Mendel, Weldon and the uncertainty of counterfactuals

Nature has an opinion piece on Mendel's legacy by Gregory Radick who is a professor at the University of Leeds. The focus of Radick's article which is titled "Teach students the biology of their time" is on a counterfactual: what if instead of Mendel's work, it was Raphael Weldon's work which had been recognized, emphasized and perpetuated by the early pioneers of genetics?

The point Radick is making is that Mendel's followers emphasized the primacy of nature (as in 'nature vs nurture') in the form of the gene so much that the role of nurture was sidelined. Weldon on the other hand seems to have been an early proponent of the role that the environment played in the sculpting of physical and behavioral traits. An accompanying comment in Nature endorses the piece and says that if Weldon's work had actually acquired the importance it should have, we might not have gotten obsessed with finding a "gene for this" and a "gene for that".

It's always interesting to consider what ifs and counterfactuals, not in the least because they serve as a useful vehicle for taking stock of what actually happened and for analyzing various currents of thought. But the real lesson in counterfactuals in my opinion is about historical contingency. My main problem with counterfactuals is that we assign them a degree of certainty that history's messy contours always seem to thwart. Since factual events themselves by definition are well-charted and reflected in the facts, we seem to think that their counterfactuals would also be well-charted. This in my opinion is affording a kind of luxury of prediction to history that it simply does not possess.

Radick's argument, as interesting as it, also suffers from these shortcomings in my opinion. I was vaguely familiar with Weldon's work but had the renewed opportunity to take a look at it in Sid Mukherjee's new book "The Gene." One thing that the Nature pieces don't mention is that Weldon had allied himself with Francis Galton and Karl Pearson in clinging to a flawed theory of fractional genetic inheritance in which one half of an offspring's genes would come from the parents, a fourth from the grandparents and so on. William Bateson enthusiastically fought against this idea and in the end prevailed.

But more pertinently here, it's interesting to consider some of the details of the counterfactuals that Radick and Nature are discussing here. Let's say it was Weldon's body of work and not Mendel's that was emphasized. Would it have really diverted attention from the importance of the gene? And would it have really compelled observers to take the environment more seriously and not talk about "genes for this" trait and "genes for that" trait? And if Weldon had prevailed along with Galton against Bateson, would Galton's eugenics drive have acquired an even more respectable stamp? I am not sure of the trajectory of any of these potential developments. 

More intriguingly, do we seriously think that a recognition of the environment would have stopped Thomas Hunt Morgan from actually finding important genes for specific traits in fruit flies? And would it have stopped Hermann Mueller from then finding out cartloads of mutations in these genes by exposing flies to x-rays? On the other hand, Theodosius Dobzhansky did determine the effects of environmental factors in his own fruit fly experiments in the 40s. I think that if anything, mainstream science was quite attuned to the effects of the environment in influencing traits, and genetic factors took some time to be cemented as serious determinants

I think we can agree that Morgan and Mueller's work was supremely important in the history of genetics, and if Weldon's followers had actually kept them from finding what they did it would have been a great loss for science and a strike against Weldonian theorizing. Just because trying to find genes for every single trait or disorder is messy or often a doomed process does not mean the concept itself is a problem; I would say that on balance the search for genetic determinants of traits has been enormously useful and promises to provide a bonanza especially in medicine. Strangely enough, the specific case of causal genes which the Nature piece invokes to illustrate the problems with genetic immutability in fact demonstrates the opposite point: these would be genes for heart disease. The article asks what the tangible gains are in asking whether there is a "gene for heart disease", when at least two genes for heart disease (ones for HMG-CoA reductase and PCSK9) have led to two of the most important targeted therapies for the ailment, therapies which have tangibly improved and saved tens of thousands of lives. Heart disease is of course a complex mix of genes and environment, but it's also a medical disorder where the delineation of a "gene for that" has been extremely helpful.

Secondly, it's not as if the emphasis on environment over genes has ever stopped ideologues and scientists from pursuing deeply flawed ideas with tragic consequences. It was precisely a rejection of Mendelian genetic determinism that led Trofim Lysenko and his Soviet overlords to embark on campaigns to "reeducate" wheat through "shock therapy" and to reeducate dissidents through "Gulag therapy". The noted Mendelian geneticist Nikolai Vavilov was imprisoned and tortured for his theories and he died a broken man. Other socialist ideologies have also engaged in similar campaigns. The important lesson here is that the perversion of a scientific idea for ideological purposes does not make an argument either for or against the idea itself. The use of social Darwinism in supporting Nazism makes as much of a case for rejecting genetic causes as the use of environmental leveling in supporting Soviet socialism makes for rejecting environmental causes.

The piece asks whether teaching counterfactuals might be a good tool for exposing students to different schools of thoughts and provoking them to think about other directions that history might have taken. Generally speaking I am always in favor of teaching students the history of scientific ideas, but I also think that this works only if we also teach them the inadequacy - in fact the futility - of post-factual historical prediction. The actual unfolding of history is so messy and subject to so many contingent forces that its march looks linear only in retrospect, when we have its one true manifestation in the form of bare facts at hand. Any speculation regarding what ifs remains speculation at best.

