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Why it’s hard to explain drug discovery to physicists

The views expressed are those of the author and are not necessarily those of Scientific American.

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The binding of a drug to its target protein - in this case a protein named HIV protease involved in the progression of AIDS - cannot be usefully reduced to physics-based first principles.

I minored in physics in college, and ever since then I have had a lively interest in the subject and its history. Although initially trained as an organic chemist, part of the reason I decided to study computational and theoretical chemistry is because of their connections to physics by way of quantum chemistry, electrostatics and statistical thermodynamics. No other science can boast the kind of fundamental insights into the most basic workings of the universe that physics has provided in the twentieth century. Even today when we think of the purest, most exalted science we think of physics.

Not surprisingly, I have several physicist friends with whom I often talk shop. It’s always interesting to hear about their work which ranges from cosmology to solid-state physics. Yet I find that I sometimes I have trouble explaining my own work to them. And this is certainly not because they lack the capacity to understand it. It’s because the nature of drug discovery is sometimes rather alien to physicists and especially to theoretical physicists. The physicists have trouble understanding drug discovery not because it’s hard but because it seems too messy, unrigorous, haphazard, subject to serendipity.

But drug discovery and design is indeed all this and more, and that’s precisely why it works. Success in drug discovery demands a diverse mix of skills that range from highly rigorous analysis to statistical extrapolation, gut feeling and intuition, and of course, a healthy dose of good luck. All of these are an essential part of the cocktail (to borrow a drug metaphor). A good drug not only binds to a defective protein in the body with high affinity and regulates its activity but it also has optimal properties like minimum side effects and the right rate of absorption, distribution, metabolism and excretion. In addition it has to be made from cheap raw materials and amenable to large-scale production with low environmental impact. Designing a drug is thus the quintessential multi-objective optimization problem; it basically boils down to engineering a small organic molecule that’s going to interact with a mind-bogglingly intricate system which intimately interacts with that molecule.

No wonder that models play an integral role in the discovery of new drugs. Complex systems yield themselves to modeling much more than simple systems, since the much greater number of moving parts often makes them refractory to rigorous theorizing. In this sense drug discovery is very much like chemistry which the Nobel Prize winning chemist Roald Hoffmann has trouble explaining to physicists for similar reasons. Provocatively Hoffmann says:

“When I am trying to explain complex chemical concepts, I have three kinds of audiences in mind: my fellow academics in the humanities, intelligent laymen and physicists. Out of these I find that it’s hardest to explain chemistry to physicists, because they think they understand, but they don’t.”

Hoffmann makes a point which was made more explicit by another Nobel Laureate, the chemist William Lipscomb. Lipscomb lamented the difficulty that physicists present in assuming that chemistry is “physics without rigor”. They think that chemistry is not as useful as physics because it can’t always be approached from a first-principles viewpoint. For a theoretical physicist, anything that cannot be accurately expressed as a differential equation subject to numerical if not analytical solution is suspect. True success in physics is exemplified by quantum electrodynamics, the most accurate theory that we know which agrees with experiment to 12 decimal places. While not as stunningly accurate as QED, most of theoretical physics in the twentieth century consisted of rigorously solving equations and getting answers that agreed with experiment to an unprecedented degree. The tremendous success that physics enjoyed in predicting phenomena spread over 24 orders of magnitude made physicists fall in love with precise measurement and calculation. The goal of many physicists was, and still is, to find three laws that account for at least 99% of the universe. But the situation in drug discovery is more akin to the situation in finance described by the physicist-turned-financial modeler Emanuel Derman; we drug hunters would consider ourselves lucky to find 99 laws that describe 3% of the drug discovery universe.

