Thoughts on personalized medicine

This is a piece I had written up for the annual report of this year's Lindau Meeting of Nobel Laureates. The final version had to be significantly edited because of space limitations so I thought I would post the full version here.

The future of personalized medicine

In this year’s Lindau meeting, the Israeli biochemist Ciechanover expressed great hope for the future of personalised medicine, an age in which medical treatments are customized and tailored to individual patients based on their specific kind disease.

In some ways personalised medicine is already here. Over centuries of medical progress, astute doctors have fully recognized the diversity of patients who are suffering from what appears to be the same disease. Based on their rudimentary knowledge of disease processes, empirical data and experience, physicians would then prescribe different combinations of medicines for different patients. But in the absence of detailed knowledge of disease at the genetic and molecular level, this kind of approach was naturally subjective; it continued to rely on extensive personal experience and ad hoc interpretations of incompletely documented empirical data.

This approach saw a paradigm shift in the latter half of the twentieth century as our knowledge of DNA and genetics revealed to us the rich diversity and uniqueness of individual genomes. Concomitantly, our knowledge of the molecular basis of disease led us to recognize molecular determinants unique to every individual. We are already taking advantage of this knowledge and harnessing it to personalize therapy.

Take the case of the anticancer drug temozolomide for instance. Temozolomide is prescribed for patients with a particularly pernicious form of brain cancer with poor prognosis. The drug belongs to a category of compounds called alkylating agents, a common class of anticancer drugs in which a reactive chemical group is transferred onto DNA in cancer cells, rendering them incapable of efficient cell division and causing their death. The problem is that because of its key role in sustaining life processes, DNA division is tightly controlled. Any kind of modification of the kind caused by temozolomide is treated as DNA damage and- for good reason- life has evolved multiple mechanisms to reverse such damage. In this case the body produces an enzyme that strips DNA of the reactive functionality attached by the drug. Thus the body unwillingly helps cancer cells by reversing the drug’s action. The understanding of this mechanism has led doctors to personalize temozolomide treatment only for individuals who have low levels of the drug-resisting enzyme. For other patients that produce high levels of the enzyme, temozolomide will unfortunately not be effective and doctors will have to turn to other drugs.

We will undoubtedly witness the proliferation of such advances in personalizing individual treatments in the future. But what appears to be an even more promising approach is to start at the source, at the fundamental genomic sequences that dictate the phenotypical changes associated with enzymes and proteins. The deciphering of the human genome has opened up exciting and promising new avenues for mapping differences in individual genomes and harnessing these differences in drug discovery. The most important strategy has been to compare genomes of individuals for single nucleotide polymorphisms (SNPs) which are changes in single base pairs in the DNA sequence. In fact much of the genetic variation between individuals and populations arises from these single nucleotide changes. SNPs have been of enormous value in tracing genetic diseases and generally categorizing variations in our species. They are typically utilised in genome-wide association studies in which the genomes of members of a certain homogeneous population with and without a disease are compared. Knowing the differences can enable scientists to pinpoint genetic markers responsible for the disease. These genetic markers can then be linked to phenotypes like enzyme overproduction or deficiency that are more directly related to the disease. In addition SNPs are unusually stable and remain constant between generations, providing scientists with a relatively time-invariant handle to study genetic disorders. One of the most notable instances of using SNPs to determine propensity toward disease involves the so-called ApoE gene in Alzheimer’s disease. Two SNPs in this gene lead to three alleles- E2, E3 and E4. Each individual inherits one maternal and one paternal copy of the ApoE gene and there is now solid evidence that the inheritance of the E4 allele leads to a greatly increased risk of Alzheimer’s disease.

In the long run, SNP’s may provide the foundation for much of personalised medicine. This is because SNPs also often dictate individuals’ propensity toward drugs, pathogens and vaccines. Thus in an ideal scenario, one might be able to predict a patient’s response to a whole battery of drugs using knowledge of specific SNPs associated with his or her disease.

Unfortunately this ideal scenario may be much farther than imagined. For one thing, we have still only scraped the surface of all possible SNPs, and there are already an estimated three million out there. But more importantly, the difference between knowing all the SNPs and knowing their causal connections to various diseases is almost like the difference between a list of all human beings on the planet on one hand and everything about their lives on the other; their professions, origins, hobbies, political views, family lives. Knowing the former is far from understanding the latter.

In this sense the problem with SNPs illustrates the problems with all of personalised medicine. In fact it’s a problem that plagues scientific research in general, and that’s the dilemma of separating correlation from causation. The problem is even more acute in a complex biological system like a human being where the ratio of extraneous unrelated correlations to genuinely causative factors is especially high. Simply knowing the SNP variations between a healthy and diseased individual is very different from being able to pinpoint the SNP that is directly connected to the disease. The situation is made exponentially more complex by the fact that these putative determinants usually act in combination with each other. Thus one has to now account not only for the effect of an individual SNP but also for the differential effects of its combination with other SNPs. And as if this complexity were not enough, there’s also the fact that many SNPs occur in non-coding regions of the human genome, leading to even bigger questions about their exact relevance. Sophisticated computers and statistical methods are enabling us to sort through this jungle of data, but as of now the data itself clearly outnumbers our ability to intelligently analyse it. We need to become far more capable at distinguishing signal from noise if we are to translate genetic understanding into practical therapeutic strategies.

