The Billion-Dollar Heartbreak

Fellow blogger, current colleague and friend Keith and I spent an enjoyable evening two days ago at an event which I wouldn’t have anticipated if you had asked me about it before: a sort of fund-raiser/pitch for a movie based on Barry Werth’s book about the creation of Vertex Pharmaceuticals, “The Billion-Dollar Molecule”.

I have to confess being blown away by the book when I first read it in graduate school. The breathless descriptions of the science and the scientists, the glitter of structure based drug design and and the sheer effort of drug discovery really left an impression of me. After working in the reality of drug discovery for a decade or so, I perhaps don’t feel as breathless as I did the first time around. Yes, drug design is exciting, but no, most of the work that we do in the field is far more mundane and boring than what appears in the book (and this is true for the rest of science). And the science of drug design is also far more sobering and limited than what it seemed in the 80s. Nonetheless, if there was a short list of books on biopharmaceutical research that would seem likely to transition to the silver screen, Werth’s volume would probably be on top of that list for me because of its sheer novelistic qualities.

The event itself featured a panel of three scientists and one lawyer who were present at the creation and subsequent developments at Vertex in the late 80s and early 90s: Manuel Navia, Mark Murcko, Roger Tung and Ken Boger would all be familiar to anyone who has read the book. The event was fittingly organized in the old Vertex building near 3^rd street in Cambridge, and not surprisingly it drew a lot of Vertex old timers which inadvertently turned it into a Vertex reunion. An ancillary side session featured a silent auction for photographs taken by Nobel Laureate (and Keith’s graduate school co-advisor) Wally Gilbert who was also there.

Much of the discussion really focused on the scientists’ views of what they thought should really come across from the movie, and I largely agreed with their suggestions. The overwhelming consensus was that the movie needs to communicate the sheer and appalling rate of failure – probably unprecedented relative to any other industry – that we in pharma and biotech have to deal with. 99% of everything that we do, right from the most basic research to the most applied clinical work, simply fails. Almost all of us go through our entire careers without contributing to the discovery of a single important drug. And it all fails because of one overriding factor which I and others have discussed before – our ignorance of basic biology and human disease. It seems that this is probably the preponderant feature of drug discovery that simply fails to make its way across to the public: almost every argument that the public makes against drugs, from their high cost to their side effects, boils down to the simple fact that we simply don’t know how to do it any better. I agree with the participants that if there’s one message that really needs to shine forth from any movie about drug discovery it needs to be this one about attrition, failure and ignorance. Not exactly an uplifting message, but essential for an accurate perception of drug research.

One of the panelists also raised the very relevant issue of how to accurately strike a balance between the sheer tedium of everyday research and the occasional breakthroughs that permeate the entire practice of science. If there’s one flaw in “The Billion Dollar Molecule” it’s that it seems to downplay the former aspect and really emphasize the latter. Yes, drug discovery is a high stakes enterprise and yes, the scientists who do drug discovery can have titanic-sized egos and can have their emotions running high and wild and yes, the science of drug design can sometimes seem as exciting as the ‘science’ in ‘Avatar’, but for every one of these facts the opposite is also true: drug discovery scientists are normal people with a spouse and kids and a mortgage, and 90% of the science of drug discovery is like 90% of science in general – incremental, unflashy and mundane; less Holmesian detective work and more 9 AM-5 PM office job. What the book did was compress all of this into a heady, heroic 350-page narrative, and one wonders if the movie should try to do the same. Another way to tackle the issue might be to make a documentary that’s more realistic, although admittedly it would then be harder to get Kevin Spacey to play Josh Boger (one of the more fanciful suggestions bandied about).

Curiously, the entire project that the book hinges on - the quest to find a breakthrough immunosuppressant - actually failed because they were looking at the wrong target (the curse of biological ignorance struck again), so communicating the reality of the fantastic failures that emerge from a fantastic effort should come naturally to the narrative in the movie. It's a testament to the vision and resilience of the company's BOD and management that they successfully pivoted away from this major failure. It also seems that the movie should heavily capitalize on the sequel to “The Billion-Dollar Molecule” (“The Antidote”): while that’s far less sensational, it deals with the two breakthrough projects at Vertex (hepatitis C and cystic fibrosis) that actually succeeded in a very big way.

