Field of Science

An unusual epoxidation of amides

One of the nice reactions I remember from graduate school is the Johnson-Corey-Chaykovsky reaction which entails epoxidizing a carbonyl group. The carbonyl is treated with dimethylsulfonium ylide, the ylide attacks the carbonyl, and the negative oxygen then knocks off the sulfur to form the expoxide. This epoxide can of course do a lot of interesting chemistry.

I always wondered if amides can be epoxidized in a similar way and I had not seen an example until now, and for good reason. Epoxyamines are inherently unstable because the nitrogen can act as an internal nucleophile and open the ring and the resulting product can undergo all kinds of unwanted reactions like polymerization. So if we want to form such compounds, the question naturally is how we can tie up that lone pair on the nitrogen so that it won't intervene.

Now it's been known for a long time that bridgehead amides behave more like ketones, and the reason postulated by Anthony Kirby of Cambridge among others (who did a lot of nice work on this topic) was that the C-N bond is twisted, making the lone pair unavailable for delocalization. With this background Jeffery Aube and his colleague have used a bridgehead amide to demonstrate Corey-Chaykovksy epoxidation in amides to generate spiro epoxyamines. They use their model system for illustrating several known reactions including protonation and ring opening with nucleophiles, electrophiles and Lewis Acids. The system behaves like a traditional epoxide in some cases but also shows exceptions (like inertness to ethereal boron trifluoride).

In organic chemistry, anything can be made to undergo a specific reaction if the right conditions and considerations of physical organic principles are judiciously applied. Biological organisms have put this fact to spectacular use. That's probably the most fascinating aspect of the field.

An industrial tour de force laid bare

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Statins revolutionized the prevention and treatment of heart disease and saved hundreds of thousands of lives that may have been otherwise lost through heart attacks and stroke and millions of dollars that would have been paid by patients for surgery and other invasive treatments. The best selling molecule in this class(atorvastatin, Lipitor) is the best selling drug of all time and makes more than 12 billion dollars for its parent company, Pfizer. In this engaging and informative book Jie Jack Li, a scientist at Bristol-Myers Squibb company, tells us their story and drives home the importance of the pharmacautical industry at a time when much of the public has become cynical about its motives.

What makes the book valuable is that Li traces not just the history of the drugs themselves but the history of cardiovascular and obsesity research as well as the major players involved in this research. Li also spices up his accounts with amusing ancedotal information about scientists and companies. He narrates the famous Framingham study which definitively established the connection between high cholesterol and heart disease, a connection that has been tentatively explored for more than a hundred years. Also included are interesting historical accounts of several major pharmaceutical companies including Merck, Parke-Davies and Pfizer.

Cholesterol is a remarkable molecule that is the classic embodiment of a double edged sword. Michael Brown, a Nobel prize winning cholesterol researcher calls it a "Janus-faced" molecule, one which is critical in biological function while being harmful when employed incorrectly. No less than thirteen Nobel Prizes have been awarded to researchers who worked on this molecule. Lie traces the pioneering research of several chemists like R B Woodward and Konrad Bloch (Harvard), Lewis Sarrett and Max Tishler(Merck), Dorothy Hodgkin (Cambridge), John Cornforth (MRC, 91 and still going strong) and Wieland and Windhaus (Germany) who were key in elucidating both the pathway of cholesterol synthesis and metabolism, as well as the structures and syntheses of cholesterol and its analogs.

Most of the cholesterol in the body (~70%) is biosynthesized while the rest of it comes from the diet. It forms a crucial component of membranes and is a key signaling molecule. 23% of body cholesterol ends up in the brain where its critical functions are still being investigated. The connection between high cholesterol and heart disease was suspected early on but had to await much pioneering research in order to be deciphered in detail. The Framingham study in Massachusetts studied thousands of local subjects spread over almost 50 years and two generations and established the best correlation between heart disease and cholesterol to date. The study is a landmark because it also analyzed several of the now widely known risk factors for heart disease, including the effects of diet, smoking and exercise. It also established a critical standard; a 1% lowering of cholesterol can lead to a roughly 1% reduced risk of heart disease.