In addition, while a certain kind of SNP may be able to determine disease tendency, there are also many false positives and negatives. Only a small percentage of SNPs are typically linked to a condition, especially when it comes to complex conditions like cancer, diabetes and psychological disorders. Many SNPs may simply be surrogate SNPs that have little to do with the disease themselves but which have come along for the ride with other SNPs. It is a difficult task to say the least to separate the wheat from the chaff and hone in on the few SNPs that are truly serving as disease determinants or markers. In such cases it is instructive to borrow from the example of temozolomide and remember that ultimately we will be able to untangle cause and effect only by looking at the molecular level interaction of drugs and biomolecules. No amount of data sequencing and analysis can really be a substitute for a robust study designed to directly demonstrate the role of a particular enzyme or protein in the etiology of a disease. It’s also worth noting that such studies have always benefited from the tools of classical biochemistry and pharmacology, and thus practitioners of these arts will continue to stand on an equal footing with the new genomics experts and computational biologists in unraveling the implications of genetic differences.

Finally, there’s the all-pervasive question of nature versus nurture. Along with genomics, one of the most important advances of the last decade has been the development of epigenetics. Epigenetics refers to changes in the genome that are induced by the environment and not hard-coded in the DNA sequence. An example includes the environmentally stimulated silencing or activation of genes by certain classes of enzymes. Epigenetic factors are now known to be responsible for a variety of processes in diseases and health. Some of these factors can even operate in the fetal stage and influence physiological responses in later life. While epigenetics has revealed a fascinating new layer of biological control and has much to teach us, it also adds another layer of complexity to the determination of individual responses to therapy. We have a long way to go before we can perfect the capability to clearly distinguish genetic from epigenetic factors as signposts for individualized therapy.

The future of personalised medicine is therefore both highly exciting as well as extremely challenging. There is much promise to be had in mapping the subtle genetic differences that make us react differently to diseases and their cures, but we will also have to be exceedingly careful in not leading ourselves astray with incomplete data, absence of causation and confirmation bias. It is a tough, but ultimately rewarding problem which will lead to both fundamental understanding and new medical advances. It deserves our attention in every way.

Image source

Are chemists much more secretive and obsessive than physicists?

Derek said it on his blog today and I have been saying it for some time. The physics community did itself and others a great service by floating ArXiv, which has become the standard venue for publication of premium physics papers focused on theory and computation. As Derek asks, why isn't there such a free service started by chemists for their community?

I concur, and a related question I have concerns being able to look at citations. The APS website (which hosts the JACS-equivalent physics journal Physical Review among others) allows readers to view the number of citations for all its papers and therefore allows us to sort papers by citations. No such feature exists for ACS or Wiley chemistry journals; as far as I know one has to log in to a paid site like Web of Science to be able to view citations.

This leads me to a question of psychology. Are chemists much more secretive and obsessive about their data and results compared to physicists? Are they much more self-conscious about revealing the impact (or lack thereof) of their publications to the public? Does some vestigial culture of secrecy going back to the alchemists' creed still linger in our minds?

It could not have to do with the status of the field since many branches of physics are as cutting edge as fields of chemistry. The first explanation that comes to my mind has to do with the color green. It's pretty clear that compared to physics, many fields of chemistry such as medicinal chemistry and materials science have money-making written on them. Unlike most physicists, chemists can patent their molecules and make money from them to a much greater extent. If this is the case, then a control group might be that of engineers. Is a reluctance to make publications or citations easily available also prevalent among the engineering community?

Yet such money-making results constitute only one part of the chemical literature. What about the several academic chemistry papers that have no tangible commercial potential? Why not make them available for free and make their citations available? I don't know the right explanation for this habit, but simple inertia and lack of vigorous discussion and initiative seem to clearly play a role. I do hope it's not because of a statistically significant difference between chemists and physicists that causes the former to hoard results.

The way I see it, the chemistry community clearly should borrow a page from the physicists. Firstly, certain kinds of chemistry papers (just like theoretical papers on ArXiv) need to be made available for free. Secondly, we all deserve a look at citation data which should not be so inaccessible and expensive. If science is supposed to be a community enterprise, this seems to be the least we can do.

Why biology (and chemistry) is not physics

In the Wall Street Journal, the physics writer Jeremy Bernstein has a fine review of a new joint biography by Gino Segre of George Gamow and Max Delbruck named "Ordinary Geniuses" which I just started reading.

Gamow and Delbruck were not as well known as some of their more famous peers but as Segre demonstrates, both made very important contributions to cosmology and molecular biology through direct experimentation and theorizing as well as by inspiring others' research. In addition the two were colorful and engaging characters which makes the book a pleasure to read.

