Big Trouble in Little Synthetic Organic Chemistry?

Michael Rafferty who teaches in the Department of Medicinal Chemistry at the University of Kansas has a thought-provoking article in the Journal of Medicinal Chemistry in which he questions whether it's time to reinvent the model for training academic scientists in graduate programs to better equip them for the complexity and rigors of modern drug discovery. His target is the cadre of synthetic organic chemists who for decades have functioned as the indispensable backbone of the pharmaceutical industry. The title of the article - "No Denying It: Medicinal Chemistry Training Is In Big Trouble" - should be self-explanatory, in case anyone is wondering where exactly the author's sentiments lie on the topic.

Even today when you say that someone is a "medicinal chemist" it usually means someone who is trained as a synthetic organic chemist, who either goes into the lab and makes molecules himself or herself or who directs other people to do the same. Rafferty is asking whether the decades-old standard of recruitment into medicinal chemistry groups in the pharmaceutical industry - sound training in synthetic organic chemistry - might have to be revised.

Rafferty's basic point is that the kind of wisdom needed to find hits, advance them into lead compounds and finally into drug candidates does not really benefit from having a background in pure synthetic organic chemistry: it's much more about SAR analysis and understanding pharmacological properties. As he points out, the pharmaceutical industry has of course realized and maintained that all that wisdom can be learnt on the job. But Rafferty is not sure, and part of his skepticism comes from two revealing studies that basically showed two things: first, that even experienced medicinal chemists do not agree when picking good leads, and second, that most medicinal chemists even now don't really take optimum properties into account when designing compounds. The problem with lead picking is thus not synthesis, it's an ability to parse a complex landscape of multiple properties. Multiparameter optimization is still a beast whose footprints are rarely found among the thinking of medicinal chemists.

I think in general he's right. Advances in pharmacology, toxicology, computational chemistry and other fields over the past few decades have made it possible to both calculate as well as use property-based information in early stages of drug discovery. The article focuses on lipophilicity as one parameter which really should be considered on a regular basis but which isn't a lot of time. The problem is that a lot of synthesis has turned into a machine for cranking out molecules, so drug discovery scientists end up making molecules because they can be easily made. It's a theme that I and others have written about previously: making molecules is no longer the rate determining step in drug discovery: design is the important paradigm. One of the reasons is that CROs in China and India can now often make molecules as easily as in-house synthetic chemists. In one sense what the article is saying is because these CROs can now pick up the slack, chemists can use the time to more productively think about property-based optimization.

Now while I think it's cogent to include as much property information as possible in early drug discovery, it's worth noting that some of this information is dubious and some is valuable; the problem is that often it's hard to say which information would be dubious and which would be valuable. One of the reasons medicinal chemists disagree on compound selection is because gut instincts and experience can sometimes overrule what may seem like cogent limits on properties like lipophilicity. Nonetheless, having medicinal chemists who are tuned by default to thinking about properties would be a good idea. 

The second caveat I would apply to approaches like this is to not discount the value of a classical synthetic organic chemistry education. As has been amply demonstrated, making a complex molecule over a long period of time is more about handling setbacks, persisting with grit and developing the kind of character that can handle repeated failures than about making the molecule per se. And god knows we need all these qualities in drug discovery, a field which is literally a glutton for attrition and failure. In addition, even today there are molecules which often stump the best efforts of standard synthetic routes. Thus, it's always a good idea to have a core group of accomplished synthetic chemists in any program. In one sense the argument is really about degree, it's about what the size of this core should be, and the article argues that maybe it should be smaller than what has been traditionally thought.

Rafferty's main prescription is that graduate programs training chemists for drug discovery should now focus less on synthesis and more on multiparameter optimization and on other disciplines which can be used to think about properties upfront. The industry should do likewise in deemphasizing training of synthetic organic chemistry and emphasizing broader training in medicinal chemistry during recruitment. When I was in graduate school I was fortunate to study under a world-class medicinal chemist. Not only did his group teach students to think about properties at a relatively early stage, but more in line with what this article says, he also created a very good drug discovery course which gave students a solid flavor of the process and emphasized the contributions of other disciplines like pharmacology, formulation, metabolic studies and molecular modeling. Rafferty is encouraging more graduate programs to include such courses, and I definitely agree with him on this. The second prescription he has is to create more industry-academic partnerships in which industry contributes personnel, scholarships and funding to expose students to actual drug discovery and not just synthesis. A scheme like this has been in place in Europe for some time now.

Wikipedia seems to have caught up with the times when it defines medicinal chemistry as a discipline which 

"In its most common practice —focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology, enzymology and structural biology, together aiming at the discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities (biological activities and properties), i.e., understanding their structure-activity relationships (SAR)."

Perhaps academia and industry can embrace this definition more fully.

Image: Amriglobal

The rise of translational research and the death of organic synthesis (again)?

The journal ACS Neuroscience has an editorial lamenting the shortage of qualified synthetic organic chemists and pharmacologists in the pharmaceutical and biotech industries. The editorial lays much of the blame at the feet of flagging support for these disciplines at the expense of the fad of 'translational research'. It makes the cogent point that historically, accomplished synthetic organic chemists and pharmacologists have been the backbone of the industry; whatever medicinal chemistry and drug design they learnt was picked up on the job. The background and rigor that these scientists brought to their work was invaluable in discovering some of the most important drugs of our time, including ones against cancer, AIDS and heart disease.

The current fascination of applied basic science, i.e., translational science, to funding agencies, due in large part to the perception of a more immediate impact on human health, is a harbinger of its own doom. Strong words? It is clear in the last 10 years that research funding for basic organic chemistry and/or molecular pharmacology is in rapid decline. However, the quality of translational science is only as strong as the basic science training and acumen of its practitioners—this truth is lost in the translational and applied science furor. A training program that instills and trains the “basics” while offering additional research in applied science can be a powerful combination; yet, funding mechanisms for the critical first steps are lacking. 

Historically, the pharmaceutical industry hired the best classically trained synthetic chemists and pharmacologists, and then medicinal chemistry/drug discovery was taught “on the job”. These highly trained and knowledge experts could tackle any problem, and it is this basic training that enabled success against HIV in the 1990s. When the next pandemic arises in the future, we will have lost the in-depth know-how to be effective. Moreover, innovation will diminish.

I have a problem pushing translational research at the expense of basic research myself. As I wrote in a piece for the Lindau Nobel Laureate meeting a few years ago, at least two problems riddle this approach:

The first problem is that history is not really on the side of translational research. Most inventions and practical applications of science and technology which we take for granted have come not from people sitting in a room trying to invent new things but as fortuitous offshoots of curiosity-driven research...For instance, as Nobel Laureates Joseph Goldstein and Michael Brown describe in a Science opinion piece, NIH scientists in the 60s focused on basic questions involving receptors and cancer cells, but this work had an immense impact on drug discovery; as just one glowing example, heart disease-preventing statins which are the world’s best-selling drugs derive directly from Goldstein and Brown’s pioneering work on cholesterol metabolism. Examples also proliferate other disciplines; the Charged-Coupled Device (CCD), lasers, microwaves, computers and the World Wide Web are all fruits of basic and not targeted research. If the history of science teaches us anything, it is that curiosity-driven basic research has paid the highest dividends in terms of practical inventions and advances. 