Notwithstanding the challenges, I have to say I am game for any cinematic, literary or other endeavor that makes the science, art and business of drug discovery more comprehensible to the layman. There are few activities both more profoundly misunderstood and more fundamentally important to human society than the creation of new entities that save or improve the lives of millions, and any project whose express goal is to make the general public appreciate this reality – even at the expense of some glamorization – would be one I fully support. Good luck to the film-makers!

Big things come in little packages: How Willis Lamb's tiny measurement revolutionized 20th century physics

It's the end of World War 2. Scientists and especially physicists have spent the last four years working on military hardware, culminating in radar and the atomic bomb. Many of these talented men and women are eager to go back to their university campuses and resume normal civilian life; some of them are distraught at their role in engineering such horrific weapons and want to return to the carefree life of fundamental physics research which they knew before the war.

To reconnect the country's leading physicists with each other and with the great research problems which they left behind, the National Academy of Sciences decides to organize a series of conferences on the frontiers of physics. It's not hard to decide who should lead these conferences. Robert Oppenheimer has just led the wartime Los Alamos laboratory which produced the first nuclear weapons to high fame and glory. At Los Alamos and before at Berkeley, Oppenheimer has been widely acknowledged as the founder of the modern school of American theoretical physics and a man whose intellectual mastery of a wide array of disciplines is unmatched. It seems natural to have Oppenheimer be in charge of this post-war re-organization of physics in the country.

Oppenheimer and the National Academy of Sciences put together a list of the scientists they want to invite. Except for the famous Solvay Conferences organized in Europe during a more peaceful time, it's hard to think of another scientific gathering that attracted such an unprecedented constellation of talent. A dozen or more of the attendees have already won Nobel Prizes or would go on to win them; some for work which they would present during the conferences. The list of names is an all-star list in every respect: Hans Bethe, Enrico Fermi, Isidor Rabi, Robert Serber, Victor Weisskopf, Edward Teller, Abraham Pais, John Wheeler, Richard Feynman, Julian Schwinger and Hendrik Kramers. The meeting brings together both the new stars and the old guard (I mentioned Bohr and Dirac earlier, but as M Tucker points out in the comments section, they were present at a later conference: more on this equally interesting meeting in a future post).

Some of the participants at the Shelter Island conference:
Lamb (far left), Oppenheimer, (on arm rest) Feynman (seated
and writing) and Schwinger (second from right)

The first conference takes place in June 1947 at a tiny island called Shelter Island, situated in the jaws of the Long Island crocodile. The exclusive list of attendees gets escorted by a special police escort through major towns during their bus ride. Their selection as attendees, the cutting edge topics at the conference and Oppenheimer's leadership all make it clear that the center of physics has decidedly shifted from Europe to the United States. Shelter Island would go down in history as one of the most important conferences in the history of 20th century physics, but the participants don't quite know it yet.

One attendee in particular, a young protege of Oppenheimer's from Columbia University, is perhaps not as well known as the others: Willis Lamb. Lamb comes from a robust working class household and has obtained both his undergraduate and graduate degrees at Berkeley. Right before the war he got married to a German emigre, and as the story goes, for some time the authorities forbade him from walking on the beach and confiscated his shortwave radio for fear that he might be sympathetic with his wife's German compatriots and might try to communicate with German submarines. During the war he has worked on microwave radar with Rabi and others at Columbia. What is also perhaps not as well known is Lamb's versatility as a physicist. He is an experimental physicist now, but he got his PhD with Oppenheimer at Berkeley in the 1930s. This makes him one of the few scientists around to excel in both theoretical and experimental physics. Lamb's presence is already consequential since the participants at Shelter Island are pondering a discovery he made right after the war: a discovery important enough to be enshrined with his name - the Lamb Shift. The Lamb Shift will herald a new age in physics.

To understand the Lamb Shift, let's descend deep into the world of the atom with its electrons, protons and neutrons. Let's look at the simplest atom, hydrogen. As most of us have learnt in high school and college, electrons exist in energy levels defined by atomic orbitals. Each electron is defined by four so-called quantum numbers. In hydrogen, for the principal quantum number 2, the lone electron can exist in two orbitals defined by the secondary or angular quantum number: 2S and 2P. During the 1930s, in the heyday of quantum mechanics, the great English physicist Paul Dirac had worked out that the energy of the electron in these levels should be the same. Dirac's theory which also achieved the feat of marrying Einstein's special theory of relativity to the new quantum mechanics was the spectacular culmination of a decade of revolution in physics, a revolution led by men like Heisenberg, Bohr and Born, going back all the way to Einstein and Planck at the beginning of the century. The Dirac theory promises to be the icing on the cake of quantum mechanics, and its prediction of equivalent energies for the 2S and 2P orbitals of the hydrogen atom seems solid and indisputable.