But it was the first paragraph of the review that really caught my eye:

Some sciences are more unruly than others. Here's a parable to illustrate what I mean. Imagine that when the first life form appeared there was a superintelligent freak. If this freak had had a complete knowledge of the laws of physics, what could it have predicted? Quite a lot. All atomic nuclei consist of neutrons and protons, and the number of protons determines each element's chemical nature. Knowing this, the freak could have predicted all the elements that could possibly exist, along with their respective characteristics. Suppose that it also knew all the laws of biology, including the "central dogma," which explains how genes are expressed as proteins. Even so, it could not have predicted the existence of giraffes, nor even the fact that my brother and I share only half our genes. Both of these are evolutionary accidents. If it had not been for random mutation there would be no giraffes, and my brother and I might have shared all our genes, as male bumblebees do. Biology is not like physics.

This paragraph succinctly pretty much nails down the fundamental limitations of physics-based reductionism and it's a point that applies to chemistry as well. It's a very important point. The problem is that reductionism will never be able to account for the role of historical contingency and accident. Even if an all-powerful being could account for all biological scenarios emerging from an initial state of the universe, it could never tell us why one particular scenario is preferred over others. As Bernstein says, evolutionary accidents by definition cannot be predicted from starting conditions because they depend on chance and opportunity.

In addition function can never be uniquely derived from reductionism even if structure is. For instance in his book "Reinventing the Sacred", the complexity theorist Stuart Kauffman makes a powerful argument that even if one could derive the structure of the human heart from string theory in principle, string theory would never tell us that its most important function is to pump blood. The function of biological organs arose as an adaptive consequence of the countless unpredictable constraints that molded them during evolution. In addition the evolution of both structure and function was a mix-and-match process that depended as much on chance encounters as on strict adaptation. All this can never be captured in a reductionist worldview.

The same principle applies to chemistry. For instance the supreme being would never have been able to tell us why there are only twenty amino acids, why there are alpha amino acids instead of beta or gamma versions (which have extra carbon atoms), why amino acid stereochemistry is L while sugar stereochemistry is D, why there are four DNA bases with their unique structures, why nature chose phosphates (although Frank Westheimer comes close), why a given protein folds into only one unique functional structure, why water is the only solvent known to sustain life, and in general why the myriad small and large molecules of life are what they are. In retrospect of course one could provide several arguments for the existence of these molecules based on stability, function and structure but there is no way to predict these parameters prospectively.

The problem is that there is nothing in the nature of these molecules that dictates that their presence should have been uniquely determined. For instance we now know from synthetic studies that beta and gamma amino acids can also fold into the kind of helices and (less so) sheets that are ubiquitous for alpha amino acids. In addition these "higher order" amino acids provide extra handles for functional group attachment (see top figure). Yet for some reason they were discarded during evolution. Why? We could come up with several arguments. 

For instance because of their floppiness, maybe the higher order versions had to pay an unacceptable entropic penalty that could not compensate for their folding propensity. Or maybe the Strecker reaction that is thought to produce alpha amino acids could never be superseded by other chemical reactions for forming beta amino acids. Or perhaps alpha amino acids shield hydrophobic side chains much better than their longer chain counterparts. Cogent reasons, all of these, and yet I am sure we could find an equal number of arguments against alpha amino acids if we searched hard enough. The ultimate failure to find an explanation for the existence of alpha amino acids is a powerful reminder of the importance that chance and circumstance played in the evolution of both biomolecules as well as living organisms.

This role of contingency and accident is one of the most important reasons why the reduction of chemistry and biology to physics won't work. In addition as I have described before, reductionism cannot account for variety in chemistry. Yet another reason why chemistry and biology are not physics.

No ordinary geniuses

John Cockcroft and George Gamow rejoicing on the resolution of a thorny problem, ca. 1930. (Source)

The mathematician Mark Kac classified geniuses into two kinds. "Ordinary" geniuses were those who accomplished a lot, but who gave you the feeling that you too could be as successful if you worked hard enough. The other kind of genius was the "magician", a person whose thought processes for all intents and purposes were hidden from you and who made you feel that you could not catch up no matter how hard you tried.

Kac's distinction does apply, but it's also a little unfair to "ordinary" geniuses who happen to include many Nobel laureates. These ordinary geniuses may not have been Newton, Darwin or Einstein but collectively they were responsible for the underpinnings of most of modern science. In his book the physicist and author Gino Segre brings two such ordinary geniuses- George Gamow and Max Delbruck- to life. Gamow and Delbruck are not as famous in the public eye as some of their contemporaries like Einstein, Dirac or Feynman but as Segre marvelously demonstrates, they were founding fathers of two of the twentieth and twenty-first century's most important fields- cosmology and molecular biology. Segre does a great job of explaining the two men's discoveries, lives and working philosophies and also paints a vivid portrait of the important times which they lived in.

