Lessons from Tom Steitz, surveyor of molecular empires (1940-2018)

The ribosome is one of the most important and complicated molecular machines ever devised by evolution. Functioning as the factory and assembler for making proteins from RNA, it is as important as DNA itself and is found in every life form on planet Earth. If we find life on another planet, along with some form of DNA, it is almost certain to contain some kind of ribosome.

Tom Steitz, Venki Ramakrishnan and Ada Yonath won the Nobel Prize for chemistry in 2009 for cracking the structure of the ribosome. I was saddened to hear that Steitz passed away a few days ago. Incidentally, his demise comes after Venki Ramakrishnan published his memoir on his ribosome odyssey, a journey that both starred and owed a lot to Tom Steitz.

Over more than two decades, Steitz, Ramakrishnan, Yonath and others used laborious techniques to carefully obtain more complicated and better structures of this beast of a molecule. And a beast it certainly was; the 40S subunit of a eukaryotic ribosome contains 1900 nucleotides and 33 proteins. While protein crystallography is now routine, solving the structure of a multiprotein assembly like the ribosome is incredibly daunting even now, and is a tribute to both the perseverance and the creativity of these scientists. Crystallography is the ultimate example of marathon running in science, something that at its highest levels can easily take a decade and long hours in the lab. Even before he attacked the ribosome, Steitz had already established a reputation as one of the world's top crystallographers, doing a detailed study of the enzyme hexokinase for instance. Among other findings, his work revealed that the ribosome is composed mainly of RNA rather than proteins; another boost for the RNA world theory for the origins of life.

I have fond memories of Steitz from my time as a postdoc at the University of North Carolina, Chapel Hill. In 2010, a year after he won the prize, he was a visiting lecturer at UNC. Four or five of us had a chance to sign up for a private breakfast with him in a small room at the faculty club. There wasn't a trace of ego in Steitz's interactions with us, but what I remember best was his unending curiosity regarding each of our research projects (not surprisingly, he was particularly interested in some cryo-EM work a colleague of mine was doing). It was clear that Seitz was no prima donna, but a scientist's scientist who was not resting on his laurels but seeking new adventures.

The New York Times has a good obituary of Steitz that showcases many of his qualities. After his PhD he trained at the famed MRC Laboratory of Molecular Biology, an institution started by Watson, Crick, Perutz and others that has produced more than fifteen Nobel Laureates. The article talks about the atmosphere in the institute, where Nobel laureates sat next to graduate students during tea and lunch in the cafeteria and constantly talked science. One thing that struck Steitz was how much time they spent talking about experiments rather than doing them; later he realized that they were basically enforcing a process of ruthless elimination on the experiments by discussing them beforehand, so that they would pursue only the most promising ones. That's a good lesson.

I remember another MRC-related anecdote that Steitz told us during our breakfast eight years ago; he was constantly surprised how the famous scientists at the MRC asked seemingly stupid or simple questions whose answers were not as obvious as we think. For instance, he remembers Max Perutz asking everyone what a eukaryote was; the question led to an unexpectedly fascinating discussion about the molecular differences between eukaryotes and prokaryotes. Steitz emphasized to us how important it is to keep on asking simple questions and setting our egos aside, a lesson that many of us sadly don't imbibe.

Steitz's wife Joan is an equally eminent biologist in her own regard. She was awarded a Lasker Prize this year and has done much to advance RNA science in addition to serving as a role model for women in science. When Steitz was looking for a faculty position he was offered one at Berkeley, but they declined to offer Joan - a protégé of James Watson - one, so Steitz turned down the job, and the couple moved to Yale where both of them acquired prestigious positions.

Tom Steitz was a scientist's scientist and an honorable man who did much to advance progress in molecular biology and the cause of honest, sound science. He will be missed.

Leroy Hood and the tool-driven revolution in biology

The Galisonian view of science - named after historian of science Peter Galison - says that science is driven as much or even more by new techniques and instruments as by new ideas. Sadly most people have always placed theoretical ideas at the forefront of scientific revolutions, a view enforced by Thomas Kuhn's famous book "The Structure of Scientific Revolutions". But a study of the history of science shows that new tools have been as instrumental in opening up whole new areas of science as new ideas. In fact one may argue that ideas allow you to largely explain while novel tools allow you to largely discover new things.