The second more practical but equally important problem with translational research is that it puts the cart before the horse. First come the ideas; then come the applications. There is nothing fundamentally wrong with trying to build a focused institute to discover a drug, say, for schizophrenia. But doing this when most of the basic neuropharmacology, biochemistry and genetics of schizophrenia are unknown is a great diversion of focus and funds. Before we can apply basic knowledge, let's first make sure that the knowledge exists. Efforts based on incomplete knowledge would only result in a great squandering of manpower, intellectual and financial resources. Such misapplication of resources seems to be the major problem for instance with a new center for drug discovery that the NIH plans to establish. The NIH seeks to channel the newfound data on the human genome to discover new drugs for personalized medicine. This is a laudable goal, but the problem is that we still have miles to go before we truly understand the basic implications of genomic data.

It is only recently that we have started to become aware of the "post-genomic" universe of epigenetics and signal transduction. We have barely started to scratch the surface of the myriad ways in which genomic sequences are massaged and manipulated to produce the complex set of physiological events involved in disease and health. And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.

As an aside, that piece also mentions NIH's NCATS translational research center that has been the brainchild of Francis Collins. It's been five years since that center was set up, and while I know that there are some outstanding scientists working there, I wonder if someone has done a quantitative analysis of how much the work done there has, well, translated into therapeutic developments.

The editorial also has testimonials from leading organic chemists like Phil Baran, E J Corey and Stephen Buchwald who attest to the power of basic science that they discovered in their academic labs, power that they see almost disappearing from today's labs and funding agencies. This basic science which they have pioneered unexpectedly found use in industry. Buchwald's emphasis on C-N cross-coupling reactions is especially noteworthy since it was these kinds of reactions which really transformed drug synthesis and which led to Nobel Prizes for their inventors.

Baran's words are worth noting:

“It is ironic that a field with such an incredible track record for tangible contributions to the betterment of society is under continual attack. Fundamental organic synthesis has been defending its existence since I was a graduate student. If the NIH continues to disproportionally cut funding to this area, progress in the development of medicines will slow down and a vital domestic talent pool will evaporate leaving our population reliant on other countries for the invention of life saving medicines, agrochemicals, and materials.”

Baran is right that fundamental organic synthesis has been defending its existence for the last twenty years or so, but as has been discussed on this blog and in other sources, it's probably because it worked so well that it became a victim of its own success. The NIH is simply not interested in funding more total synthesis for its own sake. To some extent this is a mistake since the training that even a non-novel total synthesis imparts is valuable, but it's also hard to completely blame them. The number of truly novel reactions that have been invented in the last thirty years or so can be counted on one hand, and while chemists like Baran continue to perform incredibly creative feats in the synthesis of complex organic molecules, what they are doing is mostly applying known chemistry in highly imaginative new ways. I have no doubt that they will also invent some new chemistry in the next few years, but how much of it will compare to the fundamental explosion of new reactions and syntheses in the 1960s and 70s? I don't think this blog as well as others have denied the kind of training that synthetic organic chemistry provides, but I have certainly questioned the aura that sometimes continues to surround it (although it has declined in the last few decades) as well as the degree to which the pharmaceutical industry truly needs it.

To some extent the argument is simply about degree. The biggest challenge in most of the pharmaceutical company's postwar history was figuring out the synthesis of important drugs like penicillin, niacin and avermectin. In the era of massive screening of natural products, design wasn't really a major consideration. Contrast this period to today. The general problem of synthesis is now solved, and the major challenge facing today's drug discovery scientists is design. The big question today is not "How do I make this molecule?" but rather "How do I design this molecule within multiple constraints (potency, stability, toxicity etc.) all at the same time?" Multiparameter optimization has replaced synthesis as the holy grail of drug discovery. There are still undoubtedly tough synthetic puzzles that would benefit from creative problem-solving, but nobody thinks these puzzles won't yield to enough manpower or resources or would necessitate the discovery of fundamental new chemical principles. We of course still need top-notch synthetic organic chemists trained by top-notch academic chemists like Corey and Baran, but we equally (or even more) need chemists who are trained in solving such multiparameter design problems. Importantly, the solution to these problems is not going to come only from synthesis but also from other fields like pharmacokinetics, statistics and computer-aided design.

Another major point which I think the editorial does not touch on is the massive layoffs and outsourcing in industry which have bled it dry of deep and hard-won institutional knowledge. Drug discovery is not theoretical physics, and you cannot replenish lost talent and discover new drugs simply by staffing your organization with smart twenty-five year old wunderkinds from Berkeley or Harvard. Twenty or thirty years' experience counts for a hell of a lot in this industry; far from being a fever chill, age is a unique asset in this world. To me, this loss of institutional knowledge is a tragedy that is gargantuan compared to the lack of support for training synthetic organic chemists, and one that may have likely hobbled pharmaceutical chemistry for decades to come, if not longer.

Other than that the editorial gets it right. Too much emphasis on translational research can detract from the kind of rigorous, character-building experience that organic synthesis and classical pharmacology provide. As with many other things we need a bit of both, and some moderation seems to be in order here.

Lessons on management styles from Edward Teller, Hans Bethe and Robert Oppenheimer: A question of temperament

Oppenheimer entertaining at Los Alamos. He could be a
wonderful host.

March, 1943. War is raging across the European continent. The Nazis have faced two significant drawbacks in their relentless quest for racial and geographical conquest - one at El Alamein in North Africa and the other at Stalingrad in the Soviet Union - but Hitler's war machine shows no sign of stopping.

Meanwhile, halfway across the world, the largest and most secret scientific project in history is underway. A laboratory high up in the New Mexico mountains is being staffed with some of the world's best physicists, chemists, engineers, army officers and other personnel. Its express purpose is to build an atomic bomb before Hitler's scientists do so. The brilliant, conflicted Robert Oppenheimer, a polymath equally at home with nuclear physics and Sanskrit poetry, has been chosen to lead the project. He has tapped universities, industrial laboratories and other institutions across the country, recruiting the wealth of brilliant emigre scientists who have fled Nazi Germany for new shores; Adolf Hitler's greatest gifts to the United States. His well known powers of persuasion are on full display as he convinces friends and colleagues to join a secret project whose details he cannot yet fully divulge.