Both started as physicists, Gamow in Russia and Delbruck in Germany. Both grew up amidst war and civil strife and ended up emigrating to the United States as refugees from communism and fascism; Gamow and his wife had to literally flee from the Soviet Union to escape Stalin's yoke. Both were lucky to grow up during the heyday of modern physics when quantum mechanics was being created in Germany, England and Denmark. Gamow made an early name for himself by pioneering nuclear physics while Delbruck floundered as a physicist for some time before finding his niche in biology. The two met in Niels Bohr's famous institute in Copenhagen where they discovered their common interests and struck up a lifelong friendship.

One of the biggest virtues of the book is in bringing out the distinctive working style of the two scientists. This style was marked by independence of thought, an unwillingness to follow the beaten track and a relentless enthusiasm for staking out new grounds. Both men were mavericks who, in Gamow's words, were always looking for the next "pioneering thing". Inspired by Bohr, Delbruck turned to molecular biology when the subject did not even formally exist. Thinking of a basic experimental unit in biology akin to the hydrogen atom in physics which would shed light on key biological processes and be amenable to experiment, Delbruck picked bacteriophages- viruses which attack bacteria. Along with another emigre, the Italian Salvador Luria, he performed foundational studies that demonstrated the fundamental role of mutations and their effect on bacterial phenotypes; one of their most important experiments proved that mutations that arise in response to selection are preexisting and not induced by the selection agent. With a few such elegant studies Delbruck and Luria connected genetics to bacteriology. Since then microbial genetics has been the source of some of our most important insights into heredity, genetic engineering and medicine. The phages whose importance they highlighted continue to be tools of incredible utility in our search for genetic mechanisms and new medical therapies. Along with Alfred Hershey, Delbruck and Luria were awarded the Nobel Prize for their work in 1969.

Delbruck and Luria at Cold Spring Harbor Laboratory, 1953 (Source)

While Delbruck was tinkering with viruses, Gamow turned to nuclear and astrophysics when the fields were not too popular. He was the first to explain the so-called bizarre "tunnel effect" in alpha decay, a quintessentially quantum mechanical phenomenon which allows particles to surmount energy barriers which are classically unsurmountable. The tunnel effect underlies many important processes in physics and chemistry, from nuclear decay to the workings of enzymes. But Gamow's main contribution was in formulating the Big Bang Theory which is at the foundation of modern cosmology. He thought longer and harder about the origin of the universe than most of his contemporaries and he did this long before the physicists Arno Penzias and Robert Wilson discovered the cosmic microwave background radiation emanating from the Big Bang, which Gamow had actually predicted. It is a pity that Gamow did not share the Nobel Prize with them.

Later in life, Gamow became a world-renowned popularizer of science. His popular physics books inspired many children to study science and his "Mr. Tompkins" series brought the bizarre mysteries of quantum mechanics to the masses. I myself remember being greatly inspired as a child by the wit and insight in these volumes. As if these contributions were not enough, Gamow later turned to molecular biology and collaborated with the founders of molecular biology including James Watson and Francis Crick. He supplied some of the early thinking about the genetic code and even though the details of his ideas were not correct, he stimulated others to think in the right direction. Delbruck himself was inspired by Gamow's ideas. In his later life he became a mentor to a whole generation of biologists, mostly at Caltech and at Cold Spring Harbor Laboratory, who founded the study of genomics. Delbruck contributed as much through his mentorship as through his research.

In addition as the book showcases, the two were eminently interesting characters. Delbruck was a man who spoke his mind, not afraid to poke, probe and question until he got to the truth. Gamow's colorful personality has become the stuff of legend. He was a practical joker who used to constantly play pranks on his colleagues and insert jokes even in technical scientific papers. Just one anecdote will suffice; in a bar, some of Gamow's friends once bribed a waitress to startle him by asking him if he was the British physicist Fred Hoyle, the Big Bang Theory's staunchest opponent. Without missing a beat Gamow replied, "Now now, don't throw Hoyle over troubled waters." Gamow and Delbruck showed us not just how to do great science but how to have fun doing it.

Max Delbruck's and George Gamow's ideas essentially underlie some of today's most important questions in biology and cosmology. For all of Kac's categorization of geniuses, there is no doubt that the two were extraordinary scientists. We will all continue to stand on their shoulders.

"Ordinary Geniuses: Max Delbruck, George Gamow and the origins of Genomics and Big Bang Cosmology"- Gino Segre

The barrier to amyloid formation is kinetic, not thermodynamic

One of the questions I have pondered in the past is why the functional form of a protein should correspond to its most thermodynamically stable structure. Although this assumption is built into almost all experimental and theoretical studies of protein folding, it is not at all obvious since one may imagine other forms which could have improved stability. For instance, two protein forms may differ in the presence of a hydrogen bond or two. Based on the location and connectivity of these bonds, sometimes this slight rearrangement can cause a radical change in function, but there's no good reason why it should in the general case.