But now, Willis Lamb has found that the two levels are different in energy by a tiny amount. It's an amount tiny enough to be undetectable except by the most sophisticated techniques and experimenters, but it causes shock waves in the world of physics and cries for an explanation. The Lamb Shift would be to quantum mechanics what the perihelion of Mercury was to astrophysics. Lamb with his background in both experimental and theoretical physics is in a unique position to measure this difference. He knows enough quantum mechanics to understand Dirac's theory of the electron. He knows enough atomic spectroscopy to understand the experimental underpinnings of the two energy levels. And, thanks to his work with microwave radar during the war, he knows enough microwave spectroscopy in particular to use microwaves to delicately probe the energies of the two levels. Microwave radiation may seem intense - it can sear your food to a crisp after all - but microwaves are actually pretty low in frequency compared to ultraviolet or visible light. By wielding them the way a surgeon wields a fine scalpel, Lamb and his graduate student Robert Retherford have probed the 2S and 2P levels of the hydrogen atom without injecting enough energetic radiation to cause other spectroscopic transitions and contaminate the experimental output. The number he gets is 1000 megahertz, a number which is a fraction of the kinds of frequencies emitted in spectroscopy and which could only have been determined by an experimenter of the first rank.

The Lamb Shift causes ripples in physics because it seems to point at physics beyond the Dirac equation. It's one of those rare, precious measurements in science which seem to inaugurate an entire field of study, a tiny, elusive number that points to great truths. In fact even during the 1930s some prescient physicists, Oppenheimer and Heisenberg among them, had suspected that the two energy levels might be different. But when they tried to calculate the actual number they started getting an absurd value for it: infinity. Nobody has bettered that result, partly because there was no experimental number to compare it with, but now at last, there is a solid reference number which the theoreticians can calibrate their calculations against. It's a rudder which they can finally use to guide the ship of their collective imagination.

The participants at the Shelter Island conference take the Lamb Shift to heart. The discussions continue into the twilight hours. Suggestions are thrown around without definite follow ups. One can sense the fomenting of a movement, but the destination is unclear. It's also clear from the conference that it's going to be the young breed of physicists who's going to crack the puzzle. First comes Julian Schwinger whose hours-long talk is like a prodigious performance by a violin virtuoso. His dazzling equations leave the attendees breathless. Then comes Richard Feynman, irreverent and colloquial with a wholly new way of looking at quantum mechanics, a language of wiggles and pictures which leaves the participants befuddled. It would take some time for his way of thinking to sink in. The proceedings of the conference are now legendary, with someone asking "What the hell should I calculate next?", Isidor Rabi asking "Who ordered that?" in response to the announcement of the muon, and Oppenheimer holding the gathering mesmerized with his splendid command over language, lightning fast mind and propensity to instantly summarize all agreements and disagreements into a concise package. And yet the Lamb Shift beckons.

It takes the resources of Hans Bethe with his unmatched ability to pound calculations into workable numbers to make the first great move; it's no wonder that years later after Bethe's death, his then promising protege Freeman Dyson called him "the supreme problem solver of the twentieth century". After the conference, Bethe astounds everyone by calculating the Lamb shift from scratch. One of his strokes of insight is to realize that even a non-relativistic calculation which ignores the effects of special relativity can give a number which is pretty damn close to the experimental value: 1040 megahertz. This requires a shift of a reference frame, so to speak, since everyone seems to have assumed that a non-relativistic calculation would be too inaccurate and unrealistic. And, as part of a Bethe story that has passed into lore, he does the calculation on the train ride home to upstate New York.