At the top of the list of scientists who Oppenheimer wants to recruit are the Hungarian-born Edward Teller and the German-born Hans Bethe. Both have arrived in the United States during the early 1930s and are now firmly ensconced in their scientific homes - Teller at George Washington University and Bethe at Cornell University. Both men who are still in their late 30s have already made significant contributions to physics. While Teller is more comfortable contributing to the more molecular and chemical aspects of the field, Bethe has uncovered the puzzle to one of science's oldest puzzles - the source of energy in the sun. Both men have been close friends for almost a decade, and Teller has been best man at Bethe's wedding. When the war started the duo wanted to help with the country's war effort, and even though they then lacked a security clearance, worked together on a theory of shock waves (ironically, the paper was classified after it was published, thus closing off access to its own authors).

Teller has also been one of the select key people responsible for sounding the alarm and alerting the government to the potential destructive applications of nuclear fission. Before Oppenheimer and Bethe had fully grasped the implications of a nuclear chain reaction, Teller had already driven his friend, Leo Szilard, to Albert Einstein's summer home in Long Island for what turned out to be a fateful meeting. Szilard had convinced his old friend Einstein to draft a letter to President Franklin Roosevelt; that letter had set the wheels of our nuclear future rolling toward their uncertain destination. Teller is thus one of three or four people, mostly Hungarian emigre scientists, to have been in the loop since the beginning as far as nuclear weapons are concerned. Along with Bethe, he has also been part of a summer study in Berkeley in 1942 led by Oppenheimer in which a handpicked group of physicists worked out the preliminary principles of a fission bomb. More than almost any other scientist and certainly more than Oppenheimer and Bethe, Teller has lived with the bomb since 1939. In fact Bethe did not even believe in an actual bomb until Teller showed him Enrico Fermi's famed nuclear reactor at the University of Chicago in late 1942.

Now, in March 1943, Oppenheimer is in the process of making some key strategic decisions that would shape the organization of the Manhattan Project. Among these decisions, few are as important important as deciding who to put in charge of the theoretical physics division at Los Alamos. It was theoretical physicists who first worked out the feasibility of a nuclear chain reaction, and it would undoubtedly be theoretical physicists who would continue to play a foundational role in the success of the project.

Teller, having lived and breathed the bomb, having contributed to both its politics and its science, having seen the vision of its even more powerful descendant (a bomb drawing its energy from nuclear fusion), thinks of himself as a logical choice to head the division.

Oppenheimer instead picks Bethe. It's an omission Teller will not forget.

The decision would have far-reaching consequences for the organization of the Manhattan Project. It would sow the seeds of discontent that would fracture the community of American physicists a decade later. And it would drive home the interplay between management philosophies and the mechanics of complex technological projects that is relevant to this day.

Why did Oppenheimer pick Bethe instead of Teller, and what does this decision say about his own management style and about those of Teller and Bethe? Teller and Bethe actually shared similar backgrounds. Both were born in the early years of the 20th century to cultured and educated middle class parents in Hungary and Germany. Both were seized by a passion for mathematics and physics, and studied the subjects under two world-class masters of the trade: Teller with Werner Heisenberg in Leipzig and Bethe with Arnold Sommerfeld in Munich. Coming as they did from enlightened Jewish families, both became ominously aware of the noose of fascism tightening around Germany in the early 1930s, and left for the United States where they established leading centers of physics research and study. 

Unlike many American scientists who had led relatively tranquil lives until then, Teller and Bethe were acutely sensitive to the spread of totalitarian regimes, and they grasped the political implications of the chain reaction before many others. But Teller who had seen both Nazi and Communist occupations was the more sensitive of the two, and this awareness led him to be an early proponent of American dominance in nuclear weapons. It was at a conference organized by Teller and his fellow physicist, Russian emigre George Gamow, that Niels Bohr brought news of fission to American shores at the end of 1938.

But there the similarities between the two physicists ended, and it was their differences that led to their very different and fateful life trajectories. Throughout his life Teller was known to be as volatile and moody as brilliant. He was often short-tempered and brooding and could not always be relied upon to carry calculations to their fruition; while to be fair to him he fully recognized this quality, most of his papers were with collaborators who made sure his calculations were fully fleshed out and correct. Teller later classified physicists as 'brick builders' and 'bricklayers', and called Bethe a 'builder of tiny bricks'. In his view his own skills as well as those of Oppenheimer were more suited to bricklaying. Interestingly, both men's bricklaying was more inspired than thorough, brilliant than always right. Their personalities too shared commonalities: both of them could be sharp-tongued, vicious and unpredictable, charming at one moment and cold at another.

Bethe in contrast was one of the most thoroughgoing scientists of the twentieth century, a steady rock of Gibraltar in both science and life. He could meticulously carry through every task to completion; in the 1930s he single-handedly authored a comprehensive survey of nuclear physics running to hundreds of pages that was so all-encompassing and up to date that it became known as 'Bethe's Bible'. He was also a universalist who could solve problems in almost any branch of pure or applied physics. Renowned for ploughing ahead through obstacles and going straight for the solution, his colleagues fondly called him "The Battleship". Stability and wholeness exemplified his personal and professional lives. Unlike Oppenheimer and Teller he was almost always mild-mannered and diplomatic, gentle if firm in his opinions.

Bethe (second from left) on a weekly mountain hike at
Los Alamos with other scientists such as Enrico Fermi.

Given these highly desirable personal qualities, it should come as no surprise that Oppenheimer picked Bethe instead of Teller to head the theoretical division. Bethe's take on the decision recognizes Teller's contribution but also drives home the requirements of the project at this stage and Bethe's suitability for these requirements.

"That I was named to head the division was a severe blow to Teller, who had worked on the bomb project almost from the day of its inception and who considered himself, quite rightly, as having seniority over everyone then at Los Alamos, including Oppenheimer. I believe I was chosen because my more plodding but steadier approach to life and science would serve the better at that stage of its development, where decisions had to be adhered to and detailed calculations had to be carried through, and where therefore a good deal of administrative work was inevitable...I believe Teller resented my being placed on top of him." 

Teller's assessment of Oppenheimer's choice is unsurprisingly critical: "Bethe was given the job to organize the effort, and in my opinion, in which I may well have been wrong, he over-organized it. It was too much of a military organization, a line organization."

Considering the fact that an explicit military style organization was rejected by Oppenheimer and weekly open seminars were set up to avoid compartmentalization, it's hard to substantiate Teller's opinion. Moreover, there is no evidence that Bethe's leadership of the theoretical division was anything but highly accomplished. Implosion, computing, the gun-type bomb design; everything proceeded smoothly under his direction, and during the process he also led outstanding theorists like Richard Feynman, Stan Ulam and Robert Serber.

Feeling sidelined by Bethe's appointment, nursing his passionate dream of a fusion weapon, increasingly loathe to do the kind of detailed calculations that Bethe's group was good at, Teller finally asked Oppenheimer to relieve him of his position in Bethe's division. He spend most of the rest of the war largely thinking about what became the hydrogen bomb. Unlike Bethe's role, Teller's role at Los Alamos was not indispensable. He made some valuable contributions in calculating the behavior of imploding plutonium cores at superdense pressures, but beyond this he seems to have mainly focused on his pet project and kept half a dozen Nobel Laureates awake at night by playing the piano.

