Book review: "Unraveling the Double Helix: The Lost Heroes of DNA", by Gareth Williams.

Newton rightly decried that science progresses by standing on the shoulders of giants. But his often-quoted statement applies even more broadly than he thought. A case in point: when it comes to the discovery of DNA, how many have heard of Friedrich Miescher, Fred Griffith or Lionel Alloway? Miescher was the first person to isolate DNA, from pus bandages of patients. Fred Griffith performed the crucial experiment that proved that a ‘transforming principle’ was somehow passing from a virulent dead bacterium to a non-virulent live bacterium, magically rendering the non-virulent strain virulent. Lionel Alloway came up with the first expedient method to isolate DNA by adding alcohol to a concentrated solution.

In this thoroughly engaging book, Gareth Williams brings these and other lost heroes of DNA. The book spans the first 85 years of DNA and ends with Watson and Crick's discovery of the structure. There are figures both well-known and obscure here. Along with those mentioned above, there are excellent capsule histories of Gregor Mendel, Thomas Hunt Morgan, Oswald Avery, Rosalind Franklin, Maurice Wilkins and, of course, James Watson and Francis Crick. The book traces a journey through a variety of disciplines, most notably the fields of biochemistry and genetics, that were key in deciphering the structure of DNA and its role in transmitting hereditary characteristics.

Williams’s account begins with Miescher’s isolation of DNA from pus bandages in 1869. At that point in time, proteins were well-recognized, and all proteins contained a handful of elements like carbon, nitrogen, oxygen and sulfur. The one element they did not contain was phosphorus. It was Miescher’s discovery of phosphorus in his extracts that led him and others to propose the existence of a substance they called ‘nuclein’ that seemed ubiquitous in living organisms. The two other towering figures in the biochemical history of DNA are the German chemist Albrecht Kossel and the Russian-born American chemist Phoebus Levene. They figured out the exact composition of DNA and identified its three key components: the sugar, the phosphate and most importantly, the four bases (adenine, cytosine, thymine and guanine). Kossel was such a revered figure that his students led a torchlight procession through the streets from the train station to his lab when he came back to Heidelberg with the Nobel Prize.

Levene’s case is especially interesting since his identification of the four bases set DNA research back by years, perhaps decades. Because there were only four bases, he became convinced that DNA could never be the hereditary material because it was too simple. His ‘tetra-nucleotide hypothesis’ which said that DNA could only have a repeating structure of four bases doomed its candidacy as a viable genetic material for a long time. Most scientists kept on believing that only proteins could be complex enough to be the stuff of heredity.

Meanwhile, while the biochemists were unraveling the nature of DNA in their own way, the geneticists paved the way. Williams has a brisk but vivid description of the lone monk Gregor Mendel toiling away with thousands of meticulous experiments on pea plants in his monastery in the Moravian town of Brünn. As we now know, Mendel was fortunate in picking the pea plant since it’s a purebred species. Mendel’s faith in his own work was shaken toward the end of his life when he tried to duplicate his experiments using the hawkweed plant whose genetics are more complex. Tragically, Mendel’s notebooks and letters were burnt after his death and his work was forgotten for thirty years before it was resurrected independently by three scientists, all of whom tried to claim credit for the discovery. The other major figure in genetics during the first half of the 20th century was Thomas Hunt Morgan whose famous ‘fly room’ at Columbia University carried our experiments showing the presence of hundreds of genes are precise locations on chromosomes. In his lab, there was a large pillar on which Morgan and his students drew the locations of new genes.

From the work of Mendel, Morgan, Levene and Kossel we move on to New York City where Oswald Avery, Colin MacLeod and Maclyn McCarty at the Rockefeller University and the sharp-tongued, erudite Erwin Chargaff at Columbia made two seminal discoveries about DNA. Avery and his colleagues showed that DNA is in fact the ‘transforming principle’ that Fred Griffith had identified. Chargaff showed that the proportions of A and T and G and C in DNA were similar. Williams says in the epilogue that of all the people who were potentially robbed of Nobel Prizes for DNA, the two most consequential were Avery and Griffith.