Friday levity: Darwin Myths

There's a hashtag named ‪#‎DarwinMyths‬ going around on Twitter. Here are a few that I made up. Except that they aren't myths, of course.
1. Darwin who was a failed doctor originally planned to write a book titled "The Origin of Sepsis" to make up for his medical school failures.
2. A little known fact about Darwin: He had multiple personality disorder. The other personality's name? Alfred Russell Wallace.
3. Fun fact: The original phrase in the first edition of "The Origin of Species"was "Endless worms, most beautiful".
4. Contrary to popular belief, the main reason why Darwin used to take hot baths in sanitariums was to play with his rubber ducky.
5. Contrary to popular belief, "Darwin's bulldog" was an actual bulldog which threatened Bishop Samuel Wilberforce (Hence Huxley's misquoted quip: "The dog hath delivered him into my hands.")
6. The story goes that Darwin once spied two attractive beetles and then spied another one which he could not bear to lose, so he simply put one of the first two in his mouth so he could catch the third one. The story is actually about madeleines, not beetles. The gluttonous Darwin later asked biographers (one of whom had titled his version "The Last Madeleine") to change that minor detail.
7. Contrary to popular belief, Darwin conned his way on to the "HMS Beagle" not by pretending to be a "gentleman scientist" but by pretending to be part of a dance troupe that was supposed to keep Captain FitzRoy entertained on the long and lonely voyage. Presumably his performances were so forgettable that he could easily transition into his other role without arousing FitzRoy's fury, or attention for that matter.

Skeptics should cast a much wider net

Professional provocateur John Horgan bravely took on a room full of skeptics a few days ago when he scolded them for what he thinks are their misplaced priorities. Horgan thinks that a lot of skeptics are taking on ‘soft’ targets – homeopathy, astrology, UFOS etc. and instead should be spending far more time on ‘hard’ targets. Horgan thinks that this kind of cherry-picking not only allows skeptics to keep on patting each others’ backs in echo chambers, but it detracts from other important issues that deserve skeptical scrutiny even more. To a large extent his argument is simply one of degree, since he clearly does not think homeopathy or UFOs don't deserve skeptical takedowns.

What are Horgan’s favorite ‘hard’ targets? One is war. He says that more skeptics should spend time debunking the idea that war is intrinsic rather than cultural. The other hard target is belief in highly speculative theories from physics like string theory, parallel universes and the idea that our universe may be a simulation created by aliens. I won’t go as far as he does to say that string theory is akin to astrology or homeopathy, and I also think that these theories have come under much harsher criticism than he thinks in the last decade or so: I am more concerned about the fact that popular science books expounding these theories are taken quite seriously by uninformed laymen. But the general idea that many informed skeptics should spend more time on talking about the shaky pillars of some of these speculations seems to be a reasonable one. The third target that Horgan addresses is the field of medical diagnosis. By now it’s quite clear that standard diagnostic tests like mammograms and PSA (prostate-specific antigen) testing are subject to such a high false positive rate that they may cause more harm than good (a very good book on these pitfalls that I read recently is Steven Hatch's “Snowball in a Blizzard”).

Many bloggers and self-proclaimed skeptics have responded to Horgan. The main criticism is simply that skeptics are far less monolithic and more diverse, both in degree and kind, than he thinks. The criticism also includes the admonition that the good is not the enemy of the great and one needs to work on both. I would also add that a target like homeopathy or even UFOs is not ‘easy’ in the sense of easily convincing its proponents. But generally speaking I think Horgan is not wrong. There are certainly some topics which would benefit from more scrutiny than what they currently get.

Skepticism has a long tradition in both eastern and western cultures, best exemplified for me by the Royal Society’s motto “Nullius in verba”, or “Nobody’s word is final”. Sadly, I think that motto points to another failing of skeptics; their tendency to steer away from politically controversial topics, either because they think the last word on such topics has already been said or because they think that saying anything about them would be dangerous. To Horgan’s list of topics that reasonable skeptics don’t criticize as much as they should, I would add climate change and the study of genetic factors underlying race and gender (Ironically, Horgan himself once wrote a post asking if research on such topics should be banned). To me it appears that many skeptics seem to think that even discussing these topics is taboo or unreasonable. Such a stance would be deeply antithetical to the skeptical spirit of free inquiry. No topic should be taboo or unreasonable as long as it contains facts to be explored and assessed.

There are several interesting aspects of each of the above topics that not only deserve attention but which can also be discussed in a reasonable and respectful manner without dealing in either/or fallacies or derailing your basic beliefs for that matter. For instance, to cite only a few examples, as writers like Steven Pinker and Diane Halpern have discussed, you can talk about biological aspects underlying gender differences without believing even an iota that one gender is ‘superior’ or ‘inferior’ to the other. Similarly, as biologists like Jerry Coyne and E O Wilson have pointed out, you can accept the existence of different races (or groups) and genetic differences underlying them without ever thinking that one race is superior or inferior to others. In fact, not only is it an elementary logical fallacy to equate ‘different’ with ‘inferior’ or ‘superior’, but it's not even clear what superior or inferior could even mean in these contexts. Halpern, Pinker, Coyne and Wilson are all proud upholders of the skeptical and liberal traditions who believe in clearly separating what is known from what is unknown. The same goes for climate change; you can clearly accept the basic reality of climate change while pointing out that certain details about the phenomenon might still be ill-understood. For instance, you don’t have to trash climate change as a whole in order to question the validity of computer models of climate. Or you can acknowledge good scientific knowledge of the atmosphere while acknowledging poor scientific knowledge of the biosphere.

Sadly, many skeptics not only shy away from discussing these topics, but they also have a tendency to vilify or ignore those on the other side who raise the kinds of interesting questions which I pointed out above. An unfortunate instance would be the time that an entire organization of scientists ended up slandering the anthropologist Napoleon Chagnon because he tried to reveal rigorously researched facts about the violent culture of the Yanomamo tribe that flew in the face of everyone’s comfortable leanings about violence and human nature. Another example would be the censure that the historian of science Alice Dreger had to go through when she brought up some inconvenient scientific questions about transgender people (this is documented well in her readable book). The reaction to physicist Freeman Dyson’s views on climate change would also be in the same category. 