From the viewpoint of tool-based science, scientists like Faraday, Rutherford, Woodward, and Lamb are as important as Newton, Dirac, Heisenberg and Pauling. To this list of tool-builders and users must be added the name of Leroy Hood. Hood is one of the most important pioneers of the genomics revolution. Seeing far ahead of most biologists in the 1980s when he was at Caltech, he invented four tools that were to revolutionize the theory and practice of genomics: the protein sequencer, the protein synthesizer, the DNA synthesizer and the DNA sequencer. At a time when most biologists positively looked down upon technology development and engineers, Hood blazed new paths in combining chemistry, instrumentation and biology. His tools not only allowed biologists to do things better, but allowed them to discover new things which they hadn't imagined before.

Luke Timmerman has written a valuable biography of Hood which would be of interest to anyone interested in the recent history of the gene. I picked it up encouraged by Keith's favorable review (http://omicsomics.blogspot.com/…/veteran-biotech-reporter-l…) and am glad I did. My only reservation is that Timmerman could have done a much better job embedding Hood's inventions in the bigger story of genetics and molecular biology. There were parts of the book where I thought the science could have been fleshed out much more, so if you are looking for a concomitant work of popular science along with a biography, this is not really it.

Hood's essential qualities were ingrained during a vigorous upbringing in rural Montana. His father was a peripatetic telephone engineer who did not give praise easily. He and Hood's mother taught their children to be self-reliant, resilient and hard-working. Throughout his career Hood has been a force of nature, displaying these qualities to an unprecedented extent and leaving behind some of his more talented competitors by sheer tenacity and dedication. As he recounts, the most valuable class for him in high school was not math or science but debating. He was also his high school's star quarterback. Even now, at the age of 75, he runs 3 miles every day and does a hundred push ups. He has also combined great scientific talent with a passion for public speaking and entrepreneurship; through these skills he has raised hundreds of millions of dollars from universities, funding agencies and wealthy philanthropists and made millions of his own. He has given generously to the cause of middle and high school education. No obstacle has been daunting for him, and by any of the usual metrics his career has been stunningly successful; as his website points out, "in addition to his ground-breaking research, Hood has published 750 papers, received 36 patents, 17 honorary degrees and more than 100 awards and honors, and has founded or co-founded 15 biotechnology companies including Amgen and Applied Biosystems."

Hood got his undergraduate and graduate degrees from Caltech along with an MD from Johns Hopkins. Caltech sought him out as an assistant professor right after graduation. Hood's early contributions were to immunology where he figured out the basis of antibody diversity. But soon he began to broaden his horizons and became one of the first biologists to truly appreciate the impact of new technology on biology. He had an amazing talent to spot big picture problems, drive himself mercilessly to crack them and recruit world class people to solve them. Using his unique skill set he built the first protein sequencer and DNA sequencer and licensed them out to the company Applied Biosystems. The DNA sequencer is at the very heart of the genomics revolution. Gene sequencing is no longer just a tool for faster and more efficient molecular biology, but it has transformed itself into a formidable instrument to explore stunning new domains of biology, from the creation of new organisms to the cracking of the genetic code for all kinds of diseases to the exploration of the world's biodiversity. Hood's work showed that not only can technology enable science but it can actually give rise to new science.

Unfortunately Hood's grand visions and the size of his lab and research projects (at one point his lab numbered more than a hundred people) soon ran afoul of Caltech's desire to stay a small, tightly knit school. Very soon he had a falling out with the faculty. One of his students who is now the head of research at Merck was then a professor at the University of Washington. He persuaded the medical school at UW to invite Hood for a few lectures. The chairman of the department in turn persuaded Bill Gates to attend those lectures. Gates who had started taking an interest in biology in the late 90s was entranced by Hood and immediately agreed to endow a $12 million dollar faculty position at UW for Hood. Hood's moved to UW was accompanied by breathless press releases proclaiming that his appointment was one of the most momentous events in the history of the university.

At UW Hood became the father of a new science: systems biology. He was no longer content to just explore genes and whole organisms, instead he wanted to bring about a completely unified view of biology by connecting atoms to molecules to cells, all the way to whole organisms and ecosystems. It was a grand vision, and one which only someone like Hood could pull off. Systems biology is now a mainstay of cutting edge biological science, bringing together biologists, mathematicians, computer scientists and other. But Hood got there first, being one of the first scientists to bring together interdisciplinary subject experts.