After the correlation was established, both academic and industrial scientists started looking for drugs that would reduce cholesterol. Key during this time was Michael Brown and Joseph Goldstein's discovery of the LDL receptor as a major player in cholesterol metabolism and the importance of LDL and HDL in causing heart disease. Today efforts are underway to both reduce LDL and increase HDL as strategies in combating heart disease. Lie talks about the three dominant pre-statin drugs that were widely used; niacin (vitamin B3), bile acid sequestrants and fibrates. All these drugs had unpleasant side effects although niacin is still seriously considered by companies like Merck as a possible cholestrol-lowering drug. It was in the 70s that research pioneered by Akiro Endo, P. Roy Vagelos and others suggested the initial steps in cholesterol synthesis as prime targets for possible drugs. The logic was rather simple; targeting later steps would lead to a buildup of high molecular weight lipophilic molecules that would cause problems. It was best to target early steps which would lead only small, relatively water soluble and easily excreted molecules to accumulate. Several studies finally settled on 3-hydroxy, 3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase) as the rate limiting enzyme in cholesterol biosynthesis, and one which could possibly be fruitfully inhibited.

It was Japanese biochemist Akiro Endo who painstakingly discovered the first statin in a broth of a Penicillum fungal strain (it's interesting that this humble mold has yielded two of the most important drugs in history, statins and peniciilin). However it was Merck who ran with the idea and brought the first statin to market (lovastatin, Mevacor). The 1980s were the golden age of Merck. During this decade Merck was led by one of the best CEOs in the industry, P. Roy Vagelos who was an accomplished researcher himself and a true visionary. Under his direction Merck was voted as the best company (and not just pharmaceutical company) in the country for three successive years. The reason why Merck thrived and indeed the reason why everyone today should emphatically remember Merck's success was because it followed a time-honored tradition of recruiting only the best scientists (frequently from academia) and more importantly, focusing intensely on basic academic-style research. In the 1950s Merck hired two brilliant academic scientists, Lewis Sarret (Princeton) and Max Tishler (Harvard) whose work catapulted the company into the front lines of drug discovery. This trend continued in the 70s and 80s. Vagelos himself had been the head of the biochemistry department at Washington University School of Medicine when he was hired and had done important work in elucidating the role of HMG-CoA reductase in cholesterol biosynthesis. During the 80s Merck regularly published papers in the best academic journals. In an age where an emphasis on profits and a relative lack of interest in basic research has slowed down drug discovery, it should be time for pharmaceutical companies to again look at the 1980s Merck model of basic research.

It was this model that brought the first statin (Mevacor) to market after intense development. Li engagingly tells us the story of both Merck and Mevacor. However the bulk of the book thereafter is the story of the best selling drug of all time, Lipitor (atorvastatin). Atorvastatin was discovered by Parke-Davis (which was subsequently bought by Pfizer). By the time the Parke-Davis group plunged into statin discovery they already had a tough act to follow since four statins were already on the market. However, as Li describes, statin research at Parke-Davis benefited from a combination of thorough assay development and highly talented scientists. Foremost among them were Bruce Roth, a synthetic chemist who first synthesized Lipitor, and Roger Newton, a biologist who developed the assays. The researchers started with some known statin structures and experimented with installing novel cores and side chains by overlapping the molecules on top of each other. One of the strategies to improve bioavailibility turned out to be to use the ring opened compound instead of the lactone which had been a mainstay of some other statins. The synthesized molecules were shuttled into animal testing which was no cakewalk. The choice of animal turned out to be important since rats are not good models for testing cholesterol lowering medicines; among other factors this is because rats have a dramatically different LDL/HDL ratio compared to humans. Other animals including dogs and monkeys yielded valuable results.

