the Superbowl back in 1995, the accuracy of claims made in science matters. When the folks at Nature faced the prevalence of chicanery taking place in big science labs and big science journals they concluded:
these days image detection software and the vigilance of media outlets such as Retraction Watch can catch irregularities—be they due to innocent error or misconduct—much sooner. The ability to track these changes provides benefits to biomedicine, as experiments in the scientific literature lay the foundation for future experiments.

The peer review process employed by science journals is the opposite of the scientific method. Peer reviewers don't repeat any experiments thus their judgments are not empirical. Peers have a bias that is not eliminated by the process. The authors and their organizations carry with them a cache that brings with it bias that is also not eliminated. The science isn't the only thing being evaluated. In a perfect world a journal would publish articles and offer only minimal interference into what the authors intend to say. Once published the true peers can evaluate the paper and agree or disagree with it. Scientists after all, are the peers.

The question that peer reviewed journals have to wrestle with is whether or not Retraction Watch is their friend or enemy. With over 1.5 million hits online Retraction Watch is clearly popular among scientists. Who else would read about retractions? It appears that the demand is there for more information. Transparency is our friend.