The most startling fact is that Dyson, Chagnon and Dreger are all liberals who have long championed liberal causes and freedom of the individual. Dreger's case is especially troubling since she has been an unusually vociferous and dedicated supporter of LGBT rights for almost her entire career; it would thus seem that the very community which she loved and fought for turned against her. She and the others also happen to be champions of going where the scientific truth leads, believing that knowledge is always better than ignorance and that even inconvenient knowledge can be prevented from being misused through our shared humanity. The antidote to misuse of knowledge is not opposition to knowing the facts, not the least because the facts have an inconvenient way of making themselves known.

The reality of critical discourse on many of these topics is more nuanced than we think; for instance, as I pointed out a few years ago, there is no doubt that some climate change “deniers” are actually deniers with vested financial or political interests, but some are also genuine skeptics who are asking fine-grained questions about specific parts of the topic in honest faith. Dreger and Chagnon were raising questions based on perfectly reasonable research and theorizing. Dyson who agrees with the basic reality of climate change nevertheless questions poorly understood aspects of computer models, cloud formation and soil chemistry. Science is complicated, and scientific disagreement is often also complicated, gray rather than black and white, and irreducible to binary categorization. Just because you are skeptical of some of the pieces does not mean you don’t trust the big picture, and just because you trust the big picture does not mean you cannot be skeptical of the little pieces.

As history demonstrates, there will always be ideologues with racial, misogynistic or otherwise ulterior motives who will use even the barest quibbling about details to bolster their prejudiced views (creationists do this in the context of evolution all the time), but opposition to these ideologues should be clearly distinguished from opposition to the inquiry itself. Ironically, in casting these skeptics as kooks or paid shills, it’s the so-called skeptics who are being close minded and the so-called kooks who are being the real open-minded skeptics.

Skepticism is tough because it involves not only modifying entrenched beliefs but rewiring emotional and gut responses that have been reinforced by conformation bias, echo chambers and community kinship. To thrive, the skeptical community needs to be diverse and open to careful consideration of arguments on all sides as long as the arguments have a good dose of serious science in them; it needs to separate empty, bullheaded or purely bigoted opposition from genuine criticism and concerns, and needs to address the latter. It needs to be tough minded in respectfully taking on politically or socially controversial topics. Perhaps some of the findings of science regarding these topics would be unsavory to our sensibilities, but as moral beings with control over their fate, we have the power to decide how to use such findings. 

The ultimate word on skepticism could well belong to Francis Bacon, one of the founders of modern science who said, “All depends on keeping the eye fixed upon the facts of nature…for God forbid we should give out a dream of our own imagination for a pattern of the world". We should strive toward our dream but build it on a foundation of facts.

The future - not in our stars but in our genes: A review of Siddhartha Mukherjee's "The Gene: An Intimate History"

Genetics is humanity and life writ large, and this book on the gene by physician and writer Siddhartha Mukherjee paints on a canvas as large as life itself. It deals with both the history of genetics and its applications in health and disease. It shows us that studying the gene not only holds the potential to transform the treatment of human disease and to feed the world’s burgeoning population, but promises to provide a window into life’s deepest secrets and into our very identity as human beings.

The volume benefits from Mukherjee’s elegant literary style, novelist’s eye for character sketches and expansive feel for human history. While there is ample explanation of the science, the focus is really on the brilliant human beings who made it all possible. The author’s own troubling family history of mental illness serves as a backdrop and keeps on rearing its head like a looming, unresolved question. The story begins with a trip to an asylum to see his troubled cousin; two of his uncles have also suffered from various "unravelings of the mind". This burden of personal inheritance sets the stage for many of the questions about nature, nurture and destiny asked in the pages that follow.

The book can roughly be divided into two parts. The first part is a sweeping and vivid history of genetics. The second half is a meditation on what studying the gene means for human biology and medicine.

The account is more or less chronological and this approach naturally serves the historical portion well. Mukherjee does a commendable job shedding light on the signal historical achievements of the men and women who deciphered the secret of life. Kicking off from the Greeks’ nebulous but intriguing ideas on heredity, the book settles on the genetics pioneer Gregor Mendel. Mendel was an abbot in a little known town in Central Europe whose pioneering experiments on pea plants provided the first window into the gene and evolution. He discovered that discrete traits could be transmitted in statistically predictable ways from one generation to next. Darwin came tantalizingly close to discovering Mendel’s ideas (the two were contemporaries), but inheritance was one of the few things he got wrong. Instead, a triumvirate of scientists rediscovered Mendel’s work almost thirty years after his death and spread the word far and wide. Mendel’s work shows us that genius can emerge from the most unlikely quarters; one wonders how rapidly his work might have been disseminated had the Internet been around.

The baton of the gene was next picked up by Francis Galton, Darwin’s cousin. Galton was the father of eugenics. Eugenics has now acquired a bad reputation, but Galton was a polymath who made important contributions to science by introducing statistics and measurements in the study of genetic differences. Many of the early eugenicists subscribed to the racial theories that were common in those days; many of them were well intended if patronizing, seeking to ‘improve the weak’, but they did not see the ominous slippery slope which they were on. Sadly their ideas fed into the unfortunate history of eugenics in America and Europe. Eugenics was enthusiastically supported in the United States; Mukherjee discusses the infamous Supreme Court case in which Oliver Wendell Holmes sanctioned the forced sterilization of an unfortunate woman named Carrie Buck by proclaiming, “Three generations of imbeciles are enough”. Another misuse of genetics was by Trofim Lysenko who tried to use Lamarck’s theories of acquired characteristics in doomed agricultural campaigns in Stalinist Russia; as an absurd example, he tried to “re educate” wheat using “shock therapy”. The horrific racial depredations of the Nazis which the narrative documents in some detail of course “put the ultimate mark of shame” on eugenics.