Clinical trials finally demonstrated that atorvastatin had much better pharmacokinetic and bioavailability characteristics compared to earlier statins. Atorvastatin also has a much more favorable profile with respect to the one serious side effect seen with statins- rhabdomylosis or muscle weakness and wasting. Indeed, statins have emerged as some of the most well-tolerated drugs of all time. Total sales are now more than 20 billion dollars. Any new drug developed for lowering cholesterol will have to meet the extremely high bar that statins have set. These drugs are the best examples of the kind of genuinely life-altering research that can come from the pharmacutical industry.

These days the pharmaceutical industry is often maligned as a notorious example of the money-milking, profit-making entities that apparently exemplify the worst in capitalism. But the story of statins reminds us of some valuable facts. Firstly, it is always worth looking at the other side of the coin, at how many lives and dollars would have been expended had such drugs not been discovered; the immense benefits accruing from the avoidance of heart attacks and stroke handsomely pay off in social and economic terms. Secondly, contrary to some public perception, scientists in the pharmaceutical company are as dedicated not just to improving the lives of people but to gaining basic scientific knowledge as are academic researchers; as a corollary to this fact, a lot of industrial research is as exciting as academic research. Thirdly, the story of statins also shows the close interplay between academic and industrial scientists and discoveries that drive innovative drug discovery. As in many other case, the choice is not binary, and it is only healthy public support of both industrial and academic research that can lead to a thriving scientific establishment. Finally and importantly, the story is ominous but also hopeful in a sense since it demonstrates that true scientific and commercial productivity can only come from focusing on basic and long-term scientific research and not just on short-term profits. This is a message that today's pharmaceutical companies should heed well.

Hans Bethe; his life, work and times

Hans Bethe was one of the most important and extraordinary scientists of the twentieth century. The sheer depth and breadth of his work is hard to comprehend. He made important contributions to nuclear physics, quantum electrodynamics, particle physics, solid state physics and astrophysics. He was a great teacher who founded a world-class center of physics at Cornell University. He won a Nobel Prize for explaining one of the oldest problems in science, the problem of the source of solar energy. He counted the greatest physicists of the century among close friends and colleagues. He played a key role in the development of the atomic and hydrogen bombs, served as a top consultant to government, valuably contributed to arms control and worked ceaseless till the ripe age of 99. He was famous not just for his science but for his wisdom and humanism, rock solid self confidence and equanimity of mind.

All these contributions and qualities would be almost impossible to capture in any one volume. Yet "Hans Bethe And His Physics" does this admirably. Several chapters span Bethe's personal traits, his work in science and public policy. Many chapters are written by close friends, students and colleagues. Accounts range from semi-technical descriptions of Bethe's science to fond personal reminiscences. The chapters provide a detailed picture of a great scientist and human being.

Probably the most valuable chapter is one by Chris Adami of Caltech who as a student spent a summer with Bethe and a close collaborator and friend, Gerald Brown of Stony Brook. The chapter is essentially a distillation of Adami's daily diary. His ruminations and first hand accounts provide a rare personal glimpse into Bethe's mind and life. Adami narrates several talks with Bethe that ranged from discussions of Bethe's childhood and education to the most current research in physics. The description of everyday life during that summer is endearing and provides wonderful insight into Bethe's personal side, including his fondness for chocolate ice cream, roast beef and history. The book would honestly be worth reading for this lengthy chapter alone. As Adami nostalgically notes, on the last day of that summer, Bethe who hated sentimental goodbyes shook Adami's hand and simply said, "Carry on". Adami says we should all remember and follow those simple words.

The rest of the chapters in the book focus on Bethe's work in various branches of physics and arms control. The chapters also include some accounts by Bethe himself on his work in solar nucleosynthesis and his recent contributions. He continued to be remarkably productive even into his 90s and during his later years worked on supernovas and on the great mystery of solar neutrinos.