The answer however is most obvious in case of amyloid, that endlessly intriguing protein form that is implicated in so many devastating neurological disorders. Amyloid is a very stable state is often highly resistant to temperature, pH and high salt conditions. It's fair to ask how stable or unstable it is with respect to functional, soluble forms of the same protein.

To answer this question, a team led by Christopher Dobson who is a world expert on amyloid performed a series of thermodynamic measurements on a diverse group of proteins in which they measured the free energy differences between the soluble and the amyloid state. The proteins included everything from the Aß protein found in Alzheimer's disease to human lysozyme and insulin. The finding was that the free energy differences (ranging from about 3 kcal/mol to 6 kcal/mol) are not terribly dependent on the exact sequence, an observation which would be consistent with the striking recently uncovered fact that amyloid formation can be induced in almost any protein independent of its sequence. In fact the free energy difference seemed to depend more on the length and seemed to be optimal for a length of 100 residues for which the amyloid form was most stable. The difference also sharply tipped away from amyloid for increasing lengths.

This observation seems to suggest that one consequence of evolving larger proteins might be steer them away from the amyloid state and is consistent with the fact that almost all amyloid proteins have relatively short lengths (for instance, the Alzheimer's disease amyloid protein Aß has a length of roughly 40 residues). The propensity toward amyloid formation also depended on the concentration and the authors derived an limiting concentration beyond which amyloid formation would be rapid. This is again not surprising since the concentration-dependence of the process has also been demonstrated.

The real surprise came when they compared these limiting concentrations of the protein to the corresponding physiological concentrations of the same proteins in plasma. Remarkably, they found that in almost every case the physiological concentration was higher than that required to achieve amyloid formation. Thus the observations clearly indicate that for many key proteins, the amyloid state is thermodynamically more stable than the native, functional state. To put it bluntly, many nicely folded and soluble proteins are actually metastable. Now, since native proteins don't constantly form amyloid and kill us all, it's clear that the barrier to amyloid formation must be kinetic. Intriguingly, the authors speculate that these barriers can be overcome when organisms are exposed to stress, mutations or aging.

This is a pretty intriguing study and seems to underscore the belief that at least for some proteins, the folded functional state is not the most stable. However in light of what we know about evolution, this should not be too surprising. Stability is just one of many factors to be optimized during natural selection and there is no reason to assume that evolution would always act to maximize this parameter at the cost of all others. It's worth always keeping in mind that evolution cannot afford to aim for the ideal but instead has to make do with what it has.

The other question in my mind is why in spite of these barriers existing in case of so many proteins like lysozyme, insulin etc. are they regularly overcome only in the case of Aß (1-42) and a select few others. Based on the speculation in the paper, this could be because these proteins are exposed to particularly harsh conditions that force them to climb past the kinetic barrier and settle into the amyloid valley of thermodynamic comfort and physiological woe.

Among many such conditions could very well be bacterial infections. A few years back I advanced a hypothesis about amyloid formation being a defense against viral and bacterial infection mediated through the production of free radicals. A kinetic barrier-surpassing mechanism of the kind speculated here might well be what allows these proteins to achieve the transition, killing the bacteria but ironically harming their owner in the process. In the context of the present study, I think there continue to be a lot of opportunities to investigate the possible infection-induced conversion of normal proteins to their amyloid form.

Hopefully someone will do the experiment.

Baldwin, A., Knowles, T., Tartaglia, G., Fitzpatrick, A., Devlin, G., Shammas, S., Waudby, C., Mossuto, M., Meehan, S., Gras, S., Christodoulou, J., Anthony-Cahill, S., Barker, P., Vendruscolo, M., & Dobson, C. (2011). Metastability of Native Proteins and the Phenomenon of Amyloid Formation Journal of the American Chemical Society DOI: 10.1021/ja2017703

Why conduct reactions at low temperature?

The other day I was talking to a synthetic chemist friend about conducting reactions at low temperature and I realized that there is another reason for doing this that is not always appreciated by beginning organic chemistry students. Most students think that the primary purpose of low-temperature reactions is to stop runaway exothermic reactions from getting out of hand and to tame explosive reagents. While this is a perfectly good reason, there is another reason connected to stereochemistry which occasionally necessitates these reactions.

Remember the all important thermodynamic relation ∆G = ∆H - T∆S and recall that life and laboratory chemistry are both games played within a 3 kcal/mol window. In this case the relevant equation would be the Arrhenius equation and the relevant free energy would be the free energy of activation (∆G††). Thus even a 1 kcal/mol energy difference between two transition states can favor the product corresponding to the lower energy TS by a substantial account; for instance you only need a 1.8 kcal/mol energy difference to effect a greater than 95% yield of the more stable species. This principle applies to everything, including conformers, stereoisomers and constitutional isomers. But the important variable for our discussion is the temperature T and it's clear that a lower temperature will affect the free energy favorably.