Teller was an accomplished pianist

Strikingly, the one thing that stands out even from the embittered Teller's view of Los Alamos is his outstanding paean to Oppenheimer's leadership. Especially considering his growing animosity toward Oppenheimer and the general resentment he must have felt, this tribute is nothing short of profound and speaks to Oppenheimer's extraordinary role in making Los Alamos work.

"Throughout the war years, Oppie knew in detail what was going on in every part of the laboratory. He was incredibly quick and perceptive in analyzing human as well as technical problems. Of the more than ten thousand people who eventually came to work at Los Alamos, Oppie knew several hundred intimately, by which I mean that he knew what their relationships with one another were and what made them tick. He knew how to organize, cajole, humor, soother feelings - how to lead powerfully without seeming to do so. He was an exemplar of dedication, a hero who never lost his humanness. Disappointing him somehow carried with it a sense of wrongdoing. Los Alamos's amazing success grew out of the brilliance, enthusiasm and charisma with which Oppenheimer led it."

Not a bad tribute to a man who, when he was appointed to lead the project, left almost everyone astonished and dismayed because of his lack of experience. A man who had not even led a university department and who, in the words of one of his eminent colleagues, was "not fit to run a hot dog stand." A man who lacked a Nobel Prize but who was asked to lead a group of the world's most brilliant physicists, many of whom would either win or had already won a Nobel Prize. And yet Oppenheimer seems to have blown everyone away, and this includes men like Bethe and Fermi who were far from easily impressed; Bethe said that Oppenheimer was "intellectually superior" to everyone at Los Alamos.

Physicist Victor Weisskopf also attested to Oppenheimer's quality of instantly comprehending everyone's problem, inspiring them and seemingly being everywhere at once:

"He did not direct from the head office. He was intellectually and physically present at each decisive step. He was present in the laboratory or in the seminar rooms, when a new effect was measured, when a new idea was conceived. It was not that he contributed so many ideas or suggestions; he did so sometimes, but his main influence came from something else. It was his continuous and intense presence, which produced a sense of direct participation in all of us; it created that unique atmosphere of enthusiasm and challenge that pervaded the place throughout its time."

Oppenheimer's quintessential quality in doing all this seems to have been that of an actor, a man who could always wear whatever role history had chosen for him like the finely tailored three piece suits which his wealthy New York father's trust fund allowed him to indulge in. Some of his qualities had been on display when he was a highly regarded professor at Berkeley. It seemed he was acutely tuned to the wishes of everyone in the room. His martinis were spicy and his parties famous for their joie de vivre, and his immensely wide knowledge of esoteric subjects like Sanskrit and 17th century French poetry mostly seemed to amplify his charisma. There were a few people who found him pretentious, but these were in the minority; his students emulated his mannerisms. At Los Alamos he was at the peak of his powers, and his instant grasp of every technical and human matter, lightning fast mind and ability to connect with everyone's problems seem to have charmed even Edward Teller.

When the war ended, Bethe, Teller and Oppenheimer went their own ways. Oppenheimer carried over his Los Alamos charm to the leadership of the Institute for Advanced Study in Princeton, where he presided over the likes of Einstein, Godel, and von Neumann. Unfortunately the same powers of persuasion that had been so effective at Los Alamos did not work so well in Washington's corridors of power. Oppenheimer made enemies among politically well-connected men who accused him of hindering the country's hydrogen bomb program. Their unconstitutional tactics and allegations of guilt by association combined with his own equivocation on some of his left wing history and casual arrogance led to a hearing in 1954 and brought about his downfall. He spent the rest of his life speaking out on the philosophy of science and on the relationship between science and society, still efficiently leading the Princeton institute and evoking admiration around the world.

Bethe spent the rest of his career - all 60 years of it - at Cornell University. In the process he elevated Cornell to a world center of physics, advised half a dozen presidents on nuclear arms control, and kept on doing significant scientific work well into his 90s. The same qualities of steadfast stability and integrity that had been on display before served him exceedingly well during the politically tumultuous times of the Cold War and gained him the admiration and loyalty of scores of friends and colleagues. Just like Oppenheimer, he became a wise man whose advice fueled and reassured the hopes of others.

Teller's trajectory was less tranquil. He became the century's most vocal proponent of nuclear weapons and spent most of the next decade obsessing over the hydrogen bomb. He started a rival laboratory which competed with Los Alamos in building the next generation of lethal nuclear weapons, and his own brand of volatile proselytizing drew the admiration of a select group of mostly right wing scientists and politicians. Like Bethe he became advisor to conservative presidents and was a key force in advocating the ill-fated 'Star Wars' weapons system during the Reagan administration's tenure. Most importantly, his fateful testimony against Oppenheimer during Oppenheimer's security clearance hearing was considered an act of betrayal by the majority of the scientific establishment. While Teller lost many of his friends as the result of his testimony, this also allowed him to shed past aspects of his life and make new friends who were more sympathetic to his cause.

By most standards Teller with his volatile temperament and inability to carry projects through to their conclusion should have been largely unsuited for leadership. And yet there was another side of him, a side that could charm and display loyalty. This side could allow him to occasionally perform the function of inspiring others which most of us expect from a good leader. It was a side that was on full display when he became part of a team put together to design an intrinsically safe nuclear reactor, one whose safety features would depend not on the IQ of the operator but on the natural laws of physics. Teller was not technically the leader of the team. The leader was a physicist named Frederic de Hoffmann who along with Teller, recruited other brilliant scientists like Freeman Dyson.

In his biography, Dyson praised the fun and inspiration that Teller brought to the project. He had interacted with Teller at the University of Chicago before and liked Teller's playful attitude toward physics; Dyson thought Teller was a man who did physics for fun rather than glory. That attitude seemed to be particularly visible during the reactor project.

"Working with Teller was as exciting as I had imagined it would be. Almost every day he came to the schoolhouse with some hare-brained new idea. Some of his ideas were brilliant, some were practical and some were brilliant and practical. I used his ideas as starting points for a more systematic analysis of the problem...I fought with Teller as I had fought with (Richard) Feynman, demolishing his wilder schemes and squeezing his intuitions down into equations. Out of our fierce disagreements the shape of the safe reactor gradually emerged."

What lessons do Bethe, Oppenheimer and Teller hold for present day managers and CEOs? Today's CEOs face the same problem that Oppenheimer faced. They have to direct the work of a large group of scientists and other personnel of diverse skill sets and temperaments. They have to soothe egos and give everyone adequate freedom to pursue their ideas while still constraining them to meet project guidelines. They have to please shareholders and the general public. And they have to do all this without appearing to do so, without giving the impression of being heavy handed and dictatorial.