Hans Bethe's life was a kaleidoscope of twentieth century physics and he was one of the most important particpants in this journey. While a book covering every aspect of his vast contributions in detail would be too big, this book is an excellent compendium that provides essential insight into this great man's science, life and work. Highly readable and recommended.

A small molecule probe discriminating between Aß amyloid oligomers and fibrils

One of the conceptual shifts that the study of Alzheimer's disease has seen in the past few years is the realization that the long-studied insoluble Aß (1-42) amyloid fibrils may not be the real culprits in the disease. Instead the dubious distinction may belong to soluble Aß oligomers whose morphology differs from that of mature fibrils. Thus instead of focusing on one kind of Aß species, researchers are focusing on a broad range of oligomers and fully formed fibrils that differ in their architecture. Some differences between these species are clear; for instance the oligomers seem to permeate the plasma membrane in cells much better than the fibrils. The factors that dictate the exact morphology of these species sometimes might be subtle (such as pH shifts), and I myself have worked a little on such subtle changes leading to drastically different morphologies (see here for instance).

However, a study of different amyloid morphologies will greatly benefit from probes that allow us to selectively target and isolate certain amyloid architectures. The principal method of doing this until now has been to raise species-specific antibodies that target either oligomers or fully formed fibrils. In this regard small molecules have not been very promising as they tend to indiscriminately bind to all amyloid species; for instance Congo Red which is the archetypal amyloid labeling dye does not discriminate between different amyloid species.

Now a group at the University of Michigan has discovered some very simple probes that seem to target only spherical oligomers and not fibrils. The probes consist of tryptophan and some rather simple and well known biological molecules containing tryptophan which exhibit fluorescence when bound to proteins, and especially hydrophobic regions of proteins. The team started by screening about 70 simple organic molecules that exhibit fluorescence. Most of these molecules did fluoresce, but when bound to both forms of amyloid, thus precluding discrimination between the two species. Some did not fluoresce at all. But about 10 of them showed differential fluorescent quenching; the fluorescence was quenched much more when bound to oligomers compared to fibrils, thus allowing their selective labeling and visualization. Antibody labeling and radiography confirmed that it was indeed the oligomers that were getting labeled.

Intriguingly these probes consist of tryptophan itself as well as some very simple naturally occurring molecules containing the Trp moiety, such as melatonin, tryptamine and serotonin. In my mind this raises a very interesting possibility; could these molecules also be interacting selectively with amyloid and somehow modulating its behavior inside living systems?

In any case, what is even more valuable is that the probe seems to selectively label the oligomers in the presence of the fibrils and this can be determined from fluorescence studies. This opens up some potentially very interesting applications; for instance if there was any way at all to use such probes in vivo, we could gain extremely valuable knowledge on the ratios of oligomers to fully formed fibrils. Recalling that amyloid is astonishingly a deformed version of a naturally occurring protein, insights gained from such studies could be critical in shedding light on the natural and unnatural roles of amyloid in living systems.

Reinke, A., Seh, H., & Gestwicki, J. (2009). A chemical screening approach reveals that indole fluorescence is quenched by pre-fibrillar but not fibrillar amyloid-β Bioorganic & Medicinal Chemistry Letters, 19 (17), 4952-4957 DOI: 10.1016/j.bmcl.2009.07.082

An outstanding one stop shop for drug discovery and development

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Drug discovery and development is a complex, highly multidisciplinary endeavor in which practitioners have to have knowledge about a disparate range of topics, from chemistry and biology to outsourcing, patent laws and business aspects. It is not physically possible for any one person to have detailed knowledge about all these areas. What is therefore necessary is a book that provides bite-sized chunks about the most relevant aspects of the science, art and commerce of drug discovery and development that will keep scientists, technologists, lawyers and businessmen up to date with the essentials.