By this time, along with biochemistry and genetics, x-ray crystallography had started to become very prominent in the study of molecules: by shining x-rays on a crystal and interpreting the resulting diffraction pattern, scientists could potentially figure out the structure of the molecule on an atomic level. Williams provides an excellent history of this development, starting with the Nobel Prize-winning father-son duo of William Henry and William Lawrence Bragg (who remains the youngest Nobel Laureate at age 25) and continuing with other pioneering figures like J. D. Bernal, William Astbury, Dorothy Hodgkin and Linus Pauling.

Science is done by scientists, but it’s made possible by science administrators. Two major characters star in the DNA drama as science administrators par excellence. Both had their flaws, but without the institutions they set up to fund and encourage biological work, it is doubtful whether the men and women who discovered DNA and its structure would have made the discoveries when and where they did. William Lawrence Bragg repurposed the famed Cavendish Laboratories at Cambridge University – where Ernest Rutherford had reigned supreme - for crystallographic work on biological molecules. A parallel effort was started by John Randall, a physicist who had played a critical role in Britain’s efforts to develop radar during World War 2, at King’s College in London. While Bragg recruited Max Perutz, Francis Crick and James Watson for his group, Randall recruited Maurice Wilkins, Ray Gosling and Rosalind Franklin.

One of the strengths of Williams’s book is that it resurrects the role of Maurice Wilkins who is often regarded as the least important of the Nobel Prize-winning triplet of Watson, Crick and Wilkins. In fact, it was Wilkins and Gosling who took the first x-ray photographs of DNA that seemed to indicate a helical structure. Wilkins was also convinced that DNA and not protein was the genetic material when that view was still unfashionable; he passed on his infectious enthusiasm to Crick and Watson. But even before his work, the Norwegian crystallographer Sven Furberg had been the first to propose a helix – although a single one – as the structure of DNA based on his density and other important features. A key feature of Furberg’s model was that the sugar and the base were perpendicular, which is in fact the case with DNA.

The last third of the book deals with the race to discover the precise structure of DNA. This story has been told many times, but Williams tells it exceptionally well and especially drives home how Watson and Crick were able to stand on the shoulders of many others. Rosalind Franklin comes across as a fascinating, complex, brilliant and flawed character. There was no doubt that she was an exceptional scientist who was struggling to make herself heard in a male-dominated establishment, but it’s also true that her prickly and defensive personality made her hard to work with. Unlike Watson, she was especially reluctant to build models, perhaps because she had identified a fatal flaw in one of the pair’s earlier models. It’s not clear how close Franklin came to identifying DNA as a helix; experimentally she came close, but psychologically she seemed reluctant and bounced back and forth between helical and non-helical structures.

So what did Watson and Crick have that the others did not? As I have described in a post written a few years ago on the 70th anniversary of the DNA structure, many others were in possession of key parts of the evidence, but only Watson and Crick put it all together and compulsively built models. In this sense it was very much like the blind men and the elephant; only Watson and Crick bounced around the entire animal and saw how it was put together. Watson’s key achievement was recognizing the precise base pairing: adenine with thymine and guanine with cytosine. Even here he was helped by the chemist Jerry Donohue who corrected a key chemical feature of the bases (organic chemists will recognize it as what’s called keto-enol tautomerism). Also instrumental were Alec Stokes and John Griffith. Stokes was a first-rate mathematician who, using the theory of Bessel functions, figured out the diffraction pattern that would correspond to a helix; Crick who was a physicist well-versed with the mathematics of diffraction, instantly understood Stokes’s work. Griffith was a first-rate quantum chemist who figured out, independently of Donohue, that A would pair with T and G with C. Before the advent of computers and what are called ab initio quantum chemical techniques, this seems like a remarkable achievement.

With Chargaff’s knowledge of the constancy of base ratios, Donohue’s precise base structures, Franklin and Gosling’s x-ray measurements and Stokes’s mathematics of helix diffraction patterns, Watson and Crick had all the information they needed to try out different models and cross the finish line. No one else had this entire map of information at their disposal. The rest, as they say, is history.

I greatly enjoyed reading Williams’s book. It is, perhaps, the best book on the DNA story that I have read since Horace Freeland Judson’s “The Eighth Day of Creation”. Even characters I was familiar with newly come to life as flawed, brilliant human beings with colorful lives. The account shows that many major and minor figures made important discoveries about DNA. Some came close to figuring out the structure but never made the leap, either because they lacked data or because of personal prejudices. Taken as a whole, the book showcases well the intrinsically human story and the group effort, playing out over 85 years, at the heart of the one of the greatest discoveries that humanity has made. I highly recommend it.