Physics strives to find universal laws, drug discovery like chemistry thrives on exceptions. While there certainly are general principles dictating the binding of a drug to its target protein, every protein-drug system is like a human being, presenting its own quirky personality and peculiar traits that we have to deconvolute by using every tool at our disposal, whether rigorous or not. In fact as anyone in the field would know, drug discovery scientists take great satisfaction in understanding these unique details, knowing what makes that particular molecule and that particular protein tick. Try to convince any scientist working in drug discovery that you have found an equation that would allow you to predict the potency, selectivity and side-effects of a drug starting from its chemical structure and which would be universally applicable to any drug and any protein, and you will be met with ridicule.

Physicists also have to understand that in drug discovery, understanding is much more important than accuracy, another principle applicable to chemistry in general. In chemistry there are a lot of rather unrigorous, semi-quantitative concepts that are nonetheless part of the chemist’s everyday vocabulary. In fact trying to make them more precise will sometimes diminish their utility. For instance there’s little point in calculating or measuring the absolute value of the energy of interaction of a protein with a drug to four decimal places, but calculating differences in this quantity could be very useful, even if there are errors in the individual numbers. Far more important than calculation however is in explaining why; why a small change in a drug causes a large change in its activity, why one enantiomer causes side-effects while another does not, why making a molecule mimicking the natural substrate of a protein failed, why adding a fluorine to a compound adversely affected solubility. “Why” in turn can lead to “what I should make next”, which is really what a drug hunter wants to know. In most of these cases the number of variables is so large that calculation would be hopelessly impossible in any case, but even if it were possible, dissecting every factor quantitatively is not half as important as explanation. And here’s the key point; the explanation can come from any quarter and from any method of inquiry, from calculation to intuition.

This brings us to reductionism which we have discussed on this blog before. Part of the reason drug discovery can be challenging to physicists is because they are steeped in a culture of reductionism. Reductionism is the great legacy of twentieth-century physics, but while it worked spectacularly well for particle physics it doesn’t quite work for drug design. A physicist may see the human body or even a protein-drug system as a complex machine whose understandings we can completely understand once we break it down into its constituent parts. But the chemical and biological systems that drug discoverers deal with are classic examples of emergent phenomena. A network of proteins displays properties that are not obvious from the behavior of the individual proteins. An aggregate of neurons displays behavior that completely belies the apparent simplicity of neuronal structure and firing. At every level there are fundamental laws governing a particular system which we have to understand. Reductionism certainly doesn’t work in drug discovery in practice since the systems are so horrendously complicated, but it may not even work in principle. Physicists need to understand that drug discovery presents reductionism in a straitjacket; it can help you a little bit at every level, but it has very little wiggle room beyond that level.

Physicists may also sometimes find themselves bewildered by the inherently multidisciplinary nature of pharmaceutical research. It is impossible to discover a new drug without the contribution of people from a variety of different fields, and no one scientist can usually claim the credit for a novel therapeutic. This concept is somewhat alien especially to theoretical physicists who are used to sitting in a room with pencil and paper and uncovering the great mysteries of the universe. To be sure, there are areas of physics like experimental particle physics which now require enormous team effort (with the LHC being the ultimate incarnation of such teamwork), but even in those cases the scientists involved have been mostly physicists.

So are physicists doomed to look at drug discoverers with a jaundiced eye? I don’t think so. The nature of physics itself has significantly changed in the last thirty years or so. New fields of inquiry have presented physicists with the kind of complex systems opaque to first-principles approaches that chemists and biologists are familiar with. This is apparent in disciplines like biophysics, nonlinear dynamics, atmospheric physics, and the physics of large disordered systems. Many phenomena that physicists study today, from clouds to strange new materials are complex phenomena that don’t succumb to reductionist approaches. In fact, as the physicist Philip Anderson reminds us, reductionism does not even help us fully understand well-known properties like superconductivity.

The new fields demand new approaches and their complexity means that physicists have to abandon strictly first-principles approaches and indulge in the kind of modeling familiar to chemists and biologists. Even cosmology is now steeped in model-building due to the sheer complexity of the events it studies. In addition, physicists are now often required to build bridges with other disciplines. Fields like biophysics are often as interdisciplinary as anything found in drug discovery. And just like in drug discovery, physicists now have to accept the fact that a novel solution to their problem may come from a non-physicist.