From Oppenheimer they can learn the value of keeping on top of all aspects of a project, whether managerial or technical, and for being informed enough about the role of every person to assure that person of their importance to the team. Like Oppenheimer at Los Alamos, they also have to inspire people to give their very best and to inject enthusiasm and hope into the work especially when things are not going well. And just like the technical seminars at Los Alamos which encouraged open and free discussion, they have to let everyone voice their opinions.

From Bethe they can learn the vital importance of being technically accomplished even as an administrator, and of the importance of perseverance and meticulousness. One of the laments about the present day pharmaceutical industry for instance is that too often you have CEOs with MBA degrees who have little understanding of the great technical challenges of biotechnology or drug discovery. A Hans Bethe would have combined deep knowledge of the science with a plodding and careful approach to getting things done. In addition he would have combined geniality with a gravity that was inspiring rather than intimidating or depressing. Just like Bethe, the best CEOs would combine technical excellence with outstanding managerial capabilities, and even CEOs without a technical background should learn enough of the technical material to empathize with the scientists in the trenches.

Teller exemplifies a different kind of lesson for today's CEOs. In an age where employees are often supposed to fit a particular mold, Teller provides a refreshing example of someone who constantly tried to think outside the box. People like Teller provide a unique function in an organization by frankly speaking their mind and pushing the envelope on what can be achieved. They are useful in shaking up everyone's conventional thinking and charting new directions. Not all their ideas work, but the ones that do can lead to novel horizons. They need to be guided by good managers like Oppenheimer and Bethe who can make them work harmoniously with other employees. These employees in turn must have the patience to actually implement the ideas of Teller-like minds. As long as the Tellers of the world are not allowed to go rogue, they can actually be valuable additions to all kinds of organizations. What matters is whether there is an Oppenheimer or Bethe to lead the way.

A Christmas message from Steve Jobs for our friends in pharma: 2015 version

I had posted this at the end of 2011, and it's both fascinating and highly disconcerting at the same time that Steve Jobs's lament about product designers' focus on sales instead of product design leading to the decline of specific industries rings even more true for pharma in 2015 than it did in 2011. If anything, the string of mergers and layoffs in Big Pharma during the last four years have underscored even more what happens when an industry starts to worry more about perception and short-term shareholder value than its core reason for existence. Most would agree that that's not how you innovate and that's not how you solve the really hard problems. Let's hope Steve will have a different message for us in 2019.

I am at the end of Walter Isaacson's excellent biography of Steve Jobs and it's worth a read even if you think you know a lot about the man. Love him or hate him, it's hard to deny that Jobs was one of those who disturbed our universe in the last few decades. You can accuse him of a lot of things, but not of being a lackluster innovator or product designer.

The last chapter titled "Legacy" has a distillation of Jobs's words about innovation, creativity and the key to productive, sustainable companies. In that chapter I found this:

"I have my own theory about why decline happens at companies like IBM or Microsoft. The company does a great job, innovates and becomes a monopoly or close to it in some field, and then the quality of product becomes less important. The company starts valuing the great salesmen, because they're the ones who can move the needle on revenues, not the product engineers and designers. So the salespeople end up running the company. John Akers at IBM was a smart, eloquent, fantastic salesperson but he didn't know anything about product. The same thing happened at Xerox. When the sales guys run the company, the product guys don't matter so much, and a lot of them just turn off."

Jobs could be speaking about the modern pharmaceutical industry. There the "product designers" are the scientists of course. Although many factors have been responsible for the decline of innovation in modern pharma, one of the variables that strongly correlates is the replacement of product designers at the helm by salespeople and lawyers beginning roughly in the early 90s.

There's a profound lesson in there somewhere. Not that wishes come true, but it's Christmas, and while we don't have the freedom to innovate, hold a stable job and work on what really matters, we do have the freedom to wish. So with this generous dose of wishful thinking, I wish you all a Merry Christmas.

Peter Thiel's interesting comparison of biotech with software

From Peter Thiel's "Zero to One" comes a comparison of the biotech and IT industries in which he presents a table contrasting the strategies and pitfalls of biotech vs IT. Thiel has said some odd things about chemistry and biotech before, so I was bracing myself for encountering some naiveté in his book. 

To my surprise the book largely makes for very thought-provoking and generally reasonable reading, even if you may not agree with all of Thiel's contrarian streak. It's rather refreshing to see him point some sharpened accusatory fingers at the current climate of technological optimism which equates things like globalization and Twitter with genuine technological breakthroughs (somewhat disingenuously but understandably he gives Facebook a free pass). Thiel's candidates for those rare soaring successes which truly changed the human condition are the Apollo program and the Manhattan project - while these do fit the description, he seems to ignore the fact that both of them were fueled by two wars and an intense fear of the Nazis and the Soviets, not exactly the kind of alignment of planets that comes around often and on demand. 

However his recommendations for building successful technology-based startups, while easier said than implemented, do seem to have some important ingredients for genuinely groundbreaking developments in the field. And here's his comparison of biotech with tech.

I actually agree with most of the contrast here except for a few things. The biotech approach is indeed 'indefinite and random' but it's not because we scientists actually enjoy throwing balls randomly at the wall - it's mostly because a lot of the 'definite and rational' approaches that we have tried over the last twenty years have worked in fits and starts at best. Biotech and drug discovery are too complex to be left to any one kind of approach so one has to try every possible strategy, from the ultra rational to the completely blind. 

I also resent Thiel's comparison of 'committed entrepreneurial hackers' in software with 'high-salaried, unaligned lab drones' in biotech and find it to be simplistic and smug: it's far easier to be a committed entrepreneurial hacker in IT, precisely because of the reasons cited above in the table - the possibility of success in a well-understood, relatively cheap and artificially engineered system. Similarly it's not like people are actively trying to shy away from the committed hacker model in biotech; it's because all the other factors listed above - heavy regulation, lack of funding and unrealistic, sky-high valuations, the fundamental complexity of biological systems etc. - simply make it harder for one to be so.

Nevertheless as illustrated below, there is a grain of truth in Thiel's diagnosis of many biotech and pharma companies. For some reason the pharmaceutical industry has lost the kind of frontier spirit that once infused it and which is now largely the province of swashbuckling Silicon Valley inhabitants. Whatever the hurdles and naiveté intrinsic to this spirit, it doesn't seem unreasonable to imagine that the industry could benefit from a bit more can-do, put-all-your-chips-on-the-table, entrepreneurial kind of spirit. It's something to ponder.

Drug costs and prices: Here we go again

Gilead's hepatitis C drug sofosbuvir (Sovaldi)

Misleading statements and conclusions regarding drug costs and prices are again being thrown around. It started with a post right here on Scientific American Blogs with the title "The Quest: $84,000 Miracle Cure Costs Less Than $150 to Make". As the title indicates, the post is about a new hepatitis C drug called Sovaldi developed by Gilead Sciences. The $150 was the manufacturing cost, the $84,000 was the price. The medicine is considered a real breakthrough and both Gilead and its shareholders have been rewarded with handsome profits during the last quarter. Sovaldi is also regarded as a first-in-class treatment for what was always considered a highly refractory disease.