Brian Greene and John Preskill on Steven Weinberg

There's a very nice tribute to Steven Weinberg by Brian Greene and John Preskill that I came across recently that is worth watching. Weinberg was of course one of the greatest theoretical physicists of the later half of the 20th century, winning the Nobel Prize for one of the great unifications of modern physics, which was the unification of the electromagnetic and the weak forces. He was also a prolific author of rigorous, magisterial textbooks on quantum field theory, gravitation and other aspects of modern physics. And on top of it all, he was a true scholar and gifted communicator of complex ideas to the general public through popular books and essays; not just ideas in physics but ones in pretty much any field that caught his fancy. I had the great pleasure and good fortune to interact with him twice.

The conversation between Greene and Preskill is illuminating because it sheds light on many underappreciated qualities of Weinberg that enabled him to become a great physicist and writer, qualities that are worth emulating. Greene starts out by talking about when he first interacted with Weinberg when he gave a talk as a graduate student at the physics department of the University of Texas at Austin where Weinberg taught. He recalls how he packed the talk with equations and formal derivations, only to have the same concepts explained by Weinberg more clearly later. As physicists appreciate, while mathematics remains the key to unlock the secrets of the universe, being able to understand the physical picture is key. Weinberg was a master at doing both.

Preskill was a graduate student of Weinberg's at Harvard and he talks about many memories of Weinberg. One of the more endearing and instructive ones is from when he introduced Weinberg to his parents at his house. They were making ice cream for dinner, and Weinberg wondered aloud why we add salt while making the ice cream. By that time Weinberg had already won the Nobel Prize, so Preskill's father wondered if he genuinely didn't understand that you add the salt to lower the melting point of the ice cream so that it would stay colder longer. When Preskill's father mentioned this Weinberg went, "Of course, that makes sense!". Now both Preskill and Greene think that Weinberg might have been playing it up a bit to impress Preskill's family, but I wouldn't be surprised if he genuinely did not know; top tier scientists who work in the most rarefied heights of their fields are sometimes not as connected to basic facts as graduate students might be. 

More importantly, in my mind the anecdote illustrates an important quality that Weinberg had and that any true scientist should have, which is to never hesitate to ask even simple questions. If, as a Nobel Prize winning scientist, you think you are beyond asking simple questions, especially when you don't know the answers, you aren't being a very good scientist. The anecdote demonstrates a bigger quality that Weinberg had which Preskill and Greene discuss, which was his lifelong curiosity about things that he didn't know. He never hesitated to pump people for information about aspects of physics he wasn't familiar with, not to mention another disciplines. Freeman Dyson who I knew well had the same quality: both Weinberg and Dyson were excellent listeners. In fact, asking the right question, whether it was about salt and ice cream or about electroweak unification, seems to have been a signature Weinberg quality that students should take to heart.

Weinberg became famous for a seminal 1967 paper that unified the electromagnetic and weak force (and used ideas developed by Peter Higgs to postulate what we now call the Higgs boson). The title of the paper was "A Model of Leptons", but interestingly, Weinberg wasn't much of a model builder. As Preskill says, he was much more interested in developing general, overarching theories than building models, partly because models have a limited applicability to a specific domain while theories are much more general. This is a good point, but of course, in fields like my own field of computational chemistry, the problem isn't that there are no general theoretical frameworks  - there are, most notably the frameworks of quantum mechanics and statistical mechanics - but that applying them to practical problems is too complicated unless we build specific models. Nevertheless, Weinberg's attitude of shunning specific models for generality is emblematic of the greatest scientists, including Newton, Pauling, Darwin and Einstein.

Weinberg was also a rather solitary researcher; as Preskill points out, of his 50 most highly cited papers, 42 are written alone. He admitted himself in a talk that he wasn't the best collaborator. This did not make him the best graduate advisor either, since while he was supportive, his main contribution was more along the lines of inspiration rather than guidance and day-to-day conversations. He would often point students to papers and ask them to study them themselves, which works fine if you are Brian Greene or John Preskill but perhaps not so much if are someone else. In this sense Weinberg seems to be have been a bit like Richard Feynman who was a great physicist but who also wasn't the best graduate advisor.

