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!

Watch "The Man Who Knew Infinity": You will be performing a public service

Last weekend we watched “TheMan Who Knew Infinity” which is based on Robert Kanigel’s marvelous biography of mathematician Ramanujan by the same name. It’s a very good production, and while it takes some liberties with the facts, it brings one of the most extraordinary characters in the history of science to life in the 21^st century. The movie is not exactly Oscar-level Hollywood material, but this fact makes it an even more notable undertaking.

The story virtually writes itself: poor Indian man from obscure village at the turn of the 19^th century possesses an amazing gift that few recognize. Fortunately – and largely by sheer chance- his gift gets recognized by one of the world’s most famous mathematicians, G. H. Hardy. Hardy then invites him to Cambridge where the two embark on a singular collaboration that unearths deep mathematical secrets, but debilitated by the weather and his exceedingly fastidious vegetarian food habits, Ramanujan returns home to India and dies at the tender age of 32; but not before being elected a fellow of both the Royal Society and of Trinity College in Cambridge, an unprecedented honor for a self-taught man from a village in British-occupied India. Even without embellishment the story is quite memorable, and yet as often happens with math and science, even today it’s known to few people in any kind of detail.

The emphasis on the film is on Ramanujan’s relationship with G. H. Hardy, and this aspect of his life was as remarkable as his mathematical prowess. There was a Q&A session with Robert Kanigel, the film’s director Matt Brown and the mathematician Manjul Bhargava (who won the Fields Medal last year) after the film, and the director told us that what really inspired him to make the film was this human story describing the bonds of mathematics that could bridge the gulf between two very different men from very different cultures. Hardy calls his association with Ramanujan “the one true romantic incident of his life”, and the film does give us an idea of why he might have thought so.

The movie also does a good job dwelling on the math which is really the meat of Ramanujan’s life. To its credit it actually features an actual explanation of one of Ramanujan’s greatest accomplishments - his work on partitions with Hardy. Ramanujan’s ability to divine great theorems virtually from scratch was legendary of course, and even today mathematicians are finding gems in his books and wondering how he could figure out all these counterintuitive and novel math results based on nothing more than a high school education. Like John von Neumann Ramanujan was the ultimate autodidact, and both his and von Neumann’s accomplishments really give us a flavor of the extraordinary hidden potential that human minds hold. But one crucial aspect of Ramanujan’s personality that the film shines light on is his sheer obsession with math and the immense amount of hard work that he put in. Almost all through his adult life until his death, math was all he did. Ramanujan was a bona fide genius, no doubt about that, but the way he ate and drank and breathed and lived math makes it clear that even geniuses’ accomplishments come only from great toil and effort.

The real message of both the book and the movie is that genius can shine even in the most unlikely and obscure corners. Beyond a point it was clear that it was sheer fate and recognition by Hardy that allowed Ramanujan to be who he was, and one wonders how many other talents are wasting away today in little known towns in Africa, India or China. Someone like Ramanujan comes along only once every hundred or two hundred years, but ignoring even half a Ramanujan from any of these corners of the world would be a terrible waste of human potential.

That’s one of the reasons I am encouraging everyone I know to watch the movie. The other reason is director Matt Brown’s dedication to making it. One thing that definitely came across from the Q&A session was that this project was a labor of love. It took 12 years to make and, considering the low financial expectations that the people who made it must have had from it, really needed a lot of dedication and commitment. At one point the movie came close to being funded, but what (rightly) prevented it was a funding source's insistence that the storyline include an affair between Ramanujan and a white nurse at Cambridge (played appropriately by some British actress with star power) to improve its financial potential. The director told us that it was Ramanujan’s feelings of isolation in chilly Cambridge that impressed themselves upon him when he was caring for his brother who had cancer (in a happy real life twist, his brother got better and composed the score for the film). It was clear that he truly believed in it.

Brown asked us all to publicize the movie since it’s playing for only three weeks or so (next weekend might be the last one) and I do think this is important. It’s important not just for the dedication that went into it, but more importantly because I think it’s awesome that someone has made a movie about mathematicians and math and tried to show both the beauty of math and the human stories behind it: How often does this happen? I therefore think that we as science writers, journalists and scientists should do all we can to encourage its wide publicity. To this end please make sure you watch the movie and publicize it as much as possible when you get a chance. This has been a public service announcement.