To its credit the piece was measured and did make the point that the $84,000 was less than the hospitalization and liver transplant costs incurred by hep C patients until now. But unfortunately I think the title of the post was inevitably misleading because it made it sound like every extra penny in addition to the $150 was a profit margin. It also did not put the cost of developing the drug in the context of the very significant barriers to new drug development in the form of formidable scientific challenges, patent cliffs and FDA hurdles. The fact is that drug pricing is a very complex beast and while the system is definitely in need of reform and rational thinking, comparing actual drug production costs with price is basically a futile endeavor that is far more likely to mislead than to enlighten.

Was I mistaken in thinking the title was misleading? Not really. A day later, a Facebook post by Scientific American highlighting the same post ran with the headline "Profit Margin for Hep C Drug: Approximately one gazillion percent". This headline is egregiously, woefully wrong: the quarterly profit margin for Gilead was 44% during the last quarter, but the standard profit margins for pharmaceutical companies are about 20%. The title is grossly simplistic and says nothing about the cost of discovering (not manufacturing) the drug. Scientific American has 1.7 million followers on Facebook so this title is going to mislead quite a few, as is evident from the comments section of that post.

The bigger question to ask is, why are the profit margins so apparently high for Sovaldi? And that's a question the post did not address. The fact is that this class of hepatitis C drugs constitutes a real breakthrough in the treatment of the disease, and one that has been sought for decades. Until now the standard of treatment for the disease consisted of a combination of PEGylated interferon and ribavirin, a stop-gag measure that results in debilitating flu-like symptoms acutely affecting quality of life. The new class of medications directly targets a viral protein called a protease that the virus uses to make new copies of itself. It hits the source and is, by any definition, a vastly superior treatment compared to what we had before. For years the pharmaceutical company has been rightly lambasted for making "me-too" drugs, medicines that are marginally better than what existed on the market and whose high sales and profits are driven mainly by aggressive marketing rather than by real benefits. In this case we actually have a novel drug that provides real benefits, a significant achievement on the part of drug research that needs to be appreciated. Let's criticize high costs, but let's not ignore the improvements in quality of life for patients that simply did not exist before. And let's not fail to congratulate the teams of researchers who actually discover these novel medicines floating in a sea of me-too drugs; it's as big a testament to human ingenuity and perseverance as anything else in scientific history.

Does the price of Sovaldi sound high? Undoubtedly. But that's when I invoke my own "Law of Large Numbers" which roughly says, "The kind of reaction you have when you see a large number seldom has much to do with what that number really means". As with many other numbers we have to put the price in context. As the original post notes, it's still lower than what the price of hospitalization and liver transplants would have been. If you have insurance then your insurance company - encouraged largely by this comparative calculation - should take care of it. Is it still not accessible to a vast number of people in poor countries? Of course; I would like that to happen as much as anything else, especially since hep C is still a disease that puts most of its burden on the poor. But it's at least accessible to a few people whose quality of life will now be much better and it's still better than nothing. That's an important step in the right direction. As happened with AIDS drugs, at some point the medication will in fact become cheap enough, especially when generics take its place a few years down the line. But none of this would have happened if pharmaceutical companies stopped making profits and had to shut down because they couldn't recover R&D costs.

The most important context we need to understand again is one that is often neglected: a comparison of the price with the high cost of drug discovery and development rather than manufacturingwhich is always going to be low. The bare fact of the matter is that it takes about $5 billion to develop a new drug and this has little to do with profit margins. As a hypothetical example, even if the profit margin on Sovaldi was 0% it would still cost about $50,000 dollars and you would still hear a lot of criticism. The cost of a drug is not $5 billion because there's much profit to be made - as I indicated above pharmaceutical profit margins are about 20% - but because drug discovery is so hard. One can quibble about the exact number but that would only serve to obscure the real challenges. I have written four posts on the complexities of drug discovery science and I intend to write more. The reality is that Sovaldi would not have been invented in the first place had companies like Gilead not put enough money from profits into the R&D that went into its development. And sure, some pharmaceutical CEO's make obscene bonuses and and we need to have important conversations about that, but even that part does not significantly contribute to the high costs.

One thing I find amusing is that the same critics who talk about high drug costs also seem to have some kind of an exaggerated picture of drug company scientists as infallible oracles, discovering drugs with their left hand and then sitting back in their sleek sofas, cackling and waiting for the shower of green. But the truth could not be more different. As a drug discovery scientist I have very few moments when I actually think I am any closer to discovering even a new lead, let alone a new drug (and sadly no, I am also not rolling around in money). As I have quoted another scientist in one of my posts, the reason why drugs cost so much is not because we are greedy, it's because we are stupid. A lot of the times we feel the way Yamamoto must have felt in 1943, knowing that he was about to fight a war of attrition that he could not possibly win.

Drug discovery is one of the most wasteful research activities on the planet and it's all because most of the times we have no idea of how to go about discovering a new drug or what's going to happen when we put it inside the human body. The complexities of human biology thwart us at every stage and luck plays an inordinately large role in our success. Even basic issues in drug discovery - understanding how drugs get past cell membranes for instance - are generally unsolved problems, and the profligate inefficiency of the process would truly shame us if we knew how to do it better. The path from a new idea in pharmaceutical research to an actual drug is akin to a path trodden by a blind man along the edge of a cliff at night; any survival, let alone success, seems like a miracle in retrospect. No drug scientist will admit it, but every drug scientist crosses his or her fingers when a new drug makes it to the market because we are just not smart enough to figure out exactly what it will do in every single patient. That is why most drugs fail in advanced clinical trials, when hundreds of millions of dollars have already been spent on them.

The scientific challenges in drug discovery are a major reason why drugs are so expensive. Of course manufacturing costs are going to be low; once you have wasted so much money on R&D and hit the right solution you only have to make the actual substance (and I don't say "only" lightly here). Would one also decry the low manufacturing costs of integrated circuit boards and ignore the massive, extensive, often unsuccessful developments in R&D that resulted in the system being able to beat Moore's Law? It's the same for drug discovery, except that in this case nobody has any idea how we would even start to approach Moore's Law, let alone beat it. So criticize drug costs and CEO bonuses and profits all you like - and continue to have a much needed debate about healthcare costs in this country - but keep in mind that those numbers are more likely to wildly obfuscate than educate if you take them at face value.

Barry Werth on the cost of new drugs

Barry Werth who wrote the swashbuckling book about the creation of Vertex (sequel out in February) has an excellent piece (also highlighted by @Chemjobber) in the MIT Technology Review about the cost of new drugs. He asks a question which is usually the first question that any pharmaceutical scientist who tells a layperson what he/she does for a living encounters: Why do drugs cost so much? (The next question is usually "Why do drugs have so many side-effects?")

