The Emperor of All Maladies

I finished yesterday Siddhartha Mukherjee's The Emperor of All Maladies. With the exception of one shocking lapse, it's a very good history of cancer therapy and I strongly recommend it for anyone interested in cancer.

Mukherjee is an oncologist and interleaves his historical view of cancer with the experiences of selected patients he tended. This humanizes the subject and brings useful context. On the historical side, he reaches all the way back to the first written description of cancer, from Pharonic Egypt (which was also the first expression of futility at treating cancer). A major thread running through the early part of the book is the career of Sidney Farber, who pioneered chemotherapy, and Mary Lasker, who reshaped the role of the U.S. government in cancer research despite having never held elective office.

The book is written for a lay audience and I think he does a good job. There are some key lessons which need to be heard widely. Mukherjee describes many of the twists and turns, the clever leaps of logic and the leaps that failed. For example, Farber's key insight was that leukemia was characterized by improperly functioning bone marrow, a trait shared with several nutritional deficiencies which had just been solved. So he tried treating childhood leukemias (deemed utterly untreatable by oncologists of the time) with B-vitamins, to disastrous results. But, then the second leap occurred -- Farber tried B-vitamin antagonists, and soon found success.

Mukherjee also captures many of the missed opportunities and the non-scientific barriers to progress. Farber was shunned by many colleagues because he was not an oncologist, but a pathologist. The initial misstep led to utter non-cooperation from the oncologists, leaving Farber's doctors to sharpen their own needles and dump their patient's bedpans. His supply of anti-folates came from an immigrant doctor who had left for chemistry and industry after his foreign credentials proved useless. Much more recently, there is the story of how Weinberg's group discovered Her-2 but didn't contemplate pursuing therapy against it. Far worse is how the lawyers at the institute Farber founded nearly iced Gleevec, and even after that issue was dealt with (when Gleevec's proponent Brian Druker moved to another institution) the management of Novartis nearly killed it. Similarly, Genentech all but dropped Herceptin; again it was an outside oncologist who drove the project to success.

The book also gives a good overview of how many things needed to be invented along the way and issues which arise. Simple epidemiology noted the high incidence of scrotal cancer in boy chimney sweeps; the intersection of a rare cancer and rare occupation made the relationship unquestionable. But later, researchers were faced with the challenge of proving a common cancer (lung) was linked to a common environmental factor (smoking) and this required new methods such as the case-control study. In the chemotherapeutic arena, the book covers many iterations of trial design and testing strategy and also brushes a bit on the changing ethical landscape.

If you've read my previous book reviews, a typical exercise for me is to ask what else could have gone in. Now, this is admittedly sometimes unfair to the author and one prior reviewee has politely chided me that some of what I missed ended up on the editor's floor. Plus, books that want to be read and not doorstops need to respect certain length limits. But, when I am writing I find it a useful exercise; only when we consider the whole range of possibilities can we be confident that the correct balance has been reached.

Perhaps the most surprising area barely touched on is angiogenesis and anti-angiogenic therapy. Some of this may have to do with timing; most of the book concerns events before about 2004, though with an impressive quick coverage of some of the learnings from cancer genomes. So many of the travails of Avastin would be after that rough divide. Still, this is a hot topic and perhaps that is why I miss it from the book. This book deserves to be widely read and probably will be (it is certainly the de facto Book-of-the-Month at work) and will therefore form the foundation for many public conversations about cancer

Another topic essentially absent from the book are various types of immunotherapy. Again, this is an area having some resurgence (with the approval of the prostate cancer vaccine Provenge), but it isn't clear how important it will be long term. I think there was a passing mention of Coley's toxins, but saw none of the late 70's excitement around interferons (which, alas, became only a niche player in oncology) or the 80's focus on interleukins.

Finally, though there is some coverage of the world of molecular analysis of cancers (such as cancer genomics), the field of microarray classification of cancer and guiding therapy isn't explored. This is a pretty complex topic with a lot of shifting (and, as noted in the recent George Poste Nature opinion piece, far more smoke than light) so it's a bit understandable it was left out.

Overall though, I can't think of anything that is clearly missing. But now my quibble and serious complaint. Certainly the book not only filled in a lot of areas I just hadn't been exposed to, but even had me running for articles very close to where I see my core training.

The quibble is a bit of a pet peeve. The book, like many (and myself), roughly divides cancer chemotherapeutics into two bins (with room for a small "unclassified" bin as well). Cytotoxics are broad-spectrum cell killers and constitute the bulk of cancer therapy agents.