Robert Rydzewski's Real World Drug Discovery:A Chemist's Guide to Biotech and Pharmaceutical Research admirably fills this void. In clear, comprehensive and sometimes witty prose he describes the most essential aspects of the field. He begins with the basics of drug development, including a history of the industry and the challenges that it had to face along the way. Then, in a series of chapters the author leads the reader through a remarkable range of topics. A sampling of examples makes the impressive diversity of scientific, business and legal topics clear; patent law, Hatch-Waxman and Bayh-Dole acts, generics, outsourcing and patent busting, high-throughput screening, stereochemical aspects, mouse knockouts and RNA interference, process research and manufacturing, gene arrays and pharmacogenomics, biotechnology, pharmacokinetics and metabolism, side-effects, structure-based drug design and computational modeling, FDA rules, mergers and acquisitions, project management and leadership and statistics and trends.

This comprehensive choice of topics will bring any interested scientist or individual up to speed with all important aspects of the science and industry. A unique feature of the book is the extensive inclusion of quotes and opinions from leading scientists and businessmen in academia and industry on the state of the art. This gives a personal and practical touch to the presentation and lets the reader know what the experts actually think. It also makes the writing lively and engaging. Rydzewski illustrates concepts with many real world examples and case studies and sometimes with witty analogies.

There are many books on drug discovery and development out there, each of which is focused on one particular specialized aspect. However this is probably the best single stop shop I have seen for individuals who want to get only the most important and current information in the field without delving into too many details. An admirable and comprehensive book that deserves a place on the shelf of everyone in industry and relevant researchers in academia.

A journey with the good Lord

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A lively Ludwig Wittgenstein tries to gently persuade Bertrand Russell of the veracity of his ideas in "Logicomix: An Epic Search for Truth"

In the autumn of 1939, as the world in its tormented restlessness perched on the edge of conflict, a tall, lanky man was slowly making his way towards the steps of a prominent American university, his ubiquitous pipe in hand. His face was one of the most recognizable in the world, his mind among the most respected minds of his time. He was slated to give a talk at this august institution, and as he approached he was accosted by protestors who pleaded to him to not give his talk and instead join them in their pacifist protests. Only two decades back the gentleman had been a famously eloquent pacifist, spending time in prison during World War 1 after invoking the ire of his countrymen. Now he hesitated for a moment, and then told the protestors that he would be happy to take up their cause, but only if they first attended his talk, a talk on the role of logic in human affairs.

Such begins "Logicomix: An Epic Search for Truth", a remarkable, unique and highly original graphic novel about Bertrand Russell and the foundations of mathematics. Who would have thought that something as profound and deep as the search for certainty in that most crystalline of human endeavors could be turned into a comic book. And yet Berkeley computer scientist Christos H. Papadimitriou and artist and author Apostolos Doxiadis have achieved this feat. Logicomix traces the history of the foundations of mathematics through the extraordinary life of perhaps its most famous and colorful proponent. The history of the foundations of mathematics is one of the most fascinating expositions of human thought in history, partly because it is the epitome of that ultimate human desire, a search for certainty in a world full of changes of fortune. The field itself is as old as the Greeks, but one would be hard pressed to find anyone else other than Lord Russell who witnessed so much development in the field, and who through his long and eventful life contributed so much to it. I thought that Logicomix, deftly making use of the modern medium of the comic book, provides the best introduction to the foundation of mathematics and its most famous philosopher that I have come across.

The comic book traces the foundations of mathematics through the life of Russell and begins with Russell retelling the story of his life to an audience in America on the eve of the Second World War. Russell's journey toward truth began as a child with a remarkable stay at Pembroke Lodge, where his grandfather, a past Prime Minister of Great Britain, held court with his puritanical and strict grandmother. The amiable and docile grandfather was stark contrast to his wife; sadly he did not live long enough to shield young Bertie from his overbearing grandmother. Privately schooling him at home through hand-picked teachers and drumming Bible lessons into his head, the grandmother actively tried to stifle every inquiry by Russell about his parents, which Russell later found was because of their rather scandalous lifestyle involving a three-way relationship which elicited howls in Victorian England. To escape from his grandmother Russell sought refuge in logic and mathematics. An inspiring teacher introduced Bertie to Euclid's theorems, and the airtight logic inherent in the structure of geometry took hold of Russell's mind like a spirit.