Werth compares two drugs to illustrate the strange world of drug pricing and the moral dilemma that riddles that world: Vertex's cystic fibrosis drug Kalydeco and Regeneron/Sanofi's cancer drug Zaltrap. Here's the problem: Kalydeco is a breakthrough medicine which has breathed completely new life into the treatment of a disease for which no effective therapies existed before. It costs about $300K a year. Zaltrap increases the median lifespan of patients with advanced colorectal cancer by 1.5 months. And it costs $11K a month. Now is it surprising why people are so critical of the pharmaceutical industry? I would be too, if I was constantly bombarded by news of "breakthroughs" like Zaltrap.

The reason why this whole thing seems so absurd is that the actual price of a drug often sounds almost completely arbitrary. As Werth notes, Zaltrap caused an outrage among patients and physicians, leading a group led by doctors from Memorial Sloan Kettering Hospital to protest the price of the drug in an unprecedented NYT Op-Ed. In response Sanofi cut the price of the drug by half through rebates and other schemes. If a drug company can reduce the price of a medication by 50% just like that without major catastrophe, it really makes you ask what the "true" price of the drug is.

In any case, the whole thing is definitely worth a read, especially in an age where drugs are paradoxically going to start becoming more effective - even as they are targeted toward select, small patient subpopulations - and simultaneously more expensive.

John LaMattina on the new NIH drug discovery center

There's a post by ex-Pfizer research chief John LaMattina about the new NIH drug discovery center, and predictably he does not seem too happy about it. While the initial center was supposed to be all about translational research, the latest idea is to use the NIH's resources for "repurposing", or discovering new indications for old drugs.

LaMattina echoes some of the dissatisfaction that a few of us have earlier expressed about this idea. The main point here is that the NIH should not be in the business of discovering new drugs; it should be in the business of doing the basic biological research that may enable such potential discoveries. In fact one might argue that the biggest challenge facing drug discovery today is an incomplete understanding of the complexities of the biology underlying major diseases. Just think of the conflicting data and the complications that have emerged from attacking beta amyloid in Alzheimer's disease for instance. There's hardly any doubt that better treatments can only result from a proper evaluation of the basic biology of disease. And it's also clear that this understanding is not going to come from industry. Only the NIH and academic labs can accomplish this, and spending money on therapies when it could more fruitfully be spent on such fundamental studies seems to be folly. So ironically, funding drug discovery may hinder an understanding of the very foundations that may truly enable it.

Nor is what the NIH doing truly novel. As LaMattina points out, repurposing is an obvious route and an attractive one at that, since finding a novel indication for an old drug means that the drug has already run the gauntlet of FDA approval. So we can bet that industry would have worked on repurposing if they could possibly do it. Now granted, there's always going to be compounds that were dropped for financial or project-related reasons which may be potentially valuable agents for all kinds of conditions. And we can also assume that these numbers might have grown during the last few years when projects have been axed and personnel laid off in increasing numbers. But what are the chances that hidden among those dusty vials on the shelf is the next cure for pancreatic cancer? Of course one may never find out if one does not look, but the NIH's announcements make it sound like there's pure gold among those neglected compounds, waiting to be discovered. The fact is that examples of truly repurposed drugs are quite few; as LaMattina points out, even the two repurposed drugs cited by NIH director Francis Collins are drugs for which the "other" indications were rather obvious based on their mechanism of action. Repurposing by itself is not entirely misguided, but repurposing at the cost of basic biomedical research draws resources away from more worthy endeavors.

Thus, by and large LaMattina's arguments seem to be cogent. Unfortunately the indignation on the other side of the equation is not as justified as it sounds. LaMattina refers to a statement by legendary Merck ex-CEO Roy Vagelos along the lines that if there was real benefit to something that the NIH wants to do, pharma would already be doing it. Sadly this is increasingly not the case. In the last few years pharma has defined "benefit" based on whether something's going to affect the next quarter's profits. Working on Alzheimer's disease and other CNS disorders where the rewards are long-term but undoubtedly stellar is no longer considered a beneficial strategy. So we have a situation here where industry is rightly advising the NIH to work on basic research rather than drug development, but not committing itself to its part of the deal. As well-intended as it may be, the impact of your advice gets blunted a little if you stop looking in the mirror.

If you want them to collaborate, you should let them collaborate

The past few months have seen a string of stories about major drug makers shutting down their neuroscience research, a move that seems to be the exact opposite of what they should be doing, even in times of economic distress. Many neurological disorders are the very definition of unmet needs, and one would think that pharma would pump in massive, long-term resources into Alzheimer's disease research with alacrity. But such are the times we live in.

A recent commentary in Nature brought this topic to my attention. The authors are from the ETH in Zurich and, after lamenting the withdrawal of drug companies from neuroscience research, they try to propose a way forward in the form of increased industry-academia collaboration. Whether this increasingly fashionable brainwave will work is still unknown. But one paragraph in particular caught my attention:

To reinvigorate the field and avoid repeating past problems, more exchange should be fostered between basic and clinical scientists. When spinal-cord researchers began organizing retreats and workshops to bring together basic researchers and clinicians, they saw first-hand how little each side knows about how the other works. The mutual lack of knowledge was huge; each side had completely different language to describe the same scenario.

But this is exactly what the drug companies should have been doing, putting the basic and clinical scientists under one roof. It's lamentable that they need to have special retreats for bringing these folks together. The reason why this part jumped out at me was because I have just started reading Jon Gertner's great new book about Bell Labs. Many reasons contributed to the institution's phenomenal success, but one notable factor was the concentration of the purest and the most applied scientists under one roof. The firm's pioneering research director Mervin Kelly carefully planned the physical layout of the lab so that everyone, irrespective of specialty or research level, was a stone's throw from everyone else. That way even the purest mathematician was forced to interact and learn from the most hands-on engineer. Research and manufacturing were geographically indistinguishable. There was a very long seven-hundred foot corridor with open offices and labs on each side. It was impossible to walk down the hall and not learn something from someone working in a very different field.

That formula still seems entirely relevant, especially when research has become highly complex and multidisciplinary, and it just seems relatively unproductive to hold special workshops and retreats so that the pure folks can talk to the applied folks. Sure, retreats and workshops can help, but as Bell demonstrated, there's nothing more productive than having the guy who wrote the book on spinal cord injury surgery just down the hall from the guy who wrote the book on dopamine antagonists. Startups and small companies can do this to some extent but they certainly don't have Big Pharma's resources.

Big Pharma of course seems to have stopped listening.

Image source (Update: As a commentator points out, the photo is not from Bell Labs but from Allied Chemicals. I can imagine the corridor at Bell looking quite similar though).

The unstoppable Moore hits the immovable Eroom

Thanks to Derek I became familiar with an article in the recent issue of Nature Reviews Drug Discovery which addresses that existential question that has been asked by so many plaintive members of the scientific community; why has pharmaceutical productivity declined over the last two decades with no end to this attrition in sight?

