Why foxes are more important than hedgehogs in drug discovery

A while ago I wrote about the dominance of foxes over hedgehogs in chemistry. Hedgehogs love to drill deep into one topic; foxes love to leap over interdisciplinary fences. Both creatures have been key to the progress of science: Einstein was a hedgehog, von Neumann was a fox; Darwin was a hedgehog, Crick was a fox. Many chemists are both hedgehogs and foxes, but my reading of the recent history of chemistry told me that in chemistry hedgehogs have had a greater impact.

I was reminded of hedgehogs and foxes again, this time in the context of drug discovery, as I was reading psychologist Philip Tetlock’s book on prediction, “Superforecasting: The Art and Science of Prediction”. The book describes a giant prediction project called the Good Judgment Project which Tetlock created to test people’s powers of intuiting the future. The project recruited thousands of people, both renowned experts and amateurs, and asked them to make important predictions related to finance, politics and human society in general. Participants were asked to predict the fate of particular currencies or countries, or asked to predict terrorist attacks or asked to predict the major effects of climate change.

The results of the study were published in 2005 and they caused quite a stir because they found that several amateurs handily beat experts at their own game. But another conclusion that the study found, and one that caught my eye, was that the best predictors were all foxes rather than hedgehogs. That’s because hedgehogs are more likely to fall in love with one big idea and try to apply it to most problems while foxes are more likely to be more modest and try several ideas to pick the ones that work. Hedgehogs may be deep, but foxes are nimble, and it seems that when it comes to complicated predictions flexibility is more important than depth.

It struck me that this is exactly how it should be in drug discovery, and how it often isn’t. The reason that foxes outperformed hedgehogs in the Good Judgment Project was because multifactorial, complex systems like the climate and the stock market are seldom amenable to a select few Big Ideas. What they benefit most from instead are modest but useful ideas from several different approaches – rational thinking, seat-of-your-pants intuition, rock-solid experience – that are cobbled together to produce a workable recipe.

Now drug discovery should be the poster boy for a multifactorial, complex system whose fruits are ripe for plucking by foxes, but the history of the field actually demonstrates how hedgehogs have often held it back, sometimes by their own designs but most often by blind acceptance by their followers. Consider all the Big Ideas that have permeated drug discovery in the past three decades – structure-based design, molecular modeling, HTS, combinatorial chemistry, DOS, Rule-of-5. In each of these cases the relevant Big Idea usually came from a single hedgehog or a few hedgehogs. Sometimes these individuals highlighted the utility of the idea beyond its modest but narrow reach, but often it was other scientists or business leaders that hyped the idea way beyond its domain of applicability (remember that "Designing Drugs Without Chemicals" headline from 1981?). The Big Idea escaped from its ground reality of bounded rationality and entered the stratospheric domain of Six Sigma efficiency and business mantras. The same goes for many other smaller but still influential ideas in the history of drug discovery, including druglike metrics, molecular dynamics and animal models.

None of these hedgehog-based ideas is useless, and in some cases they can be very useful, but the key thing to realize is that they have been the product of hedgehog minds which sought to revolutionize the process of drug discovery and fold its problems under one big tent. Ironically however, the very reason these ideas have found use is because they were largely adopted by foxes who then used them as part of a flexible and versatile toolkit. Equally ironically, while the hedgehogs have undoubtedly led to an understanding of the field, often that understanding has come from foxes who have illuminated the limitations of the hedgehogs’ ideas (the Ro5 is a notorious example).

It's also interesting to note that sometimes being a fox or hedgehog can be a matter of time. This is because as our understanding of complex systems grows with time we could transition a bit from foxdom to hedgehogdom. Consider all the attempts to correlate toxicity - a very complex and heterogenous variable - with simple metrics like molecular lipophilicity, flexibility, number of sp3 carbons etc. These attempts represent classic hedgehog-like strategies to usher a complex variable into the tent of a simple rule; no wonder they have been found to be woefully lacking in utility. However we might conjecture that as our understanding of the determinants of toxicity grows in the next few decades, we may potentially reach a tipping point where we may be able to come up with general rules that are at least somewhat broadly applicable. The time then may be better for hedgehogs to make general predictions.

Consider the big names in the history of drug discovery – James Black, Gertrude Elion, Paul Janssen, Albert Hoffman, Paul Ehrlich, Robert Koch – and you will find that they were either exclusively or mostly foxes. What they stressed was the plurality of judgment and the exploration of alternative ideas. The same quality applies to some leading drug hunters who I personally know. Most of these individuals don’t have one Big Thought attached to their name; rather they conceived several ideas that led to an integrated approach to drug discovery. They will not go down in history as the originators of rules and principles, but they will go down in history as actual drug inventors with names on several key patents.