This refuge quickly turned into an all-consuming quest to find absolute certainty in an uncertain world. Russell became utterly fascinated by the fact that different "infinities" could be compared (as did I when I first read George Gamow's "One, two, three, infinity"). Logicomix has him visiting the great mathematicians Gottlob Frege and Georg Cantor who were responsible for crucial developments in the field. Mulling over their work in set theory and logic and inspired by Leibniz, Russell came up with Russell's paradox, a wondrous construct which haunted him to no end and further fueled his intense desire to end contradiction in mathematics. As a student at Cambridge Russell came in contact with Alfred North Whitehead. The result of his friendship and collaboration with Whitehead was one of the most famous works ever produced in the history of human thought, the Principia Mathematica, a book which Russell toiled over like a madman and which used 362 pages to prove 1 + 1 = 2. The book was partly a result of Russell listening to a talk by David Hilbert at the turn of the century in which Hilbert posed 23 famous unsolved fundamental problems in mathematics. Perhaps the loftiest goal advanced by Hilbert was to make mathematics completely self-consistent, so that there would be absolutely no contradiction and paradox and the entire grand edifice would follow precisely and logically from a few axioms. During the process Russell married and also fell for Whitehead's wife. Throughout his life Russell was an impetuous man, and like many other deep thinkers was often cruel and indifferent to his spouses and family.

The tome that Russell and Whitehead laboriously produced was so dense that nobody could critique it, and the two had to embarrassingly publish it themselves. To this day it is doubtful whether more than a handful have digested its contents; one person who Russell was convinced was the only person he had met who had read the work, was to prove his undoing. After this monumental work Russell felt a little burnt out and, as the drums of war sounded in Europe, took refuge again in pure thought and contemplation. He also became interested in social activism. He spoke against the war and went to jail for his protests. He decided on a bicycle ride that he no longer wanted to live with his wife. His greatest discovery however was yet to come.

Just before World War 1 a young man walked into his rooms at Cambridge. Ludwig Wittgenstein had an intensity and interest in philosophy that bordered on madness. A singular character of the twentieth century who gave away all his great wealth, deliberately asked to go to the front, and composed his greatest work lying in the trenches of the Great War, Wittgenstein saw the essence of philosophy and our perception of our world lying in language. With his arrival Russell started a new chapter in his life, but his admiration and buoyant enthusiasm for his disciple soon turned to chagrin when Wittgenstein who would never mince words started telling him that the entire basis of his Principia Mathematica was flawed. Deeply shaken, Russell emerged from the war more of a writer and a public intellectual, with his best years behind him

He still commanded respect of the highest degree, and was the patron saint of the famous Vienna Circle of the 1930s, whose philosophy of logical positivism strove to put the entire world into the constraints of science, and whose luminaries included Moritz Schlick, John von Neumann, and for a time as a sort of external admirer, Karl Popper. However, it was a diffident young member of the circle who was to signal the coup de grace for Bertrand Russell. In 1932, Austrian logician Kurt Gödel produced what is perhaps the single most profound and remarkable idea of the twentieth century, and perhaps of the entire history of intellectual thought. Gödel showed that even arithmetic, the basis of all mathematics and everything that follows, that purest of pure constructs, is essentially full of unprovable statements and paradoxes; it is essentially an incomplete system. Gödel's Incompleteness Theorem dealt a death knell to hundreds of years of fond hope that mathematics could be put on a complete, secure and logically perfectly consistent foundation. Along with Heisenberg's uncertainty principle and Einstein's principle of relativity, it signaled the end of certainty for human beings. In one fell swoop Gödel dashed the hopes of Hilbert, Russell and countless others away to oblivion. Right after Godel's talk, the famous polymath von Neumann simply said "It's over"; a more literal interpretation of the phrase has rarely been expressed in history. Godel's talk signaled the most significant break in Russell's life. After this, he never produced a single significant work in mathematics and spent the rest of his life campaigning against war and nuclear weapons, pontificating on everything from happiness to Christianity to marriage, writing best-selling books on all these topics, and becoming a signature symbol of the rational life for countless in the world. He remains one of the most important intellectuals in history.