The book then moves on to Thomas Hunt Morgan’s very important experiments on fruit flies. Morgan and his colleagues found a potent tool to study gene propagation in naturally occurring mutations. Mutations in specific genes (for instance ones causing changes in eye color) allowed them to track the flow of genetic material through several generations. Not only did they make the crucial discovery that genes lie on chromosomes, but they also discovered that genes could be inherited (and also segregated) in groups rather than by themselves. Mukherjee also has an eye for historical detail; for example, right at the time that Morgan was experimenting on flies, Russia was experimenting with a bloody revolution. This coincidence gives Mukherjee an opening to discuss hemophilia in the Russian royal family – a genetically inherited disease. A parallel discussion talks about the fusion of Darwin's and Mendel’s ideas by Ronald Fisher, Theodosius Dobzhansky and others into a modern theory of genetics supported by statistical reasoning in the 40s – what’s called the Modern Synthesis.

Morgan and others’ work paved the way to recognizing that the gene is not just some abstract, ether-like ghost which transmits itself into the next generation but a material entity. That material entity was called DNA. The scientists most important for recognizing this fact were Frederick Griffiths and Oswald Avery and Mukherjee tells their story well; however I would have appreciated a fuller account of Friedrich Miescher who discovered DNA in pus bandages from soldiers. Griffiths showed that DNA can be responsible for converting non-virulent bacteria to virulent ones; Avery showed that it is a distinct molecule separate from protein (a lot of people believed that proteins with their functional significance were the hereditary material).

All these events set the stage for the golden age of molecular biology, the deciphering of the structure of DNA by James Watson (to whom the quote in the title is attributed), Francis Crick, Rosalind Franklin and others. Many of these pioneers were inspired by a little book by physicist Erwin Schrodinger which argued that the gene could be understood using precise principles of physics and chemistry; his arguments turned biology into a reductionist science. Mukherjee’s account of this seminal discovery is crisp and vivid. He documents Franklin’s struggles and unfair treatment as well as Watson and Crick’s do-what-it-takes attitude to use all possible information to crack the DNA puzzle. As a woman in a man’s establishment Franklin was in turn patronized and sidelined, but unlike Watson and Crick she was averse to building models and applying the principles of chemistry to the problem, two traits that were key to the duo’s success.

The structure of DNA of course inaugurated one of the most sparkling periods in the history of intellectual thought since it immediately suggested an exact mechanism for copying the hereditary material as well as a link between DNA and proteins which are the workhorses of life. The major thread following from DNA to protein was the cracking of the genetic code which specifies a correspondence between nucleotides on a gene and the amino acids of a protein: the guiding philosophers in this effort were Francis Crick and Sydney Brenner. A parallel thread follows the crucial work of the French biologists Francois Jacob and Jacques Monod - both of whom had fought in the French resistance during World War 2 - in establishing the mechanism of gene regulation. All these developments laid the foundation for our modern era of genetic engineering.

The book devotes a great deal of space to this foundation and does so with verve and authority. It talks about early efforts to sequence the gene at Harvard and Cambridge and describes the founding of Genentech, the first company to exploit the new technology which pioneered many uses of genes for producing drugs and hormones: much of this important work was done with phages, viruses which infect bacteria. There is also an important foray into using genetics to understand embryology and human development, a topic with ponderous implications for our future. With the new technology also came new moral issues, as exemplified by the 1975 Asilomar conference which tried to hammer out agreements for the responsible use of genetic engineering. I am glad Mukherjee emphasizes these events, since their importance is only going to grow as genetic technology becomes more widespread and accessible.

These early efforts exploded on to the stage when the Human Genome Project (HGP) was announced, and that’s where the first part of the book roughly ends. Beginning with the HGP, the second part mainly focuses on the medical history and implications of the gene. Mukherjee’s discussion of the HGP focuses mainly on the rivalries between the scientists and the competing efforts led by Francis Collins of the NIH and Craig Venter, the maverick scientist who broke off and started his own company. This discussion is somewhat brief but it culminates in the announcement of the map of the human genome at the White House in 2000. It is clear now that this “map” was no more than a listing of components; we still have to understand what the components mean. Part of that lake of ignorance was revealed by the discovery of so-called ‘epigenetic’ elements that modify not the basic sequence of DNA but the way it’s expressed. Epigenetics is an as yet ill-understood mix of gene and environment which the book describes in some detail. It’s worth noting that Mukherjee’s discussion of epigenetics has faced some criticism lately, especially based on his article on the topic in the New Yorker.

The book then talks about early successes in correlating genes with illness that came with the advent of the human genome and epigenome; genetics has been very useful in finding determinants and drugs for diseases like sickle cell anemia, childhood leukemia, breast cancer and cystic fibrosis. Mukherjee especially has an excellent account of Nancy Wexler, the discoverer of the gene causing Huntington’s disease, whose search for its origins led her to families stricken with the malady in remote parts of Venezuela. While such diseases have clear genetic determinants, as Mukherjee expounds upon at length, genetic causes for diseases like cancer, diabetes and especially the mental illness which plagues members of the author’s family are woefully ill-understood, largely because they are multifactorial and suffer from weakly correlated markers. We have a long way to go before the majority of human diseases can be treated using gene-based treatment. In its latter half the book also describes attempts to link genes to homosexuality, race, IQ, temperament and gender identity. The basic verdict is that while there is undoubtedly a genetic component to all these factors, the complex interplay between genes and environment means that it’s very difficult currently to tease apart influences from the two. More research is clearly needed.

The last part of the book focuses on some cutting edge research on genetics that’s uncovering both potent tools for precise gene engineering as well as deep insights into human evolution. A notable section of the book is devoted to the recent discovery that Neanderthals and humans most likely interbred. Transgenic organisms, stem cells and gene therapy also get a healthy review, and the author talks about successes and failures in these areas (an account of a gene therapy trial gone wrong is poignant and rattling) as well as ethical and political questions which they raise. Finally, a new technology called CRISPR which has taken the world of science by storm gets an honorary mention: by promising to edit and propagate genes with unprecedented precision - even in the germ line - CRISPR has resurrected all the angels and demons from the history of genetics. What we decide about technologies like CRISPR today will impact what our children do tomorrow. The clock is ticking.