All this can only be a good augury if it means that more physicists are going to join the working ranks of drug discoverers. And it will all work out splendidly as long as they are willing to occasionally hang their reductionist hats at the door, supply pragmatic solutions and not insist on getting answers right to twelve decimal places.

This is a revised and updated version of a previous post on The Curious Wavefunction.

Ashutosh Jogalekar About the Author: Ashutosh (Ash) Jogalekar is a chemist interested in the history and philosophy of science. He considers science to be a seamless and all-encompassing part of the human experience. Follow on Twitter @curiouswavefn.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. deneb 4:56 pm 03/1/2013

    Great piece! You really captured the essence of drug discovery. You also write extremely well. Looking forward to reading more of your blogs!
    - A physical chemist & biotech exec.

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  2. 2. curiouswavefunction 5:23 pm 03/1/2013

    Thanks for reading!

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  3. 3. antistokes 11:11 pm 03/1/2013

    Umm. I had no trouble explaining what an enzyme is to my partner, who has a PhD in theoretical physics. He had no trouble with any of the concepts once I explained the silly acronyms. I think you are making this business a bit harder than it appears. -Dr. Allison L. Stelling

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  4. 4. Dragonfall 7:39 pm 03/2/2013

    I’d imagine that theoretical physicists would understand it easily if you describe them in terms of a computational problem.

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  5. 5. antistokes 8:56 pm 03/2/2013


    Well, duh :)

    Old joke– theoretical physicists are only physicists in theory. In reality, they’re mathematicians who can render physical models in their heads.

    Also, the man may be good at math, but as someone who trained a bit in synthetic organic chemistry (mostly drug synthesis and design) and biochemistry, I do not let him cook dinner. -Dr. Allison L. Stelling

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  6. 6. ehivan24 7:26 pm 03/3/2013

    Chemistry is applied Physics, if the equations dont make sense,then, the theory/result is wrong.

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  7. 7. antistokes 9:00 pm 03/3/2013

    @ #6 that’s all well and good, just make sure you do the lab safety regiment. No dying in the lab– they really fine ya for that these days. Hacking the math just does not cut it anymore. -Dr. Allison L. Stelling

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  8. 8. mercurialpony 12:33 am 03/4/2013

    Excellent article, I’m looking forward to future blog postings. You also write better than most attorneys I know. Well done!

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  9. 9. ysksky 4:47 am 03/4/2013

    I hope physicists don’t think the way that Ashutosh describes them. Otherwise, they would be very far from “understanding the basic workings of the universe”. In social sciences, economists (wannabe physicists) have a similar problem in understanding what other social scientists do.

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  10. 10. antistokes 7:37 am 03/4/2013

    @#9 Old joke: economists are the anti-social social scientists.

    And, there’s nothing wrong with not wanting to talk with tons of people all day. Introverts (ie, people who like to quietly sit for days and do math in their heads or read a book) are people too. -Dr. Stelling

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  11. 11. Sjoerd 7:42 am 03/4/2013

    This post is a wonderful story on a problem that I have encountered a lot myself (bioinformatician working on protein-protein docking in a Physics department), but I don’t quite agree with the conclusion.

    The reason why blithe reductionism doesn’t work in these systems is not because they are emergent, but because you are forced to make bad assumptions. One could use ab-initio quantum models to determine binding affinity, which might work if we actually had an accurate protein structure: but a single global minimum from a crystal is a poor substitute for the ensemble of atomic conformations (including waters) that a protein really is.

    dr. S.J. de Vries

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  12. 12. dadster 6:55 am 03/6/2013

    Excellent observations .Entities with ” life” dealt with in Bio- science appears to be ” emergent phenomena ” only when your frame of reference is physics . The dominant energy in physics is Electromagnetism (EM). Particle physicists who dominate the universe of physics attempt to digitalize even “gravity” which is a product of space- time fabric and not a material entity , although the fabric can be shaped by interacting with material mass.