So how is all of this captured in a comic book? The answer is, most impressively. There are moving passages where Russell literally goes insane trying to search for certainty in mathematics. The book also explores the troubling connection between genius and insanity, and especially between mathematical genius and insanity. Consider the evidence; Russell's son descended into schizophrenia and his brother committed suicide, Russell himself constantly worried that he was descending into madness in the great toil of his labors, Wittgenstein was nothing short of bona fide crazy and so was Georg Cantor, Gödel became so paranoid toward the end of his life in Princeton that he starved himself to death, convinced that the doctors were trying to poison him through his food. All these men were also acknowledged geniuses. Perhaps it is not a coincidence that John Nash, after he won the Nobel Prize, indicated that there was a deep connection somewhere between his schizophrenia and his remarkable mathematical achievements, accurately observing that neuroses and genius have been commonly connected with each other throughout history; according to Nash there might even be a necessary condition between genius and what we may perceive as irrational obsession.
"...rationality of thought imposes a limit on a person's concept of his relation to the cosmos. For example, a non-Zoroastrian could think of Zarathustra as simply a madman who led millions of naive followers to adopt a cult of ritual fire worship. But without his "madness" Zarathustra would necessarily have been only another of the millions or billions of human individuals who have lived and then been forgotten
Perhaps there is indeed a price that one pays for daring to soar into the highest heights of abstract human thought.

Logicomix explores this troubling association. The illustrations in it are endearing, although they could perhaps have been better (I was reminded of the marvelous artwork in "Watchmen"). Also importantly, although almost all the characters and events are real, their placement and chronology is often fictional. For instance Russell never actually met Hilbert, nor did he attend the devastating talk by Gödel. Plus, some of the dialogue is rather unlikely; for instance did Wittgenstein really call Hilbert a "bloody ass"? The book also perhaps lacked the kind of depth that I expected at first, but then it is geared toward a popular audience after all, and concepts like Russell's paradox, countable and uncountable infinity and Gödel's theorems are difficult for laymen to understand even when simplified. Nonetheless, these are minor quibbles which don't detract from the uniqueness and substance in the book.

Keeping true to its emphasis on logic, the book follows a recursive self-referential kind of theme and cycles between two stories. The major story is of Bertrand Russell and the foundations of mathematics, and the side story is the story of the writers planning the book. Both authors are Greek and their story takes a stroll, both literally and figuratively, through the scenic gardens of Athens and through the great plays of Sophocles and Aeschylus. The writers' and artists' story is interspersed with the main story line, even as they grapple with the concepts and their presentation.

The book ends with the artists and writers attending a performance of Aeschylus's The Eumenides in the great Acropolis of Athens. Aeschylus's play extolled logic and reason, qualities that Russell and many of the book's protagonists held dearer than life. In the end, logic and reason are not enough. But they are candles in the dark, threads of Ariadne, ephemeral wisps of the human mind that keep us from wandering too far from the straight line. For this we can be grateful to the men who spent their lives struggling for certainty, and we can continue to join them in their quest.