And that is precisely why it becomes so important in stereoselective reactions. If you are dealing with two diastereometric transition states resulting from attack of a chiral reagent on two enantiomers for instance, you only need a difference of 1.13 kcal/mol to generate a diastereomeric ratio of 95:5. But this phenomenon becomes even more pronounced at -78 degrees celsius which is the temperature of a standard liquid N2 acetone/dry ice bath. For instance, if you conduct a reaction giving you a 95:5 diastereomeric ratio at -78 degrees, the same reaction done at 23 degrees will give you only a 85:15 diastereomeric ratio. And if you look at the energy you need at 23 degrees to overcome that low ratio and bump it to 95:5, it's only 0.58 kcal/mol.

It's incredible to realize how so much of life and chemistry are governed by startlingly small differences in energy between large numbers. But there you have it; a very good reason to lower the temperature of your next aldol condensation to get better stereoselectivity. Make sure to emphasize that to your curious undergrad the next time he/she asks a question about low temperature reactions.

Who are your favorite technical writers in chemistry?

There is a surprisingly common belief among scientists that the public speaking skills of most scientists are inversely correlated to their achievements in science. This is certainly true of many chemists I have seen, including some Nobel Laureates who would put a fly on the wall to sleep. I have attended three ACS meeting and I can probably count two or three speakers whose speaking skills matched the high level of their research accomplishments (Dennis Dougherty, Eric Jacobsen and Ron Breslow all come to mind; Dougherty was a hoot).

Surprisingly, this is a phenomenon also seen in technical scientific articles. Some of the best chemists in the world are also masters of long-winded explanations. So it is always refreshing to see someone who has achieved a lot in science and is also able to explain his or her science to the community in concise and creative words. I am not talking about popular chemistry writers here (although that is another rare breed); the papers I am thinking of are strictly technical in nature.

So what makes a technical chemistry paper readable? Simplicity, certainly; the material that you present should be easily understandable to someone skilled in the trade. Ideally it should also be comprehensible to fellow chemists in other fields and perhaps even to related scientists in different fields. Secondly, the material should drive home the creative impact of the work. If it's a synthesis you are describing, the language should make clear the elegance, economy and practical utility of your synthesis. If the paper is structural, it should drive home the uniqueness, interactions and functional relevance of your chemical or biochemical structure. If computational, the paper should highlight the advantage of your computational method over other approaches, emphasize the connection to experiment and clearly enlighten experimentalists about the strengths and limitations of the approach.

Ultimately, your paper should make clear the unique vantage point that your particular field of chemistry enjoys. If it's a review, it should stand as the defining review in the field by virtue of the scope and explanatory power of your writing. Most importantly, it should be a paper which you keep coming back to under diverse circumstances. During the course of my brief chemical career I have come across a handful of chemists and their papers that satisfy these criteria. In some cases there's a single memorable paper while in others there's a whole slew Here are a few from that collection:

1. Jack Dunitz: Dunitz, now in his nineties and still doing research at the ETH, is not only one of the leading crystallographers of the twentieth century but also one of the best technical writers in chemistry I have encountered. Three of his papers have especially stood out for me for their brevity and creativity. One is his papers is titled "Organic Fluorine Hardly Ever Accepts Hydrogen Bonds" which should be required reading for every structural and medicinal chemist. Another is "The Entropic Cost of Bound Water Molecules" (Science, 1994, 264, 670) which puts an upper limit on the free energy that you can get from displacing water molecules in protein binding sites. A third paper is "Win Some, Lose Some: Enthalpy-Entropy Compensation in Organic and Biological Systems" (Chem. & Biol. 1995, 2, 709) which advances an elegant and very simple argument for the relative unimportance of hydrogen bonds in molecular recognition; basically entropy and enthalpy almost perfectly cancel each other out for a hydrogen bond . All three papers are devastatingly brief and drive home some very important points.

2. Ken Dill: Ken Dill at UCSF is one of the world's leading experts on protein folding and structure. In 1990 he wrote a review titled "Dominant Forces in Protein Folding" (free PDF) which still stands as an authoritative review on the topic. This review is one of the most highly cited papers in Biochemistry since the journal's publication. What is remarkable about the article is the sheer amount of territory Dill covers, from the hydrophobic event and molecular dynamics to experimental studies of protein folding. Much has been learnt since 1990 but the basic ideas in the paper are still valid and it remains a commanding overview of the field.

3. R B Woodward: Enough has been said about the man on this blog, but his papers often constituted poetry in (electronic) motion. Woodward's language had that special tinge that comes from having a personal relationship with every single compound that he encountered, from the simple nitric acid to vitamin B12. Almost any of his papers is breathtaking in both language and content, but I will especially recommend his famous works on strychnine (Tetrahedron, 1963, 19, 247) and reserpine (Tetrahedron, 1958, 2, 1) as masterpieces of scientific writing- and of literature.

4. K C Nicolaou: Say whatever you want about the man, but his review articles have an unmistakable feel of heroic achievement. Yes, maybe he exaggerates a little and yes, maybe the rash of pictures from Greek mythology is a little too much, but the man has written some of the best reviews of organic syntheses. And like Woodward, Nicolaou does an admirable job in his reviews of bringing out the excitement, beauty and achievement of the field. My favorites? Brevetoxin B and the CP molecules.