    Similarly physicists attempt to reduce all energies to EM .They did have huge success wit matter with such attempts so far .

    But now quantum science transcends matter and mass and enters into the realms of the “mind” of the ” observer “. The energies that drive lumpen mass is not the same that drives life in a live bio- cell .Bio- energies different from mass- energies like the EM manifests through physical structures or physical bodies.

    Transmission and propagation of bio- energies follow different rules,protocols and procedures than the rules and methods of propagation of EM energies ( which ,for the purpose of the discussion here includes nuclear and subAtomic energies ) . Hard core physicists will take much longer time to digest and to accept this concept , but bio- scientists need not tarry for them to catch up but should proceed bravely and boldly forward seeking different paradigms leaving the setting up pf mathematical structures and models to describe bio- phenomena which is different from material phenomena.

    Like for proper transmission of electricity pure conductors like copper wits or aluminum wits are needed so also for transmission and propagation of bio- energies ( or “Life energies ) certain type of mass or healthy material structures are needed. With proper “food” such material structures ( called, biological
    bodies ) can be maintained in a healthy condition ; but, that does not mean that it’s the material energies in the food that’s life- energy itself.. Life- energy has cosmic origins ; it’s the same energy that drives stars and galaxies , cosmic rays , dark energies , even the formation pf thenspace- time fabric.etc. Bio- bodies are just conductors of such cosmic energies. Pure ,unadulterated material mass is a non- conductor or life- energy.

    If life energy as different from EM energy , is associated with mass what’s the quantity of bio- energy associated with a certain amount of bio- mass ? To answer this valid enquiry let us consider the equation e = mc^2,

    That equation gives the maximum EM energy that could be theoretically extracted out of any give quantity of material mass . Bit it doesn’t mean that there are other as yet non-extractible energies associated with mass .

    To understand this, one way is to analyze ( high time such an earnest attempt is made by biologists and physicists ) the nature of energies that lie in the mathematical inequality region, e> mc^2 as is evident from the cartesan straight line graph of the linear equation e= mc^2 . Such energies have propagation speeds that would exceed that of EM waves .

    At the moment we don’t have proper units of measurement for measuring the quantity or the quality pf Life-energy or bio- energy although we make do with using calories of heat ( which is but EM energy only ) which can again measure only the EM energy content .

    So long as we do not reach a stage that allows us to measure life- energy independendly of E M energy, we might have to consider
    Iife-energy as an non- quantifiable quality .

    We should develop the good old “philosophy” of ‘élan vital ” as the solid process of bio- science.

    And, not allow particle physicists to digitalize life , dissect it into parts as life- energy is a continuous wave tat does not strive for a stability state unlike EM energy which is ruled by entropy proceeding into a state of cosmic stability.
    Life- energy is dynamic almost akin to vacuum energy , quoting the nearest analogy from material physicists but not quite .

    Secondly , bio- energy can lend itself to many seemingly contradictory formats and can entertain opposites and contradictions in multi dimensions .

    Material manifestation of life- energy in purr dimensions is just one of the many manifestations possible for life- energy .

    Dr. Joglekar has hinted at these possibilities , at least, I did not find anything in Joglekar’s approach incompatible with my own understanding of his investigations on bio-energy which to my mind is NOT an emetgent phenomena but a much more organizing phenomena than the matter- energies on their path to degeneration and ultimate state of stabilization. So long as bio- energies operate in cosmos , such a state of ultimate stabilization cannot happen .

    That’s one of the predictions of the concept of bio- energy , probably testable / falsifiable mathematically , I think.

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  13. 13. Rob Turner 12:00 am 03/12/2013

    Interesting, fascinating piece. I hope that soon you have a go at physics envy.

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