Finally, both Preskill and Greene touch upon Weinberg's gifts as a science writer and communicator. More than many other scientists, he never talked down to his readers because he understood that many of them were as smart as him even if they weren't physicists. Read any one of his books and you see him explaining even simple ideas, but never in a way that assumes his audience are dunces. This is a lesson that every scientist and science writer should take to heart.

Greene especially knew Weinberg well because he invited him often to the World Science Festival which he and his wife had organized in New York over the years. The tribute includes snippets from Weinberg talking about the current and future state of particle physics. In the last part, an interviewer asks him about what is arguably the most famous sentence from his popular writings. In the last part of his first book, "The First Three Minutes", he says, "The more the universe seems comprehensible, the more it seems pointless." Weinberg's eloquent response when he was asked what this means sums up his life's philosophy and tells us why he was so unique, as a scientist and as a human being:

"Oh, I think everything's pointless, in the sense that there's no point out there to be discovered by the methods of science. That's not to say that we don't create points for our lives. For many people it's their loved ones; living a life of helping people you love, that's all the point that's needed for many people. That's probably the main point for me. And for some of us there's a point in scientific discovery. But these points are all invented by humans and there's nothing out there that supports them. And it's better that we not look for it. In a way, we are freer, in a way it's more noble and admirable to give points to our lives ourselves rather than to accept them from some external force."

A long time ago, in a galaxy far, far away

For a brief period earlier this week, social media and the world at large seemed to stop squabbling about politics and culture and united in a moment of wonder as the James Webb Space Telescope (JWST) released its first stunning images of the cosmos. These "extreme deep field" images represent the farthest and the oldest that we have been able to see in the universe, surpassing even the amazing images captured by the Hubble Space Telescope that we have become so familiar with. We will soon see these photographs decorating the walls of classrooms and hospitals everywhere.

The scale of the JWST images is breathtaking. Each dot represents a galaxy or nebula from far, far away. Each galaxy or nebula is home to billions of stars in various stages of life and death. The curved light in the image comes from a classic prediction of Einstein's general theory of relativity called gravitational lensing - the bending of light by gravity that makes spacetime curvature act like a lens. 

Some of the stars in these distant galaxies and nebulae are being nurtured in stellar nurseries; others are in their end stages and might be turning into neutron stars, supernovae or black holes. And since galaxies have been moving away from us because of the expansion of the universe, the farther out we see, the older the galaxy is. This makes the image a gigantic hodgepodge of older and newer photographs, ranging from objects that go as far back as 100 million years after the Big Bang to very close (on a cosmological timescale) objects like Stephan's Quintet and the Carina Nebula that are only a few tens of thousands of light years away.

It is a significant and poignant fact that we are seeing objects not as they are but as they were. The Carina Nebula is 8,500 light years away, so we are seeing it as it looked like 8,500 years ago, during the Neolithic Age when humanity had just taken to farming and agriculture. On the oldest timescale, objects that are billions of light years away look the way did during the universe's childhood. The fact that we are seeing old photographs or stars, galaxies and nebulae gives the photo a poignant quality. For a younger audience who has always grown up with Facebook, imagine seeing a hodgepodge of images of people from Facebook over the last fifteen years presented to you: some people are alive and some people no longer so, some people look very different from what they did when their photo was last taken. It would be a poignant feeling. But the JWST image also fills me with joy. Looking at the vast expanse, the universe feels not like a cold, inhospitable place but like a living thing that's pulsating with old and young blood. We are a privileged part of this universe.

There's little doubt that one of the biggest questions stimulated by these images would be whether we can detect any signatures of life on one of the many planets orbiting some of the stars in those galaxies. By now we have discovered thousands of extrasolar planets around the universe, so there's no doubt that there will be many more in the regions the JWST is capturing. The analysis of the telescope data already indicates a steamy atmosphere containing water on a planet about 1,150 light years away. Detecting elements like nitrogen, carbon, sulfur and phosphorus is a good start to hypothesizing about the presence of life, but much more would be needed to clarify whether these elements arise from an inanimate process or a living one. It may seem impossible that a landscape as gargantuan as this one is completely barren of life, but given the improbability of especially intelligent life arising through a series of accidents, we may have to search very wide and long.