Targeted therapies are the sticking point. For me, it is important to reserve this category for agents that have two critical properties: we know what the drug acts on in cells and we know something about the relevance of that mechanism to a tumor. Mukherjee gives a number of interesting stories about targeted therapies. For example, anti-estrogen therapy for breast cancer can trace back to a doctor hearing from Scottish shepherds that removing a ewe's ovaries would cause their udders to shrink. Another fascinating story relayed in the book shows how these categories can be tricky. By undescribed means (probably random screening), it had been found that cis-retinoic acid could be used to treat the aggressive leukemia APL, though with highly variable results. An inspired leap of logic led to the decision to test all-trans retinoic acid (ATRA) in APL, with stunningly successful results. Only later was it discovered that most APL cases are driven by a fusion protein derived from a retinoic acid receptor. So ATRA started as "other" and only later fits my definition of targeted therapy.

So what's my beef? It's when Mukherjee describes Velcade, thalidomide and Revlimid in multiple myeloma as targeted therapies. He's hardly alone; this is a common description. But in my taxonomy, Velcade is a cytotoxic. We know where it acts in the cell but not why that is important in cancer and not how to select which patients to use it in. Thalidomide and Revlimid probably should go into the "other" bucket; we're not sure of the mechanism but they aren't generically cytotoxic. Even one of the drugs I currently work on (an HSP90 inhibitor) I would generally call a cytotoxic; it's not a perjorative in my book. On the other hand, in one subset of lung cancer there is a strong hypothesis as to how such HSP90 inhibition works at a molecular level. So as with many biological classifications, they're a bit smudgy -- but I still think they are useful and worth being precise about.

Finally, the big complaint. One of the longer stories in the book concerns the apogee of intensive chemotherapy, in which breast cancer patients were given doses high enough to utterly destroy their bone marrow, followed by bone marrow transplants. This was an important and controversial approach to therapy, with patients begging to get into trials and fighting legal battles to have their insurance companies pay for these unproven treatments. Indeed, Masschusetts was one state which enacted legislation to mandate coverage of this particular treatment. However, when the clinical trial results rolled in, all but one large study showed no benefit. The outlier study showed a huge benefit. However, on closer inspection the outlier turned out to a fraud of truly monstrous proportions. In discussing that denouement, Mukerjee points out that a male patient "obviously" couldn't have been a legitimate member of the trials. Breast cancer in men is rare, but rare is not impossible and it is particularly critical for oncologists to not have that blind spot. Indeed, this is particularly important in families with a history of breast cancer; the risk of male breast cancer is much higher in BRCA1/2 familes.

That one blemish aside, though, I can strongly recommend this book. As I've noted before, if many read it then there will be a much stronger general basis for discussing cancer and the public policy around it.

Review: The $1000 Genome

Kevin Davies' "The $1000 Genome" deserves to be widely read. Readers of this space will not be surprised that there are a few changes I might have imposed had I been its editor, but on the whole it presents a careful and I think entertaining view of the past and possible future of personal genomics.

The book is intended for a far wider audience than geeky genomics bloggers, so the emphasis is not on the science. Rather, it is on some of the key movers-and-shakers in the field and some of the companies which have been dominating this space, ranging from the first personal genetic mapping companies (23 and Me, Navigenics, Pathway Genomics and deCodeMe) to the instrument makers (such as Solexa/Illumina, Helicos, Pacific Biosciences, ABI and Oxford Nanopore) to those working on various aspects of human genome sequencing services (such as Knome and Complete Genomics. Various ups and downs of these companies -- and the debates they have engendered -- are covered as well as the possible impacts on society. Along the way, we see a few glimpses of Davies exploring his own genome and some of the biological history which he seeks to enlighten through these expeditions.

It is not a trivial task to try to explain this field to an educated lay public, but I think in general Davies does a good job. The overviews of the technologies are limited but give the gist of things. Anyone writing in this space is faced with the dilemma of trying to explain too much and losing the main thread or failing to explain and preventing the reader from finding it. Mostly I think he has succeeded in threading this needle, perhaps because only rarely did I feel he had missed. One example I did note was in explaining PacBio's technology; hardly anyone in science will know what a zeptoliter is, let alone someone outside of it. On the other hand, what analogy or refactoring of that term could remove it from the edges of science fiction? Not an easy challenge!