Sadly it was here that Hood's failings become clear, and Timmerman pulls no punches in narrating them. Hood was a big picture thinker, not a detail-oriented person. He left the day to day running of his labs to postdocs and research associates. More importantly, he was terrible at interpersonal relationships. He almost never took interest in his students' lives, never picked up the check when he "took them out" for lunch and regularly played favorites. He was not an unkind person, but he was simply too busy, driven to succeed and tone deaf to the everyday human relationships that make any endeavor successful. He was not above claiming credit for others' discoveries, not intentionally but because of his relentless drive to finish that simply left him clueless about such things. He rubbed people the wrong way at Caltech and UW and found even the generous support at UW insufficient for his systems biology vision. Predictably enough, when some of his key allies passed away, he had a falling out at UW too after he tried to sell them a plan for an independent new institute. Confident that his friend Bill Gates would fund it, he went to see Gates at Microsoft, only to be turned away with an icy dismissal (Gates: "I never fund things that I think are going to fail."). Undaunted, Hood poured $5 million of his own money into the institute. Personally too he faced a tragedy: his wife Valerie who he had married out of college succumbed to Alzheimer's disease.

Since then, the Institute for Systems Biology in Seattle has become a thriving research institute that is at the forefront of investigating both basic and applied genetics. Hood continues to be a powerhouse, crisscrossing the world giving talks about how biology is going to revolutionize human life. The system's research may or may not help discover new cures for important diseases, but what's more important is the vision and accomplishment of one man in achieving all that: Lee Hood. Hood is a fantastic example of what happens when passionate tenacity for a cause, a deep appreciation of the impact of technology on science, a passion for entrepreneurship and a relentless pursuit of the big picture come together to create an explosive mix. In the DNA sequencers that are humming softly in hundreds of thousands of industrial and academic laboratories and hospitals around the world, reading and rewriting the code of life, Lee Hood's legacy keeps humming on too.

The structure of DNA, 61 years later: How they did it.

"A Structure for Deoxyribose Nucleic Acid", Nature, April 25, 1953 (Image: Oregon State University)

This month marks the sixty-first anniversary of the publication of the landmark paper on the structure of DNA by Watson and Crick, which appeared in the April 25, 1953 issue of the journal Nature. Even fifty years later the discovery is endlessly intriguing, not just because it's so important but because in 1954, both Watson and Crick were rather unlikely characters to have made it. In 2012 I wrote a post for the Nobel Week Dialogue event in Stockholm with a few thoughts on what it exactly was that allowed the duo to enshrine themselves in the history books; it was not sheer brilliance, it was not exhaustive knowledge of a discipline, but it was an open mind and a relentless drive to put disparate pieces of the puzzle together. Here's that post.

Somehow it all boils down to 1953, the year of the double helix. And it’s still worth contemplating how it all happened.

Science is often perceived as either a series of dazzling insights or as a marathon. Much of the public recognition of science acknowledges this division; Nobel Prizes for instance are often awarded either for a long, plodding project that is sustained by sheer grit (solving a protein crystal structure), a novel idea that seems to be an inspired work of sheer genius (formulating the Dirac equation) or an accumulated body of work (organic synthesis).

But in one sense, both these viewpoints of science are flawed since both of them tend to obscure the often haphazard, unpredictable, chancy and very human process of research. In reality, the marathon runner, the inspired genius and every scientist in between the two tread a tortuous path to the eureka moment, a path that’s highlighted by false alleys, plain old luck, unexpected obstacles and most importantly, the human obstacles of petty rivalry, jealousy, confusion and misunderstanding. A scientific story that fully captures these variables is, in my opinion, emblematic of the true nature of research and discovery. That is why the discovery of the double helix by Watson and Crick is one of my favorite stories in all of science.

The reason why that discovery is so appealing is because it really does not fit into the traditional threads of scientific progress highlighted above. During those few heady days in Cambridge in the dawn of those gloomy post-war years, Watson and Crick worked hard. But their work was very different from, say, the sustained effort akin to climbing a mountain that exemplified Max Perutz’s lifelong odyssey to solve the structure of hemoglobin. It was also different from the great flashes of intuition that characterized an Einstein or a Bohr, although intuition was applied to the problem – and discarded – liberally. Neither of the two protagonists was an expert in the one discipline that they themselves acknowledged mattered most for the discovery – chemistry. And although they had a rough idea of how to do it, neither really knew what it would take to solve the problem. They were far from being experts in the field.

