People always giggle when I say that, but it’s true. Of all the “basic” sciences, biology is the most slippery. By that I mean that, while the tendency is to study biomolecules and cells in isolation, the total animal, be it a bacterium or a human being, is a federation of molecules, organelles, or organs (depending on how big and multicellular you are), and they all act together to create a phenotype, a behavior, a syndrome, or a disease in the intact organism.
So it should hardly be a surprise to anyone who recognizes this fact that drugs for complex conditions, developed with reductionist biological models, yield disappointing results in the clinic. And yet it is.
I’ve been skimming the science journals, and just today I’ve come up with a few examples that underscore what I’m saying. In what appears to be her last news article as a staff writer for Science, Jean Marx (Jean was my editor when I was on the Science news staff, and I wish her the best of luck in her new endeavors), describes how cancer progression involves the collaboration of many different cell types. Not just tumor cells, but cells from the immune system, the vascular system, as well as mesenchymal cells all collude to feed tumor cells and help them metastasize.
Also in Science, I came across a piece that describes the contribution of the ras oncogene to cancer. Long thought to induce tumorigenic growth by continuously transmittiing a “growth” command to the cell, causing the cell to divide without check, it now turns out, according to the report, that ras operates as part of a network of genes. While it is encouraging the cell to grow, it is also, through a different mechanism, suppressing genes that would suppress the growth.
Finally, while I was poking around FierceBiotech.com, I came across a post that discussed a confounding role for small interference RNA (siRNA). These short stretches of nucleic acid are the recent darlings of the biotech world, as it is hoped that they can selectively block the expression of the genes underlying a particular disease. Now come reports that siRNA’s therapeutic efficacy may in fact be attributed to the nonselective action it has on the immune system.
See what I mean by perverse? In the testube, removed from the complexities of intact biological systems, these molecules and genes act one way. Put back in their native biological contexts these macromolecules can act in completely different, unintended, and unexpected ways. Systems and organs completely different from the expected locus of action can interfere for better and worse, and alter the desired outcome. What is the moral of this story for me? Drug makers have to start acknowledging these complexities when developing drugs. They have to go beyond the reductionist models they’ve been using and allow the entire biological system to guide them to therapies that are rational and effective. And if they don’t, I’ll be happy to post the sequel to this entry to remind them.