The return of the biochemists, but let's not forget selectivity

James Watson has an interesting op-ed in the NYT in which he advocates a return to biochemical methods for studying cancer. Watson thinks that while genetic studies of cancer will continue to provide important insights, we need to focus on the basic chemical reactions underlying cancer cell proliferation to come up with new therapies. I find this emphasis on chemistry gratifying, and others have also criticized the undue attention given to genetic studies of the disease. While such studies are and will remain undoubtedly important in elucidating the nature of cancer in individuals, it is only through detailed studies of the biochemical machinery of cancer cells that we can really find out the true nature of future targets for therapeutic intervention.

Watson also advocates emphasizing combinations of drugs instead of the largely single driver paradigm accepted currently. What is a little concerning for me that he does not really talk about toxicity and selectivity; there is usually a good reason why the FDA is loathe to approve combinations of chemotherapeutic agents that might cause lots of side effects. Watson seems to envisage an age when cancer, like heart disease and diabetes, might be able to be managed as a chronic disease. While this is a laudable goal, the nature of cancer compared to other chronic diseases is clearly different; it's far more invasive and involves a far trickier set of fundamental processes to understand and control (although diabetes is also not exactly the simple ailment it was initially thought to be)

Curiously, the example that Watson provides for emphasizing the biochemical basis of cancer seems to me to be potentially replete with selectivity issues. Consider this:
The idea that cancer cells may be united in having a common set of molecules not found in most other cells of our bodies was first proposed by the great German biochemist Otto Warburg. In 1924, he observed that all cancer cells, irrespective of whether they were growing in the presence or absence of oxygen, produce large amounts of lactic acid. Yet it wasn’t until a year ago that the meaning of Warburg’s discovery was revealed: The metabolism of cancer cells, and indeed of all proliferating cells, is largely directed toward the synthesis of cellular building blocks from the breakdown products of glucose. To make this glucose breakdown run even faster in growing cells than in differentiated cells (that is, cells that have stopped growing and taken on their specialized functions in the body), the growth-promoting signal molecules turn up the levels of the “transporter” proteins that move glucose molecules into cells.This discovery indicates that we need bold new efforts to see if drugs that specifically inhibit the key enzymes involved in this glucose breakdown have anti-cancer activity.
While this is definitely an interesting observation, I am not sure how productive in terms of selectivity and toxicity would targeting glucose metabolizing enzymes be. Glucose metabolizing enzymes constitute about as universal and fundamental a set of proteins as you could find in living organisms. Unless there are specific proteins with specific mutations present only in cancer cells, I can see a really big selectivity problem in targeting such proteins. Now of course we have had success in targeting all sorts of proteins that are expressed in both cancer and normal cells (consider kinases like VEGF), but still, it would be very interesting to see whether hitting such a basic part of the cellular machinery can actually provide tangible benefits.

In any case, the goals that Watson expounds on- a return to biochemistry, a balanced focus on pure and applied research, more flexible FDA guidelines for developing combination therapy, and the final goal of making cancer a chronic disease- are all sensible. The dream of winning a "war on cancer" is almost as unrealized today as it was in 1971, but maybe now we can feel confident that we are actually marching toward the front lines.

Water wires and hydrophobics

Quick survey of two interesting articles

P. Balaram's group at the Indian Institute of Science in Bangalore has turned a serendipitous observation into a nice study of a single file water wire inside a hydrophobic peptide nanotube. Based on the crystallographic data two models have been proposed for this wire. Such a structure can be the starting point for interesting MD simulations.
DOI: 10.1021/ja9038906

A group at Boston University and SLAC has found an explanation for the catalytic action of acetoacetate decarboxylase that refutes an elegant explanation provided by the famous late bioorganic chemist Frank Westheimer. Westheimer had proposed that a key lysine involved in nucleophilic attack was neutral because of proximity to another lysine; the electrostatic repulsion between two charged lysines would not favor the ionized state for both of them. The present group has obtained the crystal structure for the enzyme and finds that the two lysines are in fact far apart. Thus, electrostatic repulsion could not be responsible for the neutral nature of the lysine. Instead, using an elegant set of experiments, they find that it's being in a hydrophobic cavity that favors the lack of ionization.