Lessons From a More Advanced Field

Long ago I worked as a photographer. I learned all about setting the F-stop so as to not over or under expose the film. I learned how to process black and white, color, and slide film. I printed photographs in black and white and color. I shot portraits, crime scenes, ceremonies, and just about anything that required a professional quality image. For five years I honed my skills. I left it all behind one day and went to college to study biochemistry. Most of the skills that I learned are no longer required. Exposures on digital cameras are well balanced. Digital pictures can be corrected for using computer software. Prints come out color balanced. The exposure and contrast is taken care of via the software as well. Everything that I did subjectively is now done by objective physical qualities in the camera and by image software.

In a period of roughly 20 years the field of photography changed dramatically. It's easier now but a new set of skills are required. What brought about the change was science and engineering. What about the laboratory skills I now have in the field of biotechnology?

The science that I speak of is not medical science. In order to bring about the proper changes needed for biotechnology a new science must be elucidated. If you put a small strand of RNA into a living organism what happens to the RNA? Never mind what happens to the living organism. Focusing on the outcome of the cell culture, mouse, or the human being is ignoring the interaction of the drug and its host. The human body is also dealing with the disease. What is the fate of a foreign molecule that we design and introduce to a living organism? What happens when we change the living organism? If I have the same CDR regions in a Fab, Fab2, and a full length antibody, what is the fate of the three molecules that are the same only in the CDR region? The CDR region is what interacts with the drug target. The rest has to deal with the living organism. Perhaps they will all block the target in the cell culture but only the full length antibody will find the target inside the human body.

Here is a real time example of the kinds of questions that are too often not asked. Roche this week announced a new antibody;

an antibody with two arms. One arm was the anti-BACE1 drug; the other docked with a receptor called transferrin that carries iron to brain cells, providing a ferry across the barrier.

The system allowed the researchers to deliver anti-BACE1 to the brains of mice, blunting the impact of the BACE1 enzyme and cutting in half the amount of amyloid in the brains of mice 48 hours after injection

I am assuming that the molecule has one CDR region that binds to the transferrin receptor, and the other binds to BACE-1. How does the antibody dissociate from the receptor on the other side of the blood-brain barrier? What percentage of the drug load goes through the barrier? How does the drug reach the barrier in the first place?

Other issues are of course the amyloid beta story. The amyloid beta protein could run into a rotten bunch of brain cells that are kicking out amyloid beta denaturing agents (low pH, enzymes...) that will make the long journey of the anti-BACE molecule futile. Rather than relying on the endpoint that Roche and friends have set forth, someone should look at the entire picture from a scientific standpoint. Roche and friends wanted to tell the story that they've told. What does science have to say about it? What do we know about the measurements they took? The story they have told is more of a narrative rather than a factual description of their molecules journey into the brain and into the cascade of events involving amyloid beta. The solution here is an electronic notebook that researchers at higher levels must keep. The narrative approach to science of higher ranking scientists is an issue that software engineers can overcome. But don't ask the Bioscience PhDs to help design the software. They are not good at that type of thinking and they stand to lose a lot of BS room that they need to continue their careers. But it is their careers that have been a hindrance on advancing the field.

Photography was not advanced by photographers. Scientists and engineers were asked to answer a specific set of questions that lead to an improved system. Likewise, biotechnology research will not be advanced by anyone with a PhD in Microbiology, Immunology or Pharmacology. The sciences that rely heavily on math must get involved. Design of experiment is an example of statistics being used to help Bioscience people understand what has been missing in their research. For 30 years the big words of medicine have been used to bring in the big bucks. Now is the time for the big concepts of science to be used instead.