And therein lies the key to their success. Because they lacked expertise and didn’t really know what would solve the problem, they tried all approaches at their disposal. Their path to DNA was haphazard, often lacking direction, always uncertain. Crick, a man who already considered himself an overgrown graduate student in his thirties, was a crystallographer. Watson, a precocious and irreverent youngster who entered the University of Chicago when he was fifteen, was in equal parts geneticist and bird-watcher. Unlike many of their colleagues, both were firmly convinced that DNA and not protein was the genetic material. But neither of them had the background for understanding the chemistry that is essential to DNA structure; the hydrogen bonding that holds the bases together, the acid-base chemistry that ionizes the phosphates and dictates their geometric arrangement, the principles of tautomerism that allow the bases to exist in one of two possible forms; a form that’s crucial for holding the structure together. But they were willing students and they groped, asked, stumbled and finally triumphantly navigated their way out of this conceptual jungle. They did learn all the chemistry that mattered, and because of Crick they already understood crystallography.

And most importantly, they built models. Molecular models are now a mainstay of biochemical research. Modelers like myself can manipulate seductively attractive three-dimensional pictures of proteins and small molecules on computer screens. But modeling was in its premature days in the fifties. Ironically, the tradition had been pioneered by the duo’s perceived rival, the chemist Linus Pauling. Pauling who would be widely considered the greatest chemist of the twentieth century had successfully applied his model-building approach to the structure of proteins. Lying in bed with a bad cold during a visiting sojourn at Oxford University, he had folded paper and marked atoms with a pencil to conform to the geometric parameters of amino acids derived from simple crystal structures. The end product of this modeling combined with detailed crystallographic measurements was one of twentieth century biochemistry’s greatest triumphs; the discovery of the alpha-helical and beta-sheet structures, foundational structural elements in virtually every protein in nature. How exactly the same model-building later led Pauling to an embarrassing gaffe in his own structure of DNA that violated basic chemical principles is the stuff of folklore, narrated with nonchalant satisfaction by Watson in his classic book “The Double Helix”.

Model building is more art than science. By necessity it consists of patching together imperfect data from multiple avenues and techniques using part rational thinking and part inspired guesswork and then building a picture of reality – only a picture – that’s hopefully consistent with most of the data and not in flagrant violation with important pieces. Even today modeling is often regarded skeptically by the data-gatherers, presumably because it does not have the ring of truth that hard, numerical data has. But data by itself is never enough, especially because the methods to acquire it themselves are incomplete and subject to error. It is precisely by combining information from various sources that one expects to somehow cancel these errors or render them unimportant, so that the signal from one source complements its absence in another and vice versa. The building of a satisfactory model thus often necessarily entails understanding data from multiple fields, each part of which is imperfect.

Watson and Crick realized this, but many of their contemporaries tackling the same problem did not. As Watson recounts it in a TED talk, Rosalind Franklin and Maurice Wilkins were excellent crystallographers but were hesitant to build models using imperfect data. Franklin especially came tantalizingly close to cracking DNA. On the other hand Erwin Chargaff and Jerry Donahue, both outstanding chemists, were less appreciative of crystallography and again not prone to building models. Watson and Crick were both willing to remedy their ignorance of chemistry and to bridge the river of data between the two disciplines of chemistry and crystallography. Through Donohue they learnt about the keto-enol tautomerism of the bases that gave rise to the preferred chemical form. From Chargaff came crucial information regarding constancy of the ratios of one kind of base (purines) to another (pyrimidines); this information would be decisive in nailing down the complementary nature of the two strands of the helix. And through Rosalind Franklin they got access – in ways that even today spark controversy and resentment – to the best crystallographic data on DNA that then existed anywhere.

What was left to do was to combine these pieces from chemistry and crystallography and put together the grand puzzle. For this model building was essential; since Watson and Crick were willing to do whatever it took to solve the structure, to their list of things-to-do they added model building. Unlike Franklin and Wilkins, they had no qualms about building models even if it meant they got the answer partially right. The duo proceeded from a handful of key facts, each of which other people possessed, but none of which had been seen by the others as part of an integrated picture. Franklin especially had gleaned very important general features of the helix from her meticulous diffraction experiments and yet failed to build models, remaining skeptical about the very existence of helices until the end. It was the classic case of the blind men and the elephant.