My guess is that the reason these people worked so well as foxes rather than hedgehogs was because they realized how complex biological systems are and how ignorant we all are when it comes to perturbing these systems with small molecules. I think that the feature that distinguishes a hedgehog mindset from a fox mindset is an appreciation of the complexity of the system under consideration. When you know how incomplete your understanding of biological targets or the properties of successful drugs is, you quickly realize how hard it would be to apply a hedgehog-like, one size fits all approach to any problem in drug discovery. It is far better to diversify your portfolio of tools and ideas and improvise. The best drug hunters are foxes not always because they want to, but because they realize that they have to. While some of them understand the time-dependence of hedghogish predictions noted above, they are also sober enough to realize that we aren't there yet.

As the future of drug discovery unfolds before our eyes, I do not see hedgehogs eclipsing foxes in relevance. Both are necessary and hedgehogs will continue to come up with big ideas, but these ideas can likely mislead the field if foxes do not reveal their strengths and limitations. Hedgehogs and foxes can both co-exist and thrive in drug discovery, but only if they let each other explore their favorite haunts.

Image source

Hedgehogs and foxes in chemistry

Isaiah Berlin's parable about hedgehogs and foxes has long since served as a thought-provoking lens for looking at science and scientists. Berlin quoted the Greek poet Archilochus who said "the fox knows many things, but the hedgehog knows one big thing". Scientists who spend most or all of their careers drilling down deep into one field, problem or idea are hedgehogs. Scientists who instead spend their careers sniffing out and solving interesting problems from several areas are foxes. How does the dichotomy apply to chemists?

At the outset, one thing seems clear: chemistry is much more of a fox's game than a hedgehog's. This is in contrast to theoretical physics or mathematics which have sported many spectacular hedgehogs. It's not that deep thinking hedgehogs are not valuable in chemistry. It's just that diversity in chemistry is too important to be left to hedgehogs alone. In chemistry more than in physics or math, differences and details matter. Unlike mathematics, where a hedgehog like Andrew Wiles spends almost his entire lifetime wrestling with Fermat's Last Theorem, chemistry affords few opportunities for solving single, narrowly defined problems through one approach, technique or idea. Chemists intrinsically revel in exploring a diverse and sometimes treacherous hodgepodge of rigorous mathematical analysis, empirical fact-stitching, back of the envelope calculations and heuristic modeling. These are activities ideally suited to foxes' temperament. One can say something similar about biologists.

The dominance of foxes in chemistry is demonstrated through its long history. Robert Boyle, the first modern chemist who is widely credited for separating chemistry from alchemy, is of course universally known for Boyle's Law but also made contributions to understanding combustion, respiration, color and electricity. The father of modern chemistry, Antoine Lavoisier, discovered the all-pervasive law of conservation of mass, preceded Mendeleev in putting together a tentative classification of elements and pioneered chemical book-keeping (stoichiometry). Similarly, the great chemists of the nineteenth century- Davy, Wöhler, Liebig, Kekule, Mendeleev- were all foxes who, while known for one or two important discoveries, worked in diverse facets of their chosen discipline. Chemical foxes also proliferated in the twentieth century, with Lewis, Langmuir, Curie, Fischer and Sanger being typical examples. Linus Pauling was the ultimate fox, but more on that below.

This does not mean that chemistry has no use for hedgehogs. Far from it. If there's one field of applied chemistry which has reaped riches from hedgehogs' talents, it's crystallography and especially protein crystallography. Crystallography also belongs to physics and biology, but it has enough of a crucial chemical component for crystallographers to call themselves chemists. Among crystallographers, Max Perutz was a hedgehog par excellence. Perutz spent his entire career shining his intellect like a laser beam on the structure of hemoglobin. It was largely his efforts that turned hemoglobin into one of the best studied proteins that we know and it was because of his extensive studies on it that we gained insights into some of the most general and important concepts in protein science, including cooperative effects and allostery. The chemists who won the Nobel Prize two years ago for their solution of the ribosome structure were also supremely focused hedgehogs. Special mention must be made among this trio of Ada Yonath, the "mother" hedgehog who made the ribosome her life's mission and stuck with it longer than anyone else. There are also hedgehogs in some other subfields of chemistry. For instance, Rudolf Marcus who spent his lifetime developing a comprehensive theory of electron transfer processes comes close to being a hedgehog. Similarly, Peter Mitchell is known for one big thing- the development of the fundamental theory of chemiosmosis which is of paramount importance in understanding biological energy transfer.

