On physics envy and drug discovery

In a recent New York Times article, two prominent social scientists lament the epidemic of physics envy that has infected their ranks, and they implore their colleagues to take a more observation-based, utilitarian approach to addressing the most pressing problems of social science.

We natural scientists should empathize. Physics envy is the name of a disease that afflicts many scientists at various stages of their careers. Its main symptom is an overwhelming desire to see their science - whatever it may be - become as precise and predictable as particle physics. The victim of physics envy thinks wistfully of the glorious days of quantum mechanics and molecular biology and believes that his or her science can achieve the same six-decimal precision in its measurements and predictions. The victims may be natural or social scientists, although the disease takes on a particularly nasty form when it affects economists, as recounted by the physicist-turned-financial modeler Emanuel Derman.

Physics envy is so widespread that even physicists are affected by it. Some theoretical physicists for instance want to reduce all the world's complexities to an all-encompassing theory of "everything", preferably a single equation that would describe everything from black holes to romantic love. Presumably this will help us truly understand, from first principles, why nations go to war or why election outcomes depend on Ohio. This is in part because physics envy is closely tied to its cousin reductionism which provided untold dividends in twentieth century science. But the scientific world in the twenty-first century is a different creature. Physics envy during our times can cause tunnel vision, an exaggerated belief in the power of mathematics, and not infrequently, the loss of billions of dollars. Perhaps the worst thing about this malady may be its focused transmission to new generations of students and scientists, thus ensuring its long life and continued dominance.

Sadly, this disease is not unknown among drug discovery scientists, and I dare say that I have suffered from it myself. Drug discovery is a complex, multidisciplinary field where luck and intuition play as great a role as any rational approach. Drug hunters study complex systems that are almost always refractory to any one approach from any one science. Yet physics envy exists, implicitly or explicitly. You see it in the modeler who thinks he can find the next revolutionary drug simply by optimizing his compound's affinity for his protein, or the synthetic chemist who thinks that he can produce an army of molecular analogs that can dissect a complete biological pathway, or the biologist who thinks that inhibiting his pet protein will be all that it takes to disable a complicated biochemical pathway.

A more serious case is the scientist who thinks that if only we had knowledge of every single biological and chemical building block, if only we could map out every gene, every protein, every small molecule interacting with all these genes and proteins and present these interactions on a wall like a subway map, we will be able to understand and treat all diseases. These scientists who often but not always go by the name of systems biologists, try to produce precisely this kind of map and predict the output from an input. The output can be in the form of an upregulated protein or the manifestation of a phenotype. The input may be the activation of a gene or inhibition of a protein by a small molecule. The systems biologists think that what's necessary (and perhaps sufficient) for predicting responses in a biological system is a map.

Yet as the Nobel Prize winning biologist Sydney Brenner once wrote in a very readable article, he has been practicing "systems biology" all his life, except that in his time it was called "physiology". Brenner is supposedly practicing systems biology without a license, and yet he and many of his fellow classical physiologists seem to have been both remarkably successful and strangely immune to physics envy. Their job was to study the responses of biological systems using every tool at their disposal. It did not matter if they didn't have an overwhelming theoretical framework to tie together their diverse observations. As the authors of the NYT article indicate, the lack of deep theory does not preclude either understanding or utility. An example of this principle would be the school of pharmacology starting with Steve Brodie at the NIH and culminating with Solomon Snyder at Johns Hopkins. As illustrated in Robert Kanigel's book, these scientists made important discoveries in basic pharmacology even when detailed knowledge of genes and proteins was unavailable. They did not need the pharmacological equivalent of a "theory of everything" to proceed. In fact they did not even need a theory in some cases.

The same goes for drug discovery in general. Think of the currently fashionable paradigm of phenotypic screening which involves discovering new compounds by looking at their effects on simple phenotypic traits like locomotion or heart rate. These approaches hark back to the old days of drug discovery when the responses could be purely clinical, anything from increased urination to dry mouth to flushed faces. This approach is very far from the target-based reductionist approaches that have become popular in the last twenty years, yet nobody can deny its value.

But neither are target-based approaches useless. If you are dealing with HIV protease which can yield copious crystal structures, a structure-based approach might be, and indeed was, very fruitful. But think of a protein whose binding pocket is unknown, which is full of flexible regions and whose functional form consists of oligomers of unknown composition, and structure-based approaches might be completely useless. It might then be best to proceed based on the biology alone or by educated guesswork guided by SAR trends.

The point is, it all depends on the specific case. And therein lies the rub of drug discovery and the problem of physics envy. As I mentioned in a previous post, physics searches for general principles while drug discovery largely thrives on exceptions. The question in drug discovery is not what overarching principle can be applied to all cases, but what exact mix of different techniques would work for a given case. It's very different from physics, where the goal is to search for one equation to rule them all.

Fortunately physics envy has a potent antidote, both in physics and in drug discovery. It goes by the name of "nature". Whenever physics envy tries to go on a rampage, nature invariably steps in and straps on the straitjacket. In just the last few years we have seen nature generously cutting us down to size. From resveratrol-based SIRT inhibitors for aging to recently tainted PARP inhibitors for cancer, we have seen how nature (which in most of these cases means "biology") is smarter than us. Every time we break down a system into its constituent parts and pin down what we think is the operative entity, nature keeps reminding us that there's something else out there which is equally important which we have missed. In some sense nature is mocking us for bringing our biases to bear on what in her scheme of things is only one important component of a grand dance. In nature's eyes the rule is simple; if we want to participate, we better make sure we know who our partner is. And leave physics envy at the door.