The facts which led Watson and Crick down the road to the promised land included a scattered bundle of truths about DNA from crystallography and chemistry; the distance between two bases (3.4 Å), the distance per turn of the helix (34 Å) which in turn indicated a distribution of ten bases per turn, the diameter of the helix (20 Å), Chargaff’s rules indicating equal ratios of the two kinds of bases, Alexander Todd’s work on the points of linkage between the base, sugar and nucleotide, Donohue’s important advice regarding the preferred keto form of the bases and Franklin’s evidence that the strands in DNA must run in opposite directions. There was another important tool they had, thanks to Crick’s earlier mathematical work on diffraction. Helical-diffraction theory told them the kind of diffraction pattern that would expect if the structure were in fact helical. This reverse process – predicting the expected diffraction parameters from a model – is today a mainstay of the iterative process of structure refinement used by x-ray crystallographers to solve structures as complex as the ribosome.

Using pieces from the metal shop in Cambridge, Watson gradually accumulated a list of parts for the components of DNA and put them together even as Crick offered helpful advice. Once the pieces were in place, the duo were in the position of an airline pilot who has every signpost, flag and light on the runway paving his way for a perfect landing. The end-product was unambiguous, incisive, elegant, and most importantly, it held the key to understanding the mechanism of heredity through complementary base-pairing. Franklin and Wilkins came down from London; the model was so convincing that even Franklin graciously agreed that it had to be correct. Everyone who saw the model would undoubtedly have echoed Watson and Crick’s sentiment that “a structure this beautiful just had to exist”.

In some sense the discovery of the DNA structure was easy; as Max Perutz once said, the technical challenges that it presented were greatly mitigated because of the symmetry of the structure compared to the controlled but tortuous asymmetry inherent in proteins. Yet it was Watson and Crick and not others who made this discovery and their achievement provides insight into the elements of a unique scientific style. Intelligence they did not lack, but intelligence alone would not have helped, and in any case there was no dearth of it; Perutz, Franklin, Chargaff and Pauling were all brilliant scientists who in principle could have cracked open the secret of life which its discoverers proudly touted that day in the Eagle Pub. 

But what these people lacked, what Watson and Crick possessed in spades, was a drive to explore, interrogate, admit ignorance, search all possible sources and finally tie the threads together. This set of traits also made them outsiders in the field, non-chemists who were trying to understand a chemical puzzle; in one sense they appeared out of nowhere. But because they were outsiders they were relatively unprejudiced. Their personalities cast them as misfits and upstarts trying to disrupt the established order. Then there was the famous irreverence between them; Crick once said that politeness kills science. All these personal qualities certainly helped, but none was as important as a sprightly open-mindedness that was still tempered by unsparing rigor, the ability to ask for and use evidence from all quarters while constraining it within reasonable bounds all the time; this approach led to model building almost as a natural consequence. And the open-mindedness also masked a fearlessness that was undaunted by the imperfect nature of the data and the sometimes insurmountable challenges that seemed to loom.

So that’s how they did it; by questioning, probing, conjecturing and model building even in the presence of incomplete data, and by fearlessly using every tool and idea at their disposal. As we approach problems of increasing biological complexity in the twentieth century, this is a lesson we should keep in mind. Sometimes when you don’t know what approach will solve a problem, you try all approaches, all the time constraining them within known scientific principles. Richard Feynman once defined scientific progress as imagination in a straitjacket, and he could have been talking about the double helix.

First published on Nobel Week Dialogue and the Scientific American Blog Network.

How a college student can derive the RNA world hypothesis from scratch

One of the greatest breakthroughs in twentieth century biology was the finding that RNA can serve as a catalyst and drive some of life's essential chemical reactions. This discovery which garnered a Nobel Prize led the way to understanding ribozymes, splicing and the structure and function of the ribosome. It also propelled the conception of the so-called "RNA world hypothesis" for the origin of life which suggests that RNA was the earliest enzyme. This hypothesis in various forms has since been regarded as the single most plausible hypothesis for the origin of life.

The purpose of this post would be to postulate that, as stunning and important as the RNA world hypothesis is, it probably could be derived by a smart (admittedly a really smart) high-school or college student with no more than a basic understanding of organic chemistry, molecular biology and evolution. This exercise is in no way meant to be a put-down of the significance or difficulty of this discovery; on the contrary it drives home the beautiful simplicity and logical nature of the hypothesis.