In a project as ambitious as this there are bound to be a few gaps. Some of the gaps left me a bit befuddled though. There are a few minor scientific infelicities: for instance Linus Pauling’s structure of DNA was not really flawed because of a lack of magnesium ions but mainly because it sported a form of the phosphate groups that wouldn’t exist at the marginally alkaline pH of the human body. The book’s treatment of the genetic code leaves out some key exciting moments, such as when a scientific bombshell from biochemist Marshall Nirenberg disrupted a major meeting in the former Soviet Union. I also kept wondering how any discussion of DNA’s history could omit the famous Meselson-Stahl experiment; this experiment which very elegantly illuminated the central feature of DNA replication has been called “the most beautiful experiment in biology”. Similarly I could see no mention of Barbara McClintock whose experiments on ‘jumping genes’ were critical in understanding how genes can be turned on and off. I was also surprised to find few details on a technique called PCR without which modern genetic research would be virtually impossible: both PCR and its inventor Kary Mullis have a colorful history that would have been worth including. Similarly, details of cutting-edge sequencing techniques which have outpaced Moore’s Law are also largely omitted. I understand that a 600 page history cannot include every single scientific detail, but some of these omissions seem to me to be too important to be left out.

More broadly, there is no discussion of the pros and cons of using DNA to convict criminals: that would have made for a compelling human interest story. Nor is there much exploration of using gene sequences to illuminate the ‘tree of life’ which Darwin tantalizingly pulled the veil back on: in general I would have appreciated a bigger discussion of how DNA connects us to all living creatures. There are likewise no accounts of some of the fascinating applications of DNA in archaeological investigations. Finally, and this is not his fault, the author suffers from the natural disadvantage of not being able to interview many of the pioneers of molecular biology since they aren’t around any more (fortunately, Horace Freeland Judson’s superb “The Eighth Day of Creation” fills this gap: Judson got to interview almost every one of them for his book). This makes his account of science sound a bit more linear than the messy, human process that it is.

The volume ends by contemplating some philosophical questions: What are the moral and societal implications of being able to engineer genomes even in the fetal stage? How do we control the evils to which genetic technology can be put? What is natural and what isn’t in the age of the artificial gene? How do we balance the relentless, almost inevitable pace of science with the human quest for responsible conduct, dignity and equality? Mukherjee leaves us with a picture of these questions as well as one of his family and their shared burden of mental illness: a mirage searching for realization, a sea of questions looking for a tiny boat filled with answers.

Overall I found “The Gene: An Intimate History” to be beautifully written with a literary flair, and in spite of the omissions, the parts of genetic history and medicine which it does discuss are important and instructive. Its human stories are poignant, its lessons for the future pregnant with pitfalls and possibilities. Its sweeping profile of life’s innermost secrets could not help but remind me of a Japanese proverb quoted by physicist Richard Feynman: “To every man is given the key to the gates of heaven. The same key opens the gates of hell.” The gene is the ultimate key of this kind, and Mukherjee’s book explores its fine contours in all their glory and tragedy. We have a choice in deciding which of these contours we want to follow.

Cancer and the origins of life: The Age of Metabolism

The NYT has an interesting article on the Warburg Effect and how it can be used to provide a new weapon in the treatment of cancer (the article is part of a larger series on cancer in the weekend magazine). The effect which is named after the Nobel Prize winning German biochemist Otto Warburg pertains to the fact that tumors can grow by disproportionately consuming glucose from their environment. More specifically it deals with anaerobic respiration in tumor cells which allow them to persist even in the absence of oxygen.

This is clearly a mechanism that could be potentially targeted in cancer therapy, for example by blocking glucose transporters. But more generally it speaks to the growing importance of metabolism in cancer treatment. It seems to me that since the 1970s or so, partly because of discoveries regarding oncogenes like Ras and Src and partly because of the explosive growth in sequencing and genomics, genetics has become front and center in cancer research. This is a great thing but it's not without its pitfalls. In the race to decode the genetic basis of cancer, one gets the feeling that the study of cancer metabolism has fallen a bit by the wayside and is now being resurrected. In some sense this almost harkens back to an older period when cancer was conjectured to be caused by environmental factors affecting metabolism.

It's gratifying therefore that things like the Warburg Effect are being recognized. As the article points out, one of the simple reasons is because while many (frighteningly many in fact) genes might be mutated in cancer, a cancer cell usually has only a few ways to get energy from its surroundings: the range of targets is thus potentially fewer when it comes to energy. The recognition of this effect also speaks to the commonsense view that we should have a multipronged approach toward cancer therapy: genetics, metabolism and everything in between. Judah Folkman's idea of starving off a cancer cells's blood supply is another approach, what we may call a 'mechanical' approach (all of cancer surgery is a mechanical approach, in fact).

I could not help but also note the interesting coincidence that this tussle between emphasizing genetics vs metabolism has played out in another area which seems quite far removed from cancer medicine: the origin of life. For the longest time people focused on how DNA and RNA could have been formed on the primordial earth. It's only about 20 years ago or so that "metabolism first" started getting emphasized too: this approach emphasized the all important role that the evolution of life's energy generating apparatus (in the form of proton gradients and ATP) played in getting life jumpstarted. The metabolism first viewpoint really took off with the discovery of deep sea hydrothermal vents which can generate primitive energy-creating biochemical cycles based on proton gradients, alkaline environments and diffusion through tiny pores in the vents. Biochemists like Nick Lane and Mike Russell have been pioneers in this area.