By his own account, Hans Bethe did the first calculation of
the Lamb Shift on a train ride to Schenectady in New York

Bethe's calculation energizes the physics community. It breathes life into a new technique called renormalization which gets rid of the ugly infinities plaguing pre-war calculations. It propels Feynman, Schwinger and Dyson along with Japanese physicist Sin-Itiro Tomonaga to put the finishing touches on their theory of quantum electrodynamics which is presented in the rest of the series of the conferences. Quantum electrodynamics reveals a magical world of so-called virtual particles such as photons that can flit in and out of existence in an eye-blink as the electron transitions between the 2S and 2P energy levels. These particles may seem to violate the conservation of energy because of their sudden appearance and disappearance, but Heisenberg's uncertainty principle as applied to energy and time ensures that one can have virtual particles existing for a definite amount of time as long as there is a finite uncertainty in the value of their energies. That uncertainty manifests itself as a difference in energy which is precisely equivalent in terms of frequency to the Lamb Shift.

The Lamb Shift achieves a flowering of theoretical physics that has not been seen since the heyday of quantum mechanics in the 1930s. Quantum electrodynamics becomes the most accurate theory of physics. It calculates the magnetic moment of the electron correctly to sixteen decimal places; later Richard Feynman famously compared this to measuring the distance between New York and New Orleans to within the width of a human hair. It uncovers a universe that is alive with virtual particles and fields; these particles even permeate an absolute vacuum and give rise to so-called vacuum energy. It gives voice to a new generation of American physicists whose descendants are still housed in the country's leading physics departments. These men and women not only develop quantum electrodynamics, but the techniques they pioneer - Feynman diagrams, renormalization, scattering matrices - are used in the development of all of particle physics in the future, culminating first in the Standard Model and finally in the discovery of the Higgs Boson seven decades later. Feynman, Schwinger and Sin-Itiro Tomonaga deservedly win Nobel Prizes. The Lamb Shift and its implications of a vacuum energy even helps Stephen Hawking postulate the presence of energetic radiation from black holes.

But none of this would have been possible without Willis Lamb, the perfect incarnation of theorist and experimentalist who was present at the right place at the right time. Lamb received the Nobel Prize in physics in 1955, and spent the rest of his career at Oxford, Yale and Arizona (where he moved so that his wife could find a faculty position). He mentored other successful students and developed another highly productive career in laser physics; ironically, one of his papers in this field is cited even more extensively than the one on the Lamb Shift. He lived a long and productive life and died in 2008. But it's the Lamb Shift that will go down in history as the opening shot which inaugurated a golden age of physics. As Freeman Dyson who was one of the prime participants in that saga complimented Lamb on his 65th birthday, 

"Those years, when the Lamb shift was the central theme of physics, were golden years for all the physicists of my generation. You were the first to see that this tiny shift, so elusive and hard to measure, would clarify our thinking about particles and fields."

And that's all we are, really, particles and fields. Happy 103rd birthday, Willis Lamb.

The linguistic adventures of Robert Burns Woodward

Photo credit: Jeff Seeman

Everyone knows about the supreme scientific achievements of Robert Burns Woodward, but few chemists from today's generation are perhaps acquainted with Woodward's love of the English language. This omission would be easy to remedy, however: anyone who reads Woodward's famous papers on the total synthesis of strychnine, or reserpine or chlorophyll would notice his unusually well-formed sentences, injection of Latin or historic references and allusions to synthetic chemistry as a heroic endeavor. Chemistry being a science whose products and protocols are especially palpable and vivid because of their colors, smells, textures and general visual displays, it was particularly amenable to Woodwardian linguistic flourishes. 

All these qualities are now presented in a delightful paper by my friend, the noted historian of chemistry Jeff Seeman, in Angewandte Chemie. Jeff describes how Woodward's English ancestry and Anglophilic affinities propelled him to develop his love of language and a very distinct style of writing that influenced his peers (in his autobiography, Jack Roberts of Caltech has also commented on some of Woodward's unusual English pronunciation: "mole-e-cule" instead of "mall-e-cule" for instance). Woodward of course considered and practiced organic synthesis as a mix of extreme performance sport and high art, so it's only appropriate that his language matched the elegance of his synthetic creations.

Foremost among his descriptions of compounds, reagents and reactions is what I consider to be the ultimate paean ever paid to a molecule: his tribute to a lowly isothiazole ring and his eloquent description of it as a travel companion to whom one needed to bid farewell after a fateful and adventurous journey. This was from his synthesis of colchicine:

"Our investigation now entered a phase which was tinged with melancholy. Our isothiazole ring had served admirably in every anticipated capacity, and some others as well. … It had enabled us to construct the entire colchicine skeleton, with almost all of the needed features properly in place, and throughout the process, it and its concealed nitrogen atom had withstood chemical operations, variegated in nature, and in some instances of no little severity. It had mobilized its special directive and reactive capacities dutifully, and had not once obtruded a willful and diverting reactivity of its own. Now, it must discharge but one more responsibility—to permit itself gracefully to be dismantled, not to be used again until someone might see another opportunity to adopt so useful a companion on another synthetic adventure. And perform this final act with grace it did.”

Then there's the famous synthesis of strychnine, in which the use of a simple exclamation mark in the first sentence places the project on a whole new level of scientific stardom. Albert Eschenmoser who worked with Woodward on his vitamin B12 synthesis offers an appropriate tribute:

Then there are the military metaphors. Today we might be used to descriptions of complex, multistep, multi-personnel and multiyear syntheses as being akin to climbing great mountains or fighting great battles; one of Woodward's successors, K C Nicolaou, has especially enshrined such comparisons in his reviews, but it was Woodward who was the first to memorialize them. As Jeff explains, Woodward was a serious history buff, and his knowledge of a reference to the Battle of Berezina in which the French under Napoleon achieved a costly victory against the Russians made its way into a review on strychnine. More martial references emerge in his description of efforts to decipher chlorophyll (as an aside, even today, I am struck by how much of the jargon of drug discovery is war-inspired: "targets", "hits" and "campaigns" are only a few examples).

1961: Fresh from his dramatic conquest of the blood pigment, [Hans] Fischer hurled his legions into the attack on chlorophyll, and during a period of approximately fifteen years, built a monumental corpus of fact. As this chemical record, almost unique in its scope and depth, was constructed, the molecule was transformed and rent asunder in innumerable directions, and the fascination and intricacy of the chemistry of chlorophyll and its congeners was fully revealed.”

Jeff considers dozens of other examples where Woodward's facility with language was on generous display: Strychnine possessed a "tangled skein of atoms" and another molecule contained a "felicitously placed carboxyl group and a double bond of good augury". Yet another compound is a "substance precariously balanced on a precipice", presumably by virtue of its instability. Finally, Woodward's love of Latin found its way into more than a few of his papers ("sui generis", "sub judice" and "pari passu").

All this achieves a goal which Woodward may or may not have consciously had in mind: to make synthesis look like high art, supremely arduous mountaineering and inspired military strategy all at once. A memorable paragraph of his on the fundamental motivation for organic synthesis brings together many of these themes and pays a glowing tribute to the the whys of the creation of new molecules:

“The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men. The achievement of the objective in itself cannot but thrill all chemists, who even before they know the details of the journey can apprehend from their own experience the joys and elations, the disappointments and false hopes, the obstacles overcome, the frustrations subdued, which they experienced who traversed a road to the goal. The unique challenge which chemical synthesis provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both.”

Interestingly at the end of the article, Jeff also discusses the reactions of a few reviewers of Woodward's words who were not as taken by his linguistic playfullness, who thought that his undue emphasis on unusual language often obscured the clarity of the science. I am a bit sympathetic to this view myself. Personally I love reading Woodward's papers, but that's because I am someone who enjoys literature. Others who may not be as enamored of the felicities of language, who may have a no-nonsense approach to the writing of scientific papers and who might not want to wade through the icing before they get to the cake might not appreciate Woodward's language as much. This is not an entirely unfair point: The main purpose of scientific papers is to clarify, explain and enumerate, not to decorate, bedeck and garland. 

There's also another important aspect of scientific writing that especially needs to be considered in this age, one in which science is highly international: scientific papers have to be written for an international audience, and it's not unreasonable to think that the kind of language Woodward used might make his papers harder for those whose first language is not English to understand. In Woodward's time science was a smaller community, the Internet did not exist and the total synthesis of organic molecules was an endeavor whose leading practitioners were largely confined to Europe and the United States. One did not really worry about chemists in China appreciating the meaning of words like "adumbrate", "punctilio", "apposite" and "cavil", all of which were peppered across Woodward's writings. Today we do.

Nonetheless, in case of Woodward these stratospheric incarnations of the English language work, mostly because of the profound feats in science which they herald. The synthesis of strychnine or vitamin B12 is indeed an unprecedented achievement akin to high art, so it doesn't seem out of place for such performances to be described in language that is as novel as the achievements are groundbreaking. 

One can get away with a lot if one is Robert Burns Woodward.