For better or worse, once I've decided I generally like a book like this my next thoughts are what could be removed and what could be added. I really could find little to remove. But, there are a few things I wish were either expanded or had made it in altogether.

It would be dreary to enumerate every company which has ever thrown its hat in the DNA sequencing ring. It is valuable that Davies covers a few of the abject failures, such as Manteia (which did yield some key technology to Illumina when sold for assets) and US Genomics. There is scant coverage, other than by mention, of most of the companies which have but nascent attempts to enter the arena. However, the one story I really did miss was anything about the Polonator. It's not that I really think this system will conquer the others (though perhaps I hope it will hold its own), it just represents a very different tack in corporate strategy that would have been interesting to contrast with the other players.

Davies has been in the thick of the field as editor of Bio IT World, so this is no stitching together of secondary sources. I also appreciated that he includes both the ups and the downs for these companies, emphasizing that this has not been easy for any of them. But, that added to my surprise at several incidents which were left out (believe me, many were left in I had never heard before). Davies describes how Helicos delivered an instrument to the CRO Expression Analysis, but not that it was very publicly returned for failing to perform to spec. Nor is Helicos' failed attempt to sell themselves mentioned. An interesting anecdote on Complete Genomics is how a wildfire nearly disrupted one of their first human genome runs; left out is the near-death experience of that company when it was forced to either lay off or defer salaries for nearly all of its staff. The section on Complete's founder Rade Drmanac mentioned Hyseq, but not the company (or was it two) which he ran between Hyseq and Complete to try to commercialize sequencing-by-hybridization. This would have added to this portrait of determination -- and the travails of the corporate arena. I was also surprised that the short profile of Sydney Brenner as a personal genomics skeptic didn't include the fact he invented the technology behind Lynx, which was another early attempt in non-electrophoretic sequencing. Some would see that as irony.

Another area I would like to have seen expanded was the exploration of groups such as Patients Like Me, which are windows on how much people are willing to chance disclosing sensitive medical information. One section explores the fact that several prominent persons interested in this field became so when their children were diagnosed with rare recessive disorders, leading them to ponder whether they would have made the same marriage had they known in advance of this danger. I was surprised that little of the existing experience in this area was explored; I believe the Ashkenazi population has dealt with this in screening for Tay-Sachs and other horrific disorders which are prevalent there.

The book is stunningly up-to-date for something published the beginning of September; some incidents as late as June are reported. Despite this, I found little evidence of haste. I'm still trying to figure out what a "nature capitalist" is, but that's the only case I spotted of a likely mis-wording.

Davies briefly explores possible uses of these sequencing technologies beyond our germline sequences, but only very briefly. Personally, I think that cancer genomics will have a more immediate and perhaps greater overall impact on human medicine, and wish it had gotten a bit more in depth treatment.

Davies in a expatriot Brit, living not very far from me. The sections on the possible impact of widespread genome sequencing on medicine are written almost entirely from a U.S. perspective, with our hybrid public-private healthcare system. I suspect European readers would hunger for more discussion of how personal genomics might be handled within their socialized medical systems and different histories of handling the ethical issues (Germany, I believe, has pretty much banned personal genomics services). On this side of the pond, he does a nice job of showing how different state agencies have charged into the breach left, until recently, by the FDA.

Okay, too many quibbles. Well, maybe one last one -- it would have been nice to see more on some of the academic bioinformaticians who have created such wonderful and amazing open-source tools as Bowtie and BWA.

As I mentioned above, Davies injects a good amount of himself into all this. I've encountered books (indeed, on recently on moon walkers), in which this becomes a tedious over-exposure to the author's ego. This is not such a book. The personal bits either link pieces of the story or make them more approachable. We find out that he has already attained a greater age than his father did (due to testicular cancer, one of the few cancers in which overwhelming progress has been made), leading to questions he hopes his genome can answer. Hence, his trying out of pretty much all of the array-based personal genetic services. But, he does not address one question that the book raised in my mind: will the royalties from this project fund a complete Davies genome?

What I Didn't Read This Summer

In my last entry I commented on the stack of books that did and did not quite get read. Since yesterday marks the traditional American concept of summer, it's time to note what didn't get read in a more actively not read manner. Two books stick in the mind.