The renewed focus on metabolism in treating cancer as well as in exploring the most primeval characteristics of life seems to me to bring the study of life in both health and disease full circle. Just like you cannot discuss the genetics of life's origins without discussing life's source of energy, so can you also not disrupt cancer's spread by disabling its genes without disabling its source of energy. Both are important, and emphasizing one over the other seems mainly to be a function of research fads and fashions rather than objective scientific reasoning.

As an amusing aside, the father of a very close friend of mine knew Otto Warburg quite well when he worked in Vienna in the 50s. Here's what he had to say about Warburg's scrupulous lab protocols: "One story I've always remembered was that he would clean his own glassware, used in experiments. He didn't trust any low-level dishwasher or junior staff around the lab. He wanted to make sure everything was perfect. I can confirm that even a tiny 'foreign fragment' in glassware can wreck an experiment."

Reality is a many-splendored thing: A review of Sean Carroll's "The Big Picture"

Sean Carroll is a successful theoretical physicist, skilled ponderer of philosophical questions and gifted communicator of science. He brings all these skills to bear in his big-hearted, ambitious latest book “The Big Picture.” The book is part sweeping survey of some of the most thought-provoking ideas in modern science, part sweeping rumination on one of the most fundamental questions that we can ask: How do we gain knowledge of the world?

The book can roughly be divided into two parts. The first part can be titled “How do we know” and the second can be titled “What do we know”. The siren song weaving its way through Carroll’s narrative is called poetic naturalism. Poetic naturalism simply means that there are many ways to talk about reality, and all of them are valid as long as they are rooted in naturalism and consistent with one another. This is the central message of the book: we make up explanations about the world and we call these explanations “stories” or “models” or “ideas”, and all of them are valid in their own ways.

The first part of the book explores some of the central concepts in the philosophy of science that make up poetic naturalism. Carroll starts from Aristotle and the ancient Greeks and progresses through the Arabs. He explores the investigations of Galileo in the seventeenth century. It was Galileo and his intellectual successor Isaac Newton who showed that the world operates according to self-sufficient physical laws that don’t necessarily require external causes. One of the most important concepts explored in the book is Bayesian thinking, in which one assigns probabilities to phenomena based on one’s previous understanding of the world and then updates this understanding (or “priors”) according to new evidence. Bayesian thinking is a powerful tool for distinguishing valid science from invalid science, and for distinguishing science from nonsense: one could in fact argue that all human belief systems operate (or should operate) according to Bayesian criteria. Bayesianism does introduce an element of subjectivity in the scientific process, but as Carroll demonstrates, this supposed bias has not harmed our investigations of natural phenomena and has allowed us to come up with accurate explanations.

Another thread weaving its way through the book is that of emergence and domains of applicability. Emergence means the existence of properties that are not strictly reducible to their constituent parts. Although Carroll is a physicist and holds fundamental physics in high regard, he appreciates that chemistry has its own language and neuroscience has its own language, and these languages are as fundamental to their disciplines as photons and electrons are to physics. No field of inquiry is thus truly fundamental in an all-encompassing sense, since there are always emergent phenomena that offer stories and explanations in their own right. Emergence also manifests itself in the form of what are called effective theories in physics; these are theories in which the macroscopic behavior of a system does not depend in a unique way on a detailed microscopic description: for instance a container of air can be perfectly described by properties like its average temperature and pressure without resorting to descriptions of quarks and Higgs bosons. As long as the two domains are consistent with each other (what Carroll calls “planets of belief”) we are on firm ground.

These ideas lay the foundation for the second half of the book which takes us on a sweeping sojourn through many of the key ideas of modern science. Carroll says that the most important description of the world comes from what’s called the ‘Core Theory’. This theory ties together the fundamental forces of nature and particles like the Higgs boson; it is grounded in general relativity and quantum mechanics. It can explain the entire physical universe, from atoms to the Big Bang, certainly in principle but often in practice. Later chapters deal with topics like evolution in real time, leading theories for the origins of life, thermodynamics and networks in the brain. When Carroll talks about entropy, complexity and the arrow of time he’s in his element; one important aspect of complexity which I had not quite appreciated is that complexity can actually result from an increase, not decrease, of entropy and disorder if guided the right way.

The book also dwells in detail upon Rene Descartes since his ideas of dualism and pure thought seem to pose challenge to poetic naturalism, but as Carroll demonstrates, these challenges are illusory since both the mind and the body can be shown to operate based on well known physical principles. These ideas keep appearing in the later parts of the book in which Carroll deals with many thought experiments in philosophy and neuroscience that purport to ask questions about reality and consciousness. Some experiments involve zombies, others involve aliens simulating us; all are entertaining. A big question is subjective experience (or “qualia”) which is sometimes regarded as some kind of impenetrable domain that’s divorced from objective laws of nature. For the most part Carroll convincingly shows us that the same laws of nature that give rise to the motion of the planets also give rise to one’s perception of the color red, for instance. This section of the book involving famous conundrums like John Searle’s Chinese Room and ‘Mary the Color Scientist’ is fascinating and highly thought-provoking, and while the thought experiments have no clear resolution, Carroll’s point is that none of them violate the basic naturalistic structure of the universe and demand mysterious explanations. His discussion of consciousness is also very stimulating; he thinks that consciousness is not really a thing per se but an emergent property of organized matter. More succinctly, it’s a description of a particular way in which matter behaves rather than something that is beyond our current understanding of natural law; it is what we say rather than what is. Much of Carroll’s discussion here reminds me, as cheesy as it sounds, of a line from ‘The Matrix’: words like love, care and purpose are mere descriptions borne of language - what matters are the connections they imply.

