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Monday, March 26, 2012

Careful Observation

One of the key elements in all of the cases of scientific misconduct that I have highlighted is a lack of actual observation by the principal investigators. Modern science has taken the scientist out of the laboratory and into the office. The end result of this arrangement is the replacement of careful observations with ad hoc theories.
In science and philosophyad hoc means the addition of extraneous hypotheses to a theory to save it from being falsifiedAd hochypotheses compensate for anomalies not anticipated by the theory in its unmodified form. Scientists are often skeptical of theories that rely on frequent, unsupported adjustments to sustain them. Ad hoc hypotheses are often characteristic of pseudoscientific subjects. 
According to management, I once created a molecule so powerful the cell could barely handle it. The power of managements design made my molecular biology work result in mutations. There were no mutations however, just normal cloning issues. Some of the clones had DNA sequences that deviated from the DNA I had typed into the Invitrogen order form. This always happens when cloning single proteins. You pick 10 clones and have them sequenced. If only one clone has the right sequence you are done. Grow it up and freeze it down. But this was different. This was a library. Every clone was taken literally as a designed peptide or a mutant.

The mutation story is what I would consider an ad hoc explanation. No one besides myself anticipated the less than perfect set of sequence data. When it came in an ad hoc theory was put in place that supported the notion that the molecule was potent.
Phage libraries displaying linear or disulfide-constrained 
peptides often yield weak binders, upon screening against a 
target, and must be optimized to improve affinity. The disad- 
vantages of libraries based on larger complex proteins, such 
as single chain antibodies, have stimulated interest in the devel- 
opment of smaller nonimmunoglobulin protein scaffolds. A 
promising candidate is the Trp cage motif, a 20-residue C-terminal sequence of exendin-4.

Exendin-4 is the active biological component of Byetta. I believe the managers came up with the idea while strategizing a way of competing with Byetta. In their minds the Trp Cage would remain the same structure in spite of changing up to 7 amino acids. We did no work to ascertain the structure of our peptides. We were not allowed to do research into the mutation story.

These are observations from a person who worked in the labs. My lab observations and my leadership observations have led me to this blog. As I've watched the biotechnology industry evolve I think of these little things. What does it really matter if my library was mutating or if it was a normal cloning outcome? It mattered enough to management that no experimentation was allowed to verify the mutation story. It mattered that the mutation story supported their idea of structure. Yet it was an unverified ad hoc theory.

From my point of view I saw a group of PhD scientists who wanted to be thought of as protein engineers, "Intelligent Designers". They did not want the world to think of them as people who simply combined a piece of Byetta into a phage display library assembly kit. To me they had dreamed up the idea in ten minutes then spent over a year applying ad hoc theories to what actually happened in the lab. The patents and publications that followed are a collection of those theories. Five years on, the library has failed to deliver on its promise.

This isn't a blog were I simply complain about old bosses. It is about finding the key elements that turn good science and good money into Cargo Cults. The Trp Cage story is analogous to what I see happening at every turn in biotech and in science. Desired outcomes are formulated by management. Laboratory work is thought up by office workers and handed over to the lab staff. They obediently do the work and present the data. Back in the offices ad hoc theories begin to fly. If a theory doesn't fit we occasionally veer off into the world of fraud and misconduct. Real science is often too simple to advance a modern day scientists career.

Careful observations are important in science. Eratosthenes calculated the circumference of the Earth from careful observations. That was roughly 1,800 years ago. Perhaps our ability to Google has stopped our imaginations from thinking up ways of knowing things. All of those little unexpected details that take place in the lab are unavailable to the modern day scientist. The careful observation is at war with the ad hoc theory. 

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