Let's start with a fundamental question which a precocious college student might ask. "Why, if RNA is so unstable, does it serve as the genetic material at all?". This question actually encapsulates the entire essence of the RNA world hypothesis. The instability of RNA is obvious from its chemical structure- RNA has two hydroxyl groups at the 2' and 3' positions on its ribose sugar. The problem is that the 2' OH can serve as an internal nucleophile and break a 3' phosphodiester bond as illustrated at the top of this post; in fact that's precisely the reaction that RNA catalyzes in a ribozyme. The reaction is usually helped along by magnesium ions.

Thus, phosphodiester linkages in RNA are (relatively) quite unstable. DNA- deoxyribose as the name indicates- lacks the 2' OH group and is therefore more stable. This makes it clear why RNA cannot serve as the original genetic material (DNA) but only as the messenger; the fidelity of information storage and transfer by the original genetic material is of such paramount importance that RNA would simply be too unstable to do the job. Evolution could entrust only DNA with the core function of being the blueprint of life.

So far so good, and a fine argument for why DNA and not RNA is the genetic storage disk. But then the question arises; why use RNA at all? The question is highlighted even more by the fact that while DNA functions in the nucleus, RNA transfers to the cytoplasm and performs the key function of protein synthesis. From a chemical standpoint, the cytoplasm is a much more hostile place than the nucleus, with several oxidizing, proteolytic and other kinds of enzymes waiting to chew up biomolecules. Entrusting the translation of genetic information in such a destructive environment to an unstable molecule like RNA sounds dangerously irresponsible of evolution.

But wait! The very instability of RNA that denies it the coveted function of the original genetic material also confers on it a marvelous capability of towering significance- catalytic ability. But why would you even think of catalysis in the first place? Well, the essence of evolution is the careful weighing of tradeoffs. If RNA is too unstable as the genetic material, it likely has some other property which compensates for this apparently deal-killing instability. At this point our intrepid college freshman will have to scratch her head and remember a few basics of enzyme catalysis. A little contemplation leads to the entirely reasonable hypothesis that enzyme catalysis needs at least two catalytic groups. Even if this hypothesis is wrong, it is still certainly true that two catalytic groups are better than one, and we have to remember than evolution is a greedy miser which can hungrily seize on any incremental advantage, no matter how small. Think of any kind of enzyme catalyzed reaction involving electron flow, say, the cleavage of peptide bonds by proteases. At the very least, you need one nucleophilic group to attack the peptide bond and another group (a positively charged one) to stabilize the resulting concentration of negative charge.

With this reasoning in hand, it is not too difficult for our admirable student to arrive at two great truths. Truth no. 1: In RNA, there are two hydroxyl groups. Truth no. 2: these groups are right next to each other. This is a really big deal. Our knowledge of enzymes tells us that proximity can greatly enhance reaction rate, sometimes by several orders of magnitude. This final capstone on the chain of thinking finally leads our precocious young adventurer to compile a succinct set of steps for arriving at the RNA world hypothesis through armchair speculation:

1. DNA is the original genetic material because RNA would have been too unstable. But then why does RNA exist at all?

2. The essence of evolution is tradeoffs. Perhaps RNA could have served another very important function that could have compensated for its instability?

3. One of the key steps in the origin of life was the capacity for chemical catalysis. Enzymatic reactions probably need at least two catalytic groups in close proximity to each other.

4. RNA with its two hydroxyl groups right next to each other could possibly function as a catalyst, in stark contrast to DNA which has only a single such group. This slight but all-important structural difference would have compensated for losses incurred due to instability and would have led RNA to transcend a barrier that was of superlative importance to the origin of life- the ability to bring about chemical reactions. QED.

Of course, the fundamental psychological barrier would still have been to think of something other than proteins acting as an enzyme. But this barrier is probably not as hard to surpass as we think. A hundred years before anything was known about the RNA world, giant chemical industries were already using metal-based catalysts to speed up reactions of great economic importance- the Haber-Bosch process being only one of many. If lowly metals could bring about such a diverse variety of reactions, then it's not a long stretch to think of simple molecules unrelated to proteins doing the same.

There have been a handful of transformations that have been responsible for the ascendancy of life on this planet. The tiny modification that added a single hydroxyl group to RNA would probably rank at the very top. Rephrasing Robert Frost, two roads diverged in a wood, and I took the one with the 2' hydroxyl group.

Our precocious youngster goes peacefully to sleep that night. She dreams of life on an RNA world.