The book ends by taking us on a tour of some of the most important philosophical questions that human beings have asked themselves; questions of meaning, purpose, emotion and free will. Personally I found this section a bit rambling but I cannot really blame Carroll for this: none of these questions have a definitive answer and all are subject to speculation. On the other hand, this little tour provides non-specialists with an introduction to well-known philosophers and philosophies, including constructivism, deontology and utilitarianism. The big question here is how meaning can arise from the impersonal natural laws that have been described so far. Neither Carroll nor anyone else knows the answer, and the book simply makes the case that all these qualities are emergent properties that are all consistent with poetic naturalism. You may or may not be satisfied by this answer, but it certainly provides food for thought.

In a book as ambitious as this one there’s bound to be some disagreement, and that’s a good thing. Here are some concerns I had: Generally speaking Carroll is on more firm ground when talking about science rather than philosophy. Quite oddly at one point, he uses poetic naturalism to argue against opposition to gay marriage and LGBT rights. While his support for these issues is one I heartily share, I am not sure poetic naturalism is the best or the most persuasive reason to uphold these causes: we should support them not because of but in spite of naturalistic reasons. Also, Carroll who is an atheist spends several paragraphs describing how all of the arguments for a supernatural God violate naturalism. However I think religion has a purpose beyond describing the real world, and ironically this purpose lends itself to the same analysis that Carroll does of human qualities like care and love. I would think that based on much of the book’s narrative, religion would be described as an emergent phenomenon that provides people with a set of stories and descriptions; these stories provide succor and and a sense of community. Are these stories real? They may not be, and they are certainly not grounded in natural law, but Carroll himself says at one point that models of the world should be used because they are useful, not because they claim to be real. Shouldn’t one say the same thing about the positive and personal aspects of religion?

However, none of these concerns should detract from the sweeping scientific and philosophical journey the book takes us on. Carroll is an engaging, sympathetic and pleasant guide to the big picture, irrespective of whether you agree with him completely or not. Ranging over some of the most pressing questions that humanity has unearthed and continues to unearth, the one clear message in the book is an unambiguous one: we will always keep on searching, and this search will continue to propel humanity past unexpected and exciting horizons. More than anything else the discussion drives home the grandeur of the universe and the human mind, and this is grandeur we should all revel in. Perhaps this bit of wisdom from Carroll’s chapter on entropy where he is describing complexity in a cup of coffee sums it up best: “Those swirls in the cream mixing in the coffee? That’s us. Ephemeral patterns of complexity, riding a wave of increasing entropy from simple beginnings to a simple end. We should enjoy the ride.”

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 21st 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 19th 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.

Harry Kroto (1939-2016): A salesman of science in the best sense of the term

Harry Kroto who sadly passed away yesterday at 76 co-discovered fullerenes and was a passionate communicator of science. After he got the Nobel Prize, he devoted all his time to spreading the excitement of science in developing countries. Among other things he started the Vega Science Trust website which features interviews with and lectures by many famous scientists, from Feynman to Sanger. 

I had a nice chat with Kroto at the Lindau Nobel Laureate meeting in Germany in 2009. At Lindau he gave a sparkling multimedia presentation that was less science and more of a paean for science. After his talk I wrote a post comparing his presentation to savoring a rich parade of treats, and I think this attitude to science characterized his entire post-Nobel career. Below I reprint the post. Harry's zest for science will be missed

When I visit my favorite restaurant for lunch or dinner, I usually order a legitimate food item from the main course. But once in a while, just to indulge, I order a sample platter of appetizers. The appetizers don’t always provide the deep satisfaction that I get from eating a proper, expensive food item. But they provide me with a different kind of unique satisfaction; they give me a glimpse of what’s new, what’s possible. They provide a view of the diversity that can emerge in a plate of bite-sized chunks. And through their frequent novelty, they give me hope that there are new possibilities on the horizon. These appetizers constitute occasional but necessary fodder. Sir Harold Kroto’s talk was one of the most satisfying platter of appetizers I have sampled, and I had not even ordered it.