5. Anthony Nicholls: More recently, I have found computational chemist Anthony Nicholls of OpenEye to be an unusual clear and incisive technical writer. What is notable about his papers is the careful dissection of all factors involved in a particular system as well as an honest admission of limitations of current methods. His papers present a balanced perspective of theoretical and computational methods and clearly point out gaps and opportunities for improvement. I would especially recommend his co-authored review on metrics for evaluating and presenting computational methods in drug design and a critical and enlightening study of solvation of organic molecules that points to the challenges in calculating properties of complex systems.

What would Woodward say?: Giants of chemistry in the year 2011

Science progresses by leaps and bounds, but it's not easy to chart its progress. Metrics can only do so much to quantify scientific developments.

Yet there are periods when it's clear that the rate of progress in certain scientific fields is phenomenal. For instance, nobody can deny that physics underwent an earth-shattering transformation in the first thirty odd years of the twentieth century, perhaps the greatest it ever experienced. With relativity and quantum mechanics completely changing our view of nature, a physicist who had been flash-frozen in 1900 and resurrected in 1930 would have found the state of his science almost surreal. Similarly, biology completely changed itself and our view of life between 1950 and 2000.

What about chemistry, and especially chemistry in the last few decades? While any quantification of chemical progress is ultimately subjective, it would be an amusing and instructive exercise to ask what some of the pioneers of chemical science would have felt about the state of their discipline if they had been flash-frozen just before they died and brought back to life in the year 2011. Viewing today's world through the eyes of these men and women could be a good way to discover exactly how much their field has changed.

Let's step into a time machine then and bring back four distinguished scientists into the modern age, each of whom gained lasting fame in a distinct and key area of chemistry. Robert Burns Woodward, Linus Pauling, Irving Langmuir and Alfred Werner were all giants of chemistry. Let's imagine the reaction of each one of them to modern day chemical science, especially in their own field. How about starting with you, Prof. Woodward...

1. What would Woodward say?

"It's quite something to be transported to the year 2011 and I am glad that the technology of time travel has developed rapidly enough to make this possible. When I died in 1979 I had already pioneered the synthesis of complex molecules. I am somewhat disappointed that the state of that science, while consistently strong, has not seen any fundamental transformations in the nature of the molecules being synthesized. Using more primitive and time-intensive methods, I am confident that I could have synthesized in 1980 almost any molecule which my colleagues are synthesizing in 2011. I am however very impressed by two major advances which I did not foresee during my lifetime.

The first is the staggering growth of organometallic chemistry. With my role in the discovery of ferrocene I consider myself a founder of the field, but I could not possibly have seen such tremendously useful applications of palladium catalyzed reactions, asymmetric epoxidations and olefin metathesis. I offer my most enthusiastic congratulations to the pioneers of these novel methods. As an aside, I am also quite taken by how efficient and routine asymmetric synthesis has become. My synthesis of reserpine is considered one of the first examples of stereoselective syntheses, but the total synthesis of the same molecule by my friend Gilbert Stork in 2006 seems so much more sophisticated and rich with applications of conformational analysis and stereocontrol.

If I am impressed with the development of organometallic chemistry, I am floored by the rise of chemical biology and chemical genetics. By the time I died there were already many very competent biochemists around, but there was no concerted application of chemical synthesis to an understanding of biology. This was partly because we lacked an understanding of biological systems that was made possible by the phenomenal developments in molecular biology that followed my death. It's quite amazing to witness the routine study and manipulation of complex biological pathways using intricately designed molecules. I can only see a bright future for these ideas in chemistry and medicine, and am glad that my student Stuart Schreiber has been one of the pioneers in the field.

Well, that was nice. But I need to go back now and spend my last few days working on ideas for organic superconductors."

2. What would Pauling say?

"How wonderful to be here! Having been fortunate enough to have lived for the first 93 years of one of the most important centuries that we humans have lived in, I still could not make it to 2011 to witness the achievements of chemistry in the twenty years since my death.

Many people consider me the greatest chemist of the twentieth century and I did indeed cross disciplinary boundaries with impunity, having worked significantly in theoretical chemistry, organic chemistry, biochemistry and medicine. So there is a lot of ground to cover.

Let me start by looking at progress in the field which I am most known for. By the time I died, computers had already become prominent in molecular orbital calculations, although I could not possibly have foreseen how fast and small they would become. I am glad that computational chemistry has turned into an independent field of chemistry. It still seems almost as challenging as it was then to apply theoretical methods to complicated systems and especially biological systems, but I feel gratified by the development of 'mixed' methods such as quantum mechanics-molecular mechanics (QM/MM) which simplify calculations without sacrificing accuracy. I must especially congratulate my last student, Martin Karplus, for pioneering the applications of theoretical methods to biological systems. I see a continuing bright future in this area, along with further developments in computer science that would allow us to tackle complex systems. I am especially gratified that these methods have brought computation to the masses, so that even non-specialists can now do detailed calculations and get useful answers.

