The Nobel Prize winner confessed to the halo brought by the double helix

The Nobel Prize winner confessed to the halo brought by the double helix: half by luck, the other half by judgment and hard work.

In 1953, Crick and James Watson jointly discovered the double helix structure of deoxyribonucleic acid (DNA). This important discovery won them the 1962 Nobel Prize in Physiology or Medicine. As for how they saw Franklin’s X-ray picture, Watson said earlier that he had accidentally seen it.

In this article, Watson’s close collaborator-Crick admitted that Watson did see it back then, but he should have not remembered the details. In Crick’s impression, Watson did not meet like Franklin did. After asking the question, he just “knows the answer as soon as possible”, no matter how he got it. In the history of life sciences, what is the truth about this lingering “dark history”, let’s listen to Crick’s self-report.

 
Francis Crick, picture from quotationof.com

Article | Francis Crick (Nobel Prize Winner, Neurobiologist)

Double helix DNA is indeed a kind of magic molecule. The history of modern Homo sapiens is about 50,000 years, the history of civilization is only 10,000 years, and the history of the United States is only more than 200 years, but DNA and RNA have existed for billions of years. In these billions of years, the double helix has always existed and played a role, but we have only now begun to recognize them.

Many people have told the story of the discovery of the double helix many times from many angles, and it is difficult for me to talk about anything new. Every school kid knows that DNA is a long string of chemical messages written in four letters. The skeletons of the two chains are almost identical. The four letters, that is, the four bases, are connected to the carbon skeleton at regular intervals.

Generally speaking, the structure of DNA contains two strands that are entangled into a double helix, but the helix itself is not the real secret of the DNA structure-the real secret lies in the base pairing: adenine and thymine, guanine and cell Pyrimidine. Or abbreviated as A=T, G≡C, where the horizontal lines represent hydrogen bonds. It is the specific pairing between bases that ensures accurate replication: no matter what the sequence of one strand is, the other strand must be the corresponding complementary sequence, and the principle of base pairing is strictly followed. One of the main principles of biochemistry is the close integration of organic chemical molecules, and DNA molecules are no exception.

DNA is not a familiar term. Thirty years ago, not everyone knew it. The physical chemist Paul Doty told me that shortly after custom buttons became popular, he found gadgets with “DNA” written in New York, and he was surprised. Thinking that there must be other meanings, he asked the boss what it meant. “Listen well, buddy,” the boss told him in a strong New York accent, “this is – genes.”

Nowadays, most people know what DNA is, otherwise they might think that it is another bad thing, like “chemical substances” or “artificial synthesis”. Fortunately, those who have heard of Watson and Crick’s names often don’t know who is who. More than once, many enthusiastic admirers came to tell me how much they liked my book-meaning, “Double Helix” by Jim. After many misunderstandings, I now understand that the best response is not to explain.

An even more unexpected one was after Jim returned to work in Cambridge in 1955. One day, I went to work in the Cavendish laboratory and found that my fellow was Neville Mott, Professor Shin Ko Cavendish (Prague had already gone to the Royal Academy in London). I said to him: “Tell you about Watson. He happens to be working in your laboratory.” Mott looked at me in surprise: “Watson? What other Watson? I always thought you were Watson. · Creek.”

Some people still find DNA difficult to understand. I met a singer in a bar in Honolulu. She told me that when she was studying, she had cursed Watson and me because we had to memorize biological knowledge by rote. In fact, the structure of DNA, if taught properly, is very easy to understand, because it is not contrary to common sense like quantum mechanics or relativity.

I think there is a reason why nucleic acid is so simple. They may be traced back to the origin of life, or at least very close to the origin. At that time there was only a very simple mechanism. Of course, the existence of these chemical molecules can only be explained by quantum mechanics, but fortunately, the shape of chemical molecules can be embodied in a fairly simple mechanical model-it is this point that makes the concept of DNA easy to understand.

Franklin, picture from sciencehistory.org/Vittorio Luzzati

Considering that some readers happen to have not heard of how the double helix was discovered, I will provide a brief summary below. Astbury at the University of Leeds had taken X-ray diffraction pictures of DNA fibers, but the quality was not high. After World War II, Wilkins, who was working at the Randall Laboratory at King’s College London, took a few better pictures. Randall then hired an experienced crystal diffractometer, Franklin, to help resolve the structure of DNA.

Unfortunately, Franklin and Wilkins are a bit disagreeable at work. He hopes that she will focus on the wetter form (the so-called B-type), which can get a simpler X-ray pattern, which can reveal more information than the drier form (A-type), although the latter can be more clear X-ray picture.

In Cambridge, the subject of my PhD thesis was to solve protein structure with X-rays. Jim Watson, a visiting scholar from the United States, was only 23 years old at the time. He wanted to discover what genes are, and hoped to achieve this goal by solving the structure of DNA. We suggest that colleagues in London use modeling methods to study this problem, just as Pauling used modeling to solve the alpha spiral. We first came up with a completely wrong model, and Pauling later also got a wrong model. In the end, after some twists and turns, Jim and I came up with the correct model. This relies on some experimental data from the London team and the relative content of the four bases in DNA discovered by Chakov.