Harry Kroto exemplifies the British intellectual tradition at its best. He has three passions; science, education and humanism. And in a wonderfully entertaining talk filled with animation, quotes, videos and wit, he exemplified all three qualities. And of course no talk is ever really interesting without being a little provocative, so there was plenty of that too.
Kroto shared the Nobel Prize in 1996 for discovering a chemical structure that has become a cornerstone of our scientific imagination in the same way that DNA has. The fullerenes that he, Robert Curl and Richard Smalley discovered have symbolized scientific discovery. The myriad odd structures emerging from these structures including carbon nanotubes give us the hope of novel technologies in engineering and medicine. Since his discovery of buckyballs in 1985, Kroto has turned toward other endeavors. He has strived to make his beloved science accessible to those who would most benefit from it, namely children around the world. To do this he travels all over the world and organizes local groups in developing and developed countries who teach children about science.
Kroto believes that science should always be presented in an attractive way for it to become truly appealing. To this end his talk reflected this style. Each of the slides was highly pictorial, filled with rapid animation, videos and quotes, exactly the dose of inspiration and fun that a roomful of 500 excited science students and young researchers needed. The talk began with an exposition of “chemistry in 30 seconds”. It must have been a module that Kroto and his team designed for students; starting from simple numbers and figures Kroto derived the periodic table on the screen. The next few slides explored molecular flexibility, an important consideration which is paramount in the biological activity of drugs for instance. Kroto’s own speciality- microwave spectroscopy- examines this phenomenon and was key in the discovery of fullerenes. Kroto’s story is the quintessential story of serendipitous scientific discovery. 
His real interest was the study of molecules found in outer space. One day during this exploration he and his team accidentally discovered a peak in their spectrum, something that they were not looking for. Today a PhD. advisor may severely reprimand a graduate student if he tries to assign a chemical structure to a single signal in a complex spectrum. But Kroto and independently Smalley and Curl investigated this anomaly. As they say, the trick in science consists of seeing what everyone sees, and thinking of what nobody thinks. The rest is history, although Donald Huffman and Wolfgang Kr├Ątschmer had to synthesize fullerene in measurable quantities to meticulously characterize it.
After encapsulating chemistry in 30 seconds, Kroto moved on to the topic of science education. Some of the brightest children in the world are the most pressed for access to scientific knowledge. As I write this and look at the young scientists and bloggers around me, I ask myself, “What if we had been born in Somalia, or the DRC, or El Salvador, or a tiny village in China or India?”. We each have to realize that most of us are privileged in doing what we do not just because of our own intrinsic capabilities of learning but because of fortunate circumstances, educated parents and plain old good luck. We should continue to remember that there are kids brighter than us, kids who potentially could make Nobel Prize winning contributions, who don’t have the tiniest chance to climb the ladder of education. We owe it to ourselves to make sure if we can, to invest a tiny amount of effort in our own way to educate those who have not been fortunate to educate themselves.
To achieve this, Kroto has started the Vega Science Trust which seeks to communicate the value of science and common sense thinking to children in poor countries. In this respect Kroto is not a general who dictates from the sidelines. He is a foot soldier who is out there in the field. Photographic evidence of this fact came from several photos of Kroto teaching science to children in Mexico, Florida, China and Africa. The children were wearing t-shirts that were proudly emblazoned with fullerenes. The teaching of science extended to the spiritual; “fullerene meditation” in which children balance fullerenes on their heads while adopting a state of quiet contemplation. Kroto also emphasized the importance of the three bastions of modern information access, Google, Wikipedia and Youtube. All three constitute important forms of information access for millions of people in the future. Especially Wikipedia is a tremendous example of the remarkable wealth of high-quality knowledge and intense interest that individuals have in contributing to it.
The Vega Science Trust also has a really great website which has free access to interviews with Nobel Prize winners and other scientists, lectures by famous scientists (including a fantastic set of four one-hour lectures by Richard Feynman) and many other science resources. I have listened to several of the interviews and talks on this site and they do an admirable job of inspiring young people to study science.
However, educating children is not just educating them about science, because science itself is not simply about facts but about a process of constant questioning and revision. Sir Harold’s third passion, humanism, firmly rests on the pillars of open criticism and inquiry that exemplify science. Humanism is not necessarily a rejection of religion, but it is an active and relentless emphasis on critical thinking, equality and skeptical thought.
Here is where the talk became provocative because when you start talking about impediments to learning you inevitably have to mention religion. The science-religion controversy is so widespread that you think that everything possible that one can say about it has been said. However Kroto focused on some key aspects. He was categorically clear that children should not be indoctrinated with their parents’ religion and taught that that is the only “right” one. Kroto has spent more than a decade teaching children to be inquisitive, critical and open-minded. Religious indoctrination of children will undo much of what he has been trying to do. But for Kroto the issue goes much further. Religious indoctrination is part of many different environments that the child inhabits. To make his point Kroto showed pictures from the odious creation “museum” in Kentucky, with saddled dinosaurs and with children shown the “evolution” of the earth over the past 6000 years. Even religious moderates should find this spectacle ridiculous. Richard Dawkins has called parents bringing up their children in their own religious tradition as engaging in “child abuse”. While one might debate the merits of such a strong statement, there is no doubt that parents of all stripes must teach their children the value of open exchange and critical thinking.
But why? Why constantly stress the value of scientific thinking? Because otherwise our future generation would not be able to make the contributions that scientists at Lindau have made, and they would not be able to reap the benefits of these discoveries. The current flood of students at Lindau might well dwindle down to a trickle. We depend so intimately on continuous scientific discovery that we largely take it for granted. Too much of the science-religion debate ignores the simple fact that science has led to an enormous reduction in the amount of suffering in our world. As just two examples, Kroto quoted the discovery of anesthetics and penicillin, two discoveries which were watersheds in the amelioration of human disease and suffering. Whatever the positive and negative qualities of religion, the positive qualities of science should be apparent to any person. And it is only through the constant application of critical thinking and healthy skepticism that we have bequeathed the fruits of scientific wisdom.
Thinking about critical thinking and a balanced outlook takes us to the last point that Kroto discussed, and that was the absolutely crucial need for sustainable development. The same rational thinking that has led us away from superstition should also lead us to realize the grave danger that our activities pose to our planet, and the urgent need for prompt and cogent action. If we don’t take care of our planet, we would not be able to take care of ourselves and nothing would matter then; not fullerenes, not education and not the science-religion debate. All that would matter would be the throes of a helpless species which could not prevent its own destruction. For a species which has sequenced its own language of life, sent men to the moon, plumbed the depths of its planet and defied nature by extending its own survival and life-span by leaps and bounds, we owe ourselves more than that.
Albert Einstein once said that “all of science measured against reality is primitive and childlike- and yet it is the most precious thing we have”. This is another profound realization that is frequently lost in the science-religion debate; that science makes no claim to ultimate truths (notwithstanding the utmost self-confidence that some of its practitioners may exhibit) but it has been supremely useful in gradually helping us know and get rid of our biases; as Niels Bohr said, the rather unpretentious goal of science is the gradual removal of our prejudices. To this extent science should be the epitome of modesty. We should be humbled and reminded of our own tiny little space in the universe whenever our eyes stretch across the vast milky way or whenever we view the sheer diversity of the species that populate a rain forest and recognize the deep and intimate relationship we share with these creatures.
At the same time we should feel supremely privileged that science, with the simplest of lessons, has allowed us to transcend our dreams in ways that have been possible for no other species on our planet. Science is not perfect, but the values of open-mindedness and skepticism that it has taught us have not only allowed us to make the world a better place through practical discoveries, but have also engendered the most basic elements of humanity, including a respect for free and open minds that is independent of nationality, gender, race and language. The Lindau meeting proves that science transcends every kind of barrier like no other endeavor. This rare realization, this most unifying of paradigms, is indeed a thing of limitless value. The most precious thing that we have.