I was gratified as my twitter timeline - otherwise mostly a cesspool of arguments and ad hominem attacks punctuated by all-too-rare tweets of insight - was completely flooded with the first images taken by the JWST. The images proved that humanity is still capable of coming together and focusing on a singular achievement of science and technology, how so ever briefly. Most of all, they prove both that science is indeed bigger than all of us and that we can comprehend it if we put our minds and hands together. It's up to us to decide whether we distract ourselves and blow ourselves up with our petty disputes or explore the universe as revealed by JWST and other feats of human ingenuity in all its glory.

Image credits: NASA, ESA, CSA and STScl

Book Review: "The Rise and Reign of the Mammals: A New History, From the Shadows of the Dinosaurs to US", by Steve Brusatte

A terrific book by Edinburgh paleontologist Steve Brusatte on the rise of the mammals. Engaging, personal and packed with simple explanations and analogies. Brusatte tracks the evolution of mammals from about 325 million years ago when our reptilian answers split off into two groups - the synapsids and the diapsids. The diapsids gave rise to reptiles like crocodiles and snakes while the synapsids eventually gave rise to us. The synapsids evolved with a hole behind their eye socket: it’s now covered with a set of muscles which you can feel if you touch your cheek while chewing.

Much of the book is focused on how mammals evolved different anatomical and physiological functions against the backdrop of catastrophic and gentle climate change, including the shifting of the continents and major extinctions driven by volcanic eruptions, meteors (during the K-T extinction event that killed the dinosaurs) sea level rises and ice ages. That mammals survived these upheavals is partly a result of chance and partly a result of some remarkable adaptations which the author spends considerable time describing. These adaptations include milk production, temperature regulation, hair, bigger brains and stable locomotion, among others.

Some these changes were simple but significant - for instance, a law named Carrier’s law limits lung capacity in slithering reptiles because each lung alternately gets compressed during sidewinding motions. When mammalian ancestors were able to lift their body upward from the ground and able to install a set of bones that constrained the rib cage, it allowed their lungs to be able to breathe and expel oxygen during movement and when the animal was eating. Needless to say, the ability to breathe and move while eating was momentous for survival in an environment in which predators abounded.

Another adaptation was the development of a specialized set of teeth that mark all mammals including humans - the incisors, canines, pre-molars and molars. Because these teeth form a specialized, complex apparatus, they emerge only twice in mammals - once during infancy and one more time during adulthood. But out chewing apparatus gave rise to another remarkable adaptation - in an evolutionary migration spread out over millions of years, bones of the jaw became the bones of the ear. The ear bones are a set of finely orchestrated and sensitive sound detectors that gave mammals an acute sense of hearing and enabled them to seek out mates and avoid predators.

Quite naturally, the book spends a good amount of time describing the mystery of why mammals survived the great meteor extinction of dinosaurs and much of other life on the planet. Except that it’s no mystery. Dinosaurs were bulky and specialized cold-blooded eaters which were exposed. Mammals were furry, rodent-like warm-blooded omnivores which could hide out underground and eke out an existence on charred vegetation and dead flesh in the post-apocalyptic environment. After the K-T event, there was no turning back for mammals.

The rest of the book spends time discussing particular features of mammalian evolution like flight in bats and the odd monotremes like the duck-billed platypus which lay eggs. A particularly memorable discussion is of the whales, the biggest mammals which have ever lived, which actually evolved from land mammals that would occasionally take to water to escape predators and seek out new food. With their exceptionally big brains and bat-like echolocation, whales remain a wonder of nature.

Brusatte also spices up his account with adventurous stories of intrepid paleontologists and archeologists who have dup up pioneering fossils in extreme environments ranging from the blistering tropical forests of Africa to the Gobi desert of Mongolia. Paleontology comes across as a truly international endeavor, with Chinese paleontologists especially making significant contributions; they were among the first for instance to discover a feather dinosaur, attesting to the reptile to bird evolutionary transition. Unlike old times when Victorian men did most of the digging, women are now a healthy percentage of the field.

Human evolution occupies only a few chapters of Brusatte’s book, and for good reason. While humans occupy a unique niche because of their intelligence, evolutionarily they are no more special or fascinating than whales, bats, platypuses, elephants or indeed the earliest synapsids. What we can take heart from is the fact that we are part of an unbroken thread of evolution ranging across all these creatures. Mammals have survived catastrophic extinctions and climate change events. Humans are now being responsible for one. Whether they are responsible for their own extinction or show the kind of adaptability that their ancestors showed is a future state only they are responsible for.