I first heard about Jim from Audell. One day when I came home, she told me, “Max just came here with an American guy who wanted to make you know-you know?-he is bald!” Audrey meant Jim with a flat head , This is still a very novel thing in Cambridge. Later, Jim went to the village to follow the customs, and his hair grew longer and longer, but his hair never grew to the length of a hippie in the 1960s.

Jim and I hit it off, partly because our interests are surprisingly similar, and partly because-I guess-we are all a little bit young and frivolous and impatient with procrastinated thinking. Jim is obviously more open-mouthed than I am, but our way of thinking is quite similar, the difference is our knowledge background. At that time, I had a certain knowledge of protein and crystal diffraction. Jim doesn’t know much about these, but he knows the work on phages very well, especially the work of the phage team led by Delbrück, Salva Luria and AI Hershey. Jim also knows more about bacterial genetics. I speculate that our knowledge of classical genetics is roughly equivalent.

Needless to say, we always get together to discuss issues. This makes us a little bit different. Cavendish’s laboratory was originally small—for a period of time in 1949, we were all crowded in one room. By the time Jim joined, Perutz and Kendrew already had a small private office. At this time, we grouped into a larger room. At first, everyone didn’t know to whom this small office was assigned. Until one day, Perutz and Kendrew rubbed hands and announced to everyone that the room was assigned to Jim and me because “…so you two discuss It won’t bother you when you have questions.” In hindsight, this was a lucky decision.

When we got acquainted, Jim had already got a PhD. Although I was 12 years older, I was still a graduate student. In London, Wilkins began to use X-rays to study DNA, and Franklin took over and expanded this work. Although Jim and I have been discussing issues all day, we have never done any experimental work on DNA. Because of Pauling’s example, we believe that the way to solve DNA structure is to build models. My colleagues in London took a more difficult approach.

Our initial attempt ended in complete failure, because I very wrongly believed that there is only a small amount of water in the DNA structure. This error is partly due to my own ignorance-I should have realized that salt ions may be hydrophilic, and partly because Jim misunderstood the crystallographic terminology used by Franklin in the lecture-he confused the “asymmetric unit” (asymmetric unit). ) And “unit cell” (unit cell).

Of course the mistakes we made did not stop there. Due to the in-depth understanding of “tautomeric forms”, I mistakenly believed that the hydrogen bonds around bases may have several different positions. Later, an American crystallographer in our laboratory, Jerry Donohue (Jerry Donohue) told us that some of the chemical formulas in the textbook were wrong, and in fact each base has almost only one specific configuration. From then on, the situation became clearer.

The core discovery is that Jim has determined the nature of the two base pairings (A and T, G and C). His conclusion is not based on logical reasoning, but more like an accident (the logical way is this: first, assume that Chakov’s principle is correct, so that there is only one possible way of pairing; second, according to DNA fiber The C2 space group in the map looks for dyadic symmetry (dyadic symmetry), so that we will quickly get the correct base pairing-if necessary, we will definitely adopt this method).

In a sense, Jim’s discoveries do have a component of luck. In fact, most discoveries have a trace of luck. The point is that Jim was looking for something crucial, and when he discovered base pairing, he immediately realized its importance-“opportunity favors a prepared mind.” This episode also proves that the necessary attitude towards scientific research must be maintained.

In the first half of 1953, Jim and I wrote 4 papers on the structure and function of DNA. The first one was published in the April 25th issue of Nature. Also published in the same issue were two papers from King’s College London, one by Wilkins, Stokes, and Wilson, and the other Written by Franklin and Gosling. Five weeks later, we published our second paper in the journal Nature, discussing the genetic significance of the double helix structure (the order of the paper’s signature was determined by flipping a coin, and both times were Jim ranked first). A more general discussion on this issue was published in the report of a virus academic conference held by Cold Spring Harbor that year. A more detailed technical description of the double helix structure was published in an unknown journal in 1954.

The first “Nature” essay is short and prudent. Except for the double helix structure itself, the only remarkable thing in this article is this sentence: “Of course we did not ignore it. The base pairing we assumed immediately hinted at a possible replication mechanism of genetic material.” Many commentators considered this sentence. The words are a little bit “arrogant”, this word is generally not used to describe the author, at least a scientific worker. In fact, this is the result of compromise. I intended to discuss the genetic significance of the double helix in this article, but Jim objected. He was worried that if the structure was wrong, we would make a big joke. I understand his point, but insist that this point must be mentioned in the paper, even if it ends, otherwise others will point it out and mistakenly believe that we might not have noticed it. To put it bluntly, I want to prove our initiative right.

So why did we change our course and write a second speculative paper within a few weeks and publish it on May 30? The main reason is that when we sent the first draft of the first paper to our colleagues at King’s College, we did not read their paper, so we don’t yet know that X-ray evidence supports our structure so strongly. Jim had seen the X-ray “spiral diagram” of the B-type DNA structure published in their paper by Franklin and Gosling in advance, but he must have not remembered all the details, including the argument for the Bessel function and the distance. parameter. I had not seen that picture myself. Therefore, we were a little surprised to see them making such great progress, and we were very pleased to see their evidence supporting our ideas. With the latest support, I can easily convince Jim that we should write a second paper.