As someone who is considered to be one of the founders of molecular biology, I was fortunate to have lived long enough to witness the rise of recombinant DNA technology. But like Prof. Woodward I too am very impressed with the rapid growth of chemical genetics in the last twenty years. I am very happy that chemists have taken my ideas about molecular recognition to heart and that they continue to use these ideas to develop new drugs and antibodies against diseases. I am also awed by the sheer amount of information coming out of genetic sequencing, and as someone who described the first genetic disease at a molecular level (sickle cell anemia), I am proud that scientists are now routinely exploring the molecular basis of genetic disease as an aid to develop personalized drugs. As a chemist, I would however caution against putting too much faith in the data itself and actually looking at the molecular events.

Overall then, I am very pleased to witness this growth of science. However I must also reinforce my commitment to peace (after all I did win a Nobel Peace Prize) and emphasize that this growth should serve both the most and the least fortunate among us. We do science not just for ourselves but for others"

2. What would Langmuir say?

"It's somewhat amusing for me to realize that I am almost as famous for my description of "pathological science" and pseudoscience as I am for my eponymous isotherm. But let's stick to the actual science. I died in 1957 and I was awarded a Nobel Prize for surface chemistry in 1932. I cannot even begin to express my amazement at the phenomenal advances in surface and related sciences since my death which have partially been honored with the Nobel prize in 2007.

When I died I could not have imagined in my wildest dreams that someday we could have instruments that could literally map a surface atom by atom, sensitively rolling over the contours of a molecular landscape the way a finger might roll over a bed of marbles. The invention of the scanning tunneling and atomic force microscopes have given us a tactile view of the atomic world that is beyond anything we could have dreamt of in 1957. I am fascinated by the emergence of the entirely new discipline of nanoscience which was only being imagined in 1957 (Author's note: For instance Richard Feynman gave his famous talk about nanotechnology in 1959). I can only assume that this amazing molecular manipulation of matter will continue and will pay dividends in both pure and applied science.

Speaking of pure science, before I leave I feel a strong urge to step on my soapbox and lament its decline. Anyone who thinks that high-quality basic science cannot be sustained in industry should only cite my example. I spent my entire career at GE and yet become the first industrial scientist to win a Nobel Prize in chemistry. When I scan the history books I find many other industrial labs like IBM and especially Bell Labs that were hotbeds of prizewinning scientific talent; for crying out loud, the scanning tunneling microscope that we mentioned was developed at IBM and its developers won the Nobel Prize.

How times have changed! Former industrial labs like Bell Labs are now either non-existent or are mere shadows of their former selves. As my own example demonstrates, basic science in industry was one of the things that made this country great, and its decimation can only lead to a great decline in America's scientific health. Let me say this out loud; a nation which lionizes short-term profits at the cost of long-term investment in curiosity-driven basic science is on its way to scientific mediocrity. I dearly hope that the next generation reverses this damning trend.

On these dual notes- positive regarding the state of nanoscience but negative regarding the state of scientific research- I must now take your leave."

4. What would Werner say?

"I died in 1919, so the world that is being presented to me in 2011 is in every way beyond recognition. But let me stick to my field. I am often called the "father of coordination chemistry" but I would be lying if did not say that I barely recognize my children. At the same time I am as proud as any parent can be that my field has progressed beyond its original borders and become a vast and productive enterprise.

I merely demonstrated the existence of several inorganic complexes and postulated the concepts of primary and secondary valences and isomerism. But I had little inkling about the precise nature of bonding in these complexes. Now I see that it was about the time that I died that Irving Langmuir and Gilbert Lewis were developing ideas about the shared chemical bond. I am of course very impressed by the contribution of Linus Pauling who pioneered ideas about electroneutrality and the partial covalent character of ionic bonds. It is truly astonishing how much our knowledge of chemical bonds has developed.

However it is to scientists like Hans Bethe, John van Vleck, Carl Ballhausen and Leslie Orgel that I must doff my hat. These scientists delineated the precise nature of bonding in coordination complexes. How wonderful it is to read about the relatively simple rules that predict the coordination number of a ligand, the propensity of certain ligands to bond to certain metals, and whether a complex is high spin or low spin. I can see that my tentative ideas have been placed on a sound theoretical footing.

Ultimately however, I am astonished by the application of coordination chemistry in industry and biology. It cannot be anything but gratifying to know that EDTA can be used to mitigate lead poisoning and that other ligands can be used to mop up chemical spills. And it seems that my studies have ultimately been a part of the entire field of bioinorganic chemistry where ideas about coordination complexes are used to study the interaction of metal ions with proteins.

I feel humbled that I played a role in the development of such an important and major area of chemistry, and I feel confident that this field will thrive. I go back to my own times with the reassurance that my children will continue to instruct, grow and proliferate."

And so we can all hope and strive so that the intellectual children of these four and countless other chemists will instruct, grow and proliferate.