In every science there are also a few unique individuals who seem to be able to magically morph into both hedgehogs and foxes. The greatest chemist of the century belonged to this class. During his life, Pauling was known especially for the astounding diversity of his contributions and this puts him squarely into the fox camp. But remarkably, the hedgehogs could also claim him as one of their own since the depth of his contributions easily rivals the breadth of his interests. If Pauling had made no other contribution except his theories of chemical bonding, he would have still been hailed as one of the century's great chemical hedgehogs. That Pauling managed to be a fox and still made hedgehog-like contributions to at least three key fields (quantum chemistry, protein structure and molecular medicine) attests to the stature of his accomplishments. Among twentieth century scientists, Enrico Fermi is the only individual in my opinion who commanded both depth and breadth of this magnitude.

It is much harder to locate hedgehogs among organic chemists. The greatest of organic chemists, R B Woodward, was undoubtedly a fox, albeit one of the highest caliber. Other leading figures in the field like Corey, Stork, Djerassi, Westheimer, Breslow and Danishefsky have also been first-rate foxes. Interestingly, there are hedgehogs among synthetic chemists but they are not as well-known. One that comes to mind is the chemist John Sheehan who spent fifteen years of his life trying to synthesize penicillin. Even the great Woodward had stayed away from this molecule's perilous, highly strained beta lactam ring. Sheehan recounted his single-minded obsession in a highly readable book with a fitting title- "The Enchanted Ring". Another organic hedgehog was H C Brown who devoted his career to perfecting the chemistry of boron. Yet another example is George Olah who has had a fifty-year love affair with the chemistry of carbocations. Also, as Derek Lowe hints, organometallic chemistry may yet be a field full of hedgehog riches. The chemists who developed palladium-catalyzed reactions and olefin metathesis were very hedgehog-like.

Many leading contemporary chemists on the other hand are exceptionally gifted foxes. Harry Gray, Stephen Lippard, Stuart Schreiber, George Whitesides, David Baker, Jean-Marie Lehn, Ad Bax, Alan Fersht, Jacqueline Barton, Martin Karplus, Roald Hoffmann, Paul Schleyer, Christopher Dobson, C N R Rao, Donna Blackmond, Chad Mirkin, Eiichi Nakamura, Fraser Stoddart, Ken Houk and Dieter Seebach are but a few examples of individuals who have made first rate contributions to diverse areas of chemistry. In fact, there can be no better tribute to their identity as foxes than the fact that many of them could also be easily classified as physicists or biologists.

We mentioned the quintessential nature of chemistry as a field of dreams more attractive to foxes rather than hedgehogs. Why is this so? In chemistry unlike physics, overarching general principles are not as important as specific instances and diverse manifestations of these principles. Key unifying principles of course exist and are taught to every budding college chemist, but they are often not as deep compared with general laws in physics or theorems in mathematics. For instance, the theory of acids and bases or that of hybridization is undoubtedly a unifying theory, but it's more a set of rules derived through a mix of theoretical analysis and empirical facts. Few would equate acid-base theory with Maxwell's laws of electromagnetism, the laws of thermodynamics or the theory of Lie groups in terms of depth, fundamental importance and universal applicability. In addition, unifying concepts in chemistry (free energy, crystal field theory, conformational analysis, oxidative phosphorylation, solubility laws) are usually fathered by several individuals and not just one. The ideal of the lone thinker shunning himself or herself from society and heroically wresting nature's secrets from her grasp through single-minded pursuit is an ideal that is alien to chemistry's nature and practice. Finally, many key chemical contributions consist of methods or instrumental advances (NMR, crystallography, gene sequencing, chromatography, PCR) that are necessarily the work of many people.

Does the future of chemistry belong to hedgehogs or foxes? I see no reason for the trends of the past five hundred years to change. Chemistry will essentially remain a game for foxes. This will be even more true in the future than it was in the past because the hottest fields in chemistry like energy, nanotechnology, chemical genetics and drug discovery are especially fox-friendly. However, occasional hedgehogs of the kind described above will also remain an integral part of its development. Foxes will be needed to explore the uncharted territory of chemical discovery, hedgehogs will be needed to probe its corners and reveal hidden jewels. The jewels will further reflect light that will illuminate additional playgrounds for the foxes to frolic in. Together the two creatures will make a difference.