I tried to read The Black Swan by Nassim Nicholas Taleb, but quickly found myself skimming the pages & then not doing even that. Perhaps it was my state of tiredness or something else, but I just found the book grating. The contrast with How Doctors Think is striking: both deal a bit in the area of dealing with unusual or unique situations, and in neither case did I find myself consistently in agreement with the author. But, whereas Groopman comes through as humbled by the challenge & thoughtful of the issues, to me Taleb was obnoxious & arrogant. If someone found the book enjoyable, I'd love to hear why -- not because I want to argue, but maybe it would give me the incentive to try again. His previous book, Fooled by Randomness, was referred to me by a trusted source (actually, even loaned to me), but I never cracked it open. Debating whether to revisit that as well.

A more active avoidance was Michael Behe's latest Intelligent Design opus, The Edge of Evolution. I actually read his previous work & emitted a review, so I can do this. But it's kind of like a colonoscopy -- you know you should get one periodically but there's nothing pleasant about the thought of it. I have actually been challenged in a social situation to defend evolution -- a hazard of being known as a professional biologist (another is being asked to critique crank books & far-out 'alternative therapies' & nutrition schemes). On the one hand, it is appropriate to read what you might wish to criticize. On the other, there's only so much time for reading: why not spend it on the subset of books likely to be some combination of enjoyable & informative?

When Imagination Trumps Science

I recently finished an interesting book that was a pure impulse item at the local library -- those scheming librarians put books on display all over to snag the likes of me! Imaginary Weapons is the saga of various Department of Defense funded efforts to develop a new class of weapons based on some exotic physics, efforts that are characterized by the steady flow of funding to a scientist of dubious quality to work on a phenomenon that is unrepeatable. My tax dollars at work!

The book is flawed in many ways, and some squishy details at the beginning set me on edge. There is also a lack of a good description of the exact topic being discussed (clear isomers of hafnium), and the author all too often uses 'hafnium' as a shorthand for 'hafnium isomer', even when she is discussing nearby the ordinary, stable form of hafnium. There is also an excess focus on the strange setup of the key experimenter, who uses salvaged dental X-ray equipment for the crucial test. This is probably not the right gear, but the question why is never explored.

The key figure running the 'experiments' (to use the word charitably) is constantly updating what the doubters should have found to reproduce his experiments. "I know signature X was in the paper, but I now know you should look for Y". Negative controls -- forget about it; they were flatly refused.

The truly sad part were the enablers at DARPA, the Defense Advanced Research Projects Administration. DARPA is supposed to fund longshot stuff, and so it could be argued this work was appropriate initially. But to keep sinking money into a clear incompetent, that is the travesty.

The author actually interviewed most of the participants in the fiasco on both sides, but she really missed the golden opportunity. When asked why this research kept being funded, despite criticism from anyone with standing in the physics community, the answer was always that the applications were so promising and it was DARPA's job to fund high-risk, high-reward science. The question that apparently went unasked is 'why this topic'? Why pour so much money into hafnium isomers, rather than zero point energy or antimatter or antigravity? Once you've decided to ignore the recognized experts in a field, how do you go from there? Of course, one can hope this works as 'push polling' to reconsider the meaning of science, but more than likely the next budget request would include funds for the research arm of the Jedi Knights.

Supporting important science that isn't initially respected is a challenge. Biology has plenty of examples of scientists who fought orthodoxy and ultimately were proven correct: Mendel (genetics), Roux (oncogenic viruses), Prusiner (prions), Langer (drug release systems), Folkman (angiogenic factors), Marshall (H.pylori & ulcers), Brown (microarrays) & Venter (whole genome shotgun is just a tiny list. But it is also important to balance that against the stuff that was dodgy then and is still dodgy now, such as Moewus and Kammerer and a host of others. Even if what you claimed to do is eventually done, that doesn't mean you were right -- the claim of cloning a mouse in the 70's has nothing to do with the reality of cloning a mouse in our time. What separates the good fringe science from the crankery is an attention to the criticism, not ignorance of it. I've heard both Langer & Folkman speak, and they clearly kept addressing their critics concerns in their papers. These pioneers also weren't just right; they had done their science well. Mendel found the right laws & his data was generally good; in contrast the uniparental mouse of the 70's is still a fraud despite mammalian cloning ultimately playing out.

Bad work in the guise of science, either outright fraud or self-deception (what Feynman termed 'cargo cult science') will probably be with us forever. Great travesties have been perpetrated claiming to be scientific (e.g. the Tuskeegee syphilis horror). This year's big investigation is bubble fusion; last year's was cloning & next year it will be something else. Reading about science gone wrong isn't much fun (well, the N-ray expose is fun to contemplate!), but it is necessary.