Regarding the discovery of the double helix, I think it should be emphasized that, scientifically speaking, the way to discover it is quite ordinary. What really matters is not how to find it, but what is discovered-the double helix structure itself. Take a look at other scientific discoveries-misleading data, wrong ideas, interpersonal conflicts, these stories are not uncommon in scientific discoveries. Take the discovery of collagen structure as an example. Collagen is the main component of tendons, cartilage and other tissues. The basic fiber of collagen is made up of three long chains interlaced with each other. Its discovery process is not inferior to the discovery of the double helix: the characters involved are also very personal, the facts are very confusing, the wrong methods are also very misleading, and the competition and cooperation are equally thrilling. But no one has ever written the story of the triple helix. The reason is of course that, IMHO, collagen is not as important as DNA.

Of course, what is important is a matter of opinion. Before Alex Rich and I studied (coincidentally) collagen, we were quite disdainful of it. “After all, there is no collagen in plants.” By 1955, when we were interested in this molecule, we found ourselves saying, “Did you know that 1/3 of the protein in the human body is collagen.” But no matter from which point of view, DNA is more important than collagen and closer to the core of biology, it is of greater significance to subsequent research. Therefore, as I have said many times before: the DNA molecule is really fascinating, not the scientist who studies it.

The strangest point in the whole story is that, neither Jim nor me, studying DNA is our official job. I was still a graduate student, and my graduation project was about using X-ray diffraction to determine the structure of peptides and proteins. Jim’s job was to come to Cambridge to help Kendrew study crystalline myosin. As a friend of Wilkins, I heard a lot of work on DNA-this got their permission, and Jim was fascinated by the diffraction problem after listening to Wilkins’ report in Naples.

People often ask Jim and I how much time they spent studying DNA. It depends on how you define “research”. In almost two years, we often discussed this issue, whether it was in the experiment room, or take a walk along the riverside campus garden during lunch time, or at home (because Jim sometimes visits my home during dinner time, his eyes are full of “hungry”). Sometimes, especially when the summer outside is particularly tempting, we don’t go to work in the afternoon and go boating on the Grantchester River.

We both think DNA is very important, although we didn’t realize that it would be as important as we know it today. At first I thought it would be Wilkins, Franklin, and the others at King’s College who would use X-ray diffraction to solve the DNA fiber structure, but slowly, Jim and I became more and more impatient with their step-by-step work. In addition, the displeasure between Franklin and Wilkins also dragged them back.

The difference between our research methods is that Jim and I have a clear understanding of the discovery process of the alpha spiral. We understand that knowing the distance and angle between atoms, the remaining possibilities are few, and the regular double helix further reduces the degrees of freedom. The colleagues at King’s College are not particularly enthusiastic about this approach. Especially Franklin, she has a soft spot for her own methods. I guess she may feel that it is whimsical to start to speculate on the structural model with only this little experimental data.

There have been many discussions about Franklin’s unfair treatment as a female scientist. Undoubtedly, there were indeed many disgusting restrictions at the time. For example, some rooms were only for male teachers, and women were not allowed to enter for a cup of coffee, but these were of no importance, at least in my opinion. As far as I can see, her colleagues treat scientists of different genders equally. There are other women in Randall’s laboratory, such as Pauline Cowan. In addition, their scientific advisor is Honor B. Fell, a well-known tissue culture scientist. The only objection I know came from Franklin’s family. She came from a well-to-do bank family, and they believed that a good Jewish girl should get married and have children instead of devoting herself to scientific research, but even so, her family did not hinder her career choice.

Although she can choose her career freely, I think there are other more subtle restrictions. Part of the reason Franklin and Wilkins couldn’t get along was because she felt that Wilkins was only treating her as an assistant, not an independent colleague. Franklin studies DNA not because she thinks this large molecule is particularly important. When Randall first gave her the position, they planned to let her study the X-ray diffraction of protein solutions. Franklin has done X-ray diffraction studies of coal before, so this plan can be said to be very appropriate. Later, Randall changed her mind because the work on DNA fiber (the work Wilkins was doing at the time) became more and more interesting, and Randall suggested that she might as well study DNA. I think Franklin may not know much about DNA before.

Some feminists think that Franklin is the martyr in their camp, but I think that is not the case. Aaron Klug, who is very familiar with Franklin, once told me about a feminist book, “Franklin must be very disgusted with this book.” In my opinion, Franklin does not think he is A pioneer of equality between men and women, what she longs for is that others treat her as a serious scientist.

In any case, Franklin’s experimental work is very good, it is difficult to imagine doing better. However, when it comes to interpreting X-ray diffraction pictures, she is not very good at it. All her work is very proper-almost too proper. What she lacks is Pauling’s panache. And one of the reasons why this happened, apart from the different temperaments of the two, is that she believes that women must always show professional qualities.

Jim has no such concerns about his abilities. He just wants to know the answer to the question, whether it is through an appropriate method or a somewhat “exaggerated” method, he doesn’t mind at all. All he wanted was to know the answer as soon as possible. People sometimes say that this is because