The literature has been awash in articles discussing this topic but this piece presents one of the most perceptive and well-thought out analyses that I have recently read. The paper posits a law called "Eroom's Law", the opposite of Moore's Law, which seems to chart the regress in drug approvals and novel medicines contrary to Moore's bucolic vision of technological progress. The authors wisely avoid recommending solutions, but do cite four principal causes for the decline. Derek is planning to write a series of undoubtedly insightful posts on these causes. But here I want to list them especially for those who may not have access to the journal and discuss one of them in some detail.

The first cause is named the 'Better than The Beatles' effect. The title is self-explanatory; if every new drug that has to be developed is required to be better than its predecessor which has achieved Beatle-like medical status, then the bar for acceptance of this drug is going to be very high leading to an expensive and resource-intensive discovery process. An example would be a new drug for stomach ulcers which will have to top the outstanding success of ranitidine and omeprazole; unlikely to happen. Naturally the bar is very high for certain areas like heart disease with its statins and hypertension with its phalanx of therapies, but the downside of this fact is that it stops novel medication from ever seeing the light of day. The Better-than-The-Beatles bar is understandably lower for a disease like Alzheimer's where there are no effective existing therapies, so perhaps drug developers should focus on these areas. The same goes for orphan drugs which target rare diseases.

The second reason is the 'cautious regulator' with the title again being self-expalantory. The thalidomide disaster in the 1960s led to a body of regulatory schedules and frameworks that today severely constrain the standards for efficacy and toxicity that drugs have to meet. This is not bad in itself, except that it often leads to the elimination of potential candidates (whose efficacy and toxicity can be modulated later) very early on in the process. The stupendously crushing magnitude of the regulatory schedule is illustrated by the example of a new oncology drug, whose documentation if piled in a single stack would top the height of the Empire State Building. With this kind of regulation, scientists never tire of pointing out that many of the path breaking drugs approved in the 50s and 60s would never survive the FDA's gauntlet today. There's a lesson in there somewhere; it does not mean that every new compound should be directly tested on humans, but it does seem to suggest that maybe compounds which initially appear problematic should be allowed to compete in the race a little longer without having to pass litmus tests. It's also clear that, as with the Beatles problem, the regulatory bar is going to be lower for unmet needs and rare but important diseases. An interesting fact cited by the article is the relatively low standards for HIV drugs in the 90s which were partly a result of the intense lobbying in Washington.

The third reason cited in the article concerns the 'throw money at it' tendency. The authors don't really delve into this, partly because the problem is rather obvious; you cannot solve a complex, multifaceted puzzle like the discovery of a new drug simple by pumping in financial and human resources.

It's the fourth problem that I want to talk about. The authors call it the 'basic science-brute force' problem and it seems to point to a rather paradoxical contradiction; that the increasingly basic-science and data-driven approaches in the pharmaceutical industry over the last twenty years might have actually hampered progress.

The paradox is perhaps not as hard to understand as it looks if we realize just how complex the human body and its interactions with small molecules are. This was well-understood in the fifties and sixties and it led to the evaluation of small molecules largely through their effect on actual living systems (which these days is called phenotypic screening) instead of by validating their action at the molecular level. A promising new therapeutic would often be directly tested on a mouse; at a time when very little was known about protein structure and enzyme mechanisms, this seemed to be the reasonable thing to do. Surprisingly it was also perhaps the smart thing to do. As molecular biology, organic chemistry and crystallography provided us with new, high-throughput techniques to study the molecular mechanism of drugs, focus shifted from the somewhat risky whole-animal testing methods of the 60s to target-based approaches where you tried to decipher the interaction of drugs with their target proteins.

As the article describes, this thinking led to a kind of molecular reductionism, where optimizing the affinity of a ligand for a protein appeared to be the key to the development of a successful drug. The philosophy was only buttressed by the development of rapid molecular synthesis techniques like combinatorial chemistry. With thousands of new compounds and fantastic new ways to study their interactions at a molecular level, what could go wrong?

A lot, as it turns out. The complexity of biological systems ensures that the one target-one disease correlation more often than not fails. We now appreciate more than ever that new drugs and especially ones that target complex diseases like Alzheimer's or diabetes might be required to interact with multiple proteins for being effective. As the article notes, the advent of rational approaches and cutting-edge basic science might have led companies to industrialize and unduly systematize the wrong part of the drug discovery process - the early one. The paradigm only gathered steam with the brute-force approaches enabled by combinatorial chemistry and rapid screening of millions of compounds. The whole philosophy of finding the proverbial needle in the haystack ignored the possible utility of the haystack itself.

This misplaced systematization eliminated potentially promising compounds with multiple modes of action whose interactions could not be easily studied by traditional target-based methods. Not surprisingly, this led to compounds with nanomolar affinity and apparently promising properties often failing in clinical trials. Put more simply, the whole emphasis on target-based drug discovery and its attendant technologies might have resulted in lots of high-affinity, tight binding ligands, but few drugs.

Although the authors don't discuss it, we continue to have such misplaced beliefs today by thinking that genomics and all that it entails could help us to rapidly discover new drugs. As we constrain ourselves to accurate, narrowly defined features of biological systems, it deflects our attention from the less accurate but broader and more relevant features. The lesson here is simple; we are turning into the guy who looks for his keys under the street light only because it's easier to see there.

The authors of the article don't suggest simple solutions because they aren't any. But there is a hint of a solution in their recommendation of a new post in pharmaceutical organizations colorfully titled the Chief Dead Drug Officer (CDDO) whose sole job would be to document and analyze reasons for drug failures. Refreshingly, the authors suggest that the CDDO's renumeration could come in the form of delayed gratification a few years down the line when his analysis has been validated. It is hoped that the understanding emerging from such an analysis would lead to some simple but hopefully effective guidelines. In the context of the 'basic science-brute force' problem, the guidelines may allow us to decide when to use ultra-rational target-based approaches and when to use phenotypic screening or whole animal studies.

At least in some cases the right solution seems to be clear. For instance we have known for years that neurological drugs hit multiple targets in the brain. Fifty years of psychiatrists prescribing drugs for psychosis, depression and bipolar disorder have done nothing to hide the fact that even today we treat many psychiatric drugs as black boxes. With multiple subtypes of histamine, dopamine and serotonin receptors activated through all kinds of diverse, ill-understood mechanisms, it's clear that single target-based approaches for CNS drug discovery are going to be futile, while multiple target-based approaches are simply going to be too complicated in the near future. In this situation it's clear that phenotypic screening, animal studies, and careful observations of patient populations are the way to go in prioritizing and developing new psychiatric medication.

Ultimately the article illuminates a simple fact; we just don't understand biological systems well enough to discover drugs through a few well-defined approaches. And in the face of ignorance, both rational and "irrational" approaches are going to be valuable in their own right. As usual, knowing which ones to use when is going to be the trick.