A good year for science movies

Felicity Jones and Eddie Redmayne's remarkable
performances make "Theory of Everything" soar 

Movies about scientists get made quite rarely, so by those standards 2014 was definitely a bonanza year for such films. First there was the excellent "Particle Fever" which is now available on Netflix. Particle Fever vividly conveys the excitement of doing science as opposed to, well, movie science. And it does this by focusing not just on the leading lights of the quest for the Higgs Boson but on the foot soldiers who carry out the daily, often tedious and uncertain work of shuffling through the data and picking out signal from noise. The champagne, celebratory hurrahs and Nobel Prizes are only the tip of an iceberg which has been solidly laying its foundation for years through the toil of ordinary men and women, and Particle Fever brings out this message exceedingly well.

Particle Fever was followed by "The Imitation Game" which I saw last month. It's based on Alan Turing's definitive biography, Andrew Hodges's "The Enigma", and since I made the 'mistake' of reading the book before watching the movie I perhaps did not enjoy it as much as I could have. To its credit it gets several details right including a fair amount of detail regarding the actual Enigma machine. But where it errs in my opinion is in casting Benedict Cumberbatch as Alan Turing and Matthew Goode as his friendly rival. Now Cumberbatch and Goode are both fine actors, but the problem is that Cumberbatch is also a star, and in both achievements and personality Alan Turing was not a star, at least not until way after his death. It's a bit like casting Tom Cruise as Richard Feynman (who actually was much closer than Turing to being a star in real life). The movie also exaggerates a lot of things, including Turing's friendship with Keira Knightley's character and his authority over decision-making regarding whether or not to convey critical intelligence information to those manning the merchant convoys in the Atlantic. And while not exactly tiptoeing around his homosexuality, the film could have done a much better job of portraying how forthcoming and brave Turing was about that aspect of himself. Overall the effort is not bad, but it could have been much better if it had tried to be more of an honest biography and less of a box office hit.

That brings me to "Theory of Everything" which I watched last weekend. I had avoided watching it for days, mainly because almost everyone I asked had told me that it was a little too sappy and mawkish and was basically a love story with little and botched attention paid to Hawking's science - all the wrong ingredients in my opinion in a movie about a great scientist. But with nothing better playing I decided to go ahead anyway. The first half of the movie seemed to confirm my worst fears: not only were there some sappy moments, but even more ominously the dialogue seemed leaden, the editing poor and the treatment of the science continued to be lazy (at one point there are copies of Nature with Hawking's photoshopped *face* on the cover - displayed in *bookstores*. I guess it's never too late for a scientist to fantasize...). 

But then something remarkable happens in the second half: it's almost as if a new director has appeared on the scene and the movie has undergone a complete midstream facelift. The dialogue gets better, and while many scenes are still sappy they are also full of heart. What really changes between the first and second half and almost completely redeems the movie's shortcomings are the astonishing performances by Eddie Redmayne and Felicity Jones as Stephen Hawking and his wife Jane. In this case unlike that of "The Imitation Game", the movie really benefits from having a relatively unknown actor play the role: although Mr. Redmayne's amazing facial expressions and bearing make it clear that he is a star in the making. But if anyone could be said to top his performance it's Felicity Jones. I cannot remember when, in recent memory, I have seen an actress who could convey so much through her face and eyes without speaking. Mr. Redmayne has an eminently deserved Oscar nomination, but Ms. Jones should undoubtedly get one for her performance. The scene where she and Hawking decide to part ways is one of the most touching scenes I have seen in a recent movie.

The great achievement that the two actors manage to pull together is to paint the most human portrait of Stephen Hawking that I have ever seen committed to a public medium. Because of his brilliant mind and his almost surreal triumph over his disability, of all scientists Hawking especially is seen as a grand, legendary, distant character; perhaps the only contemporary scientist who inspires a reverence verging on the religious. Redmayne and Jones thankfully shatter this illusion and bring us a Hawking who is as human as the guy next door, who has the same follies and frustration and relationship issues as the rest of us. This true revelation alone makes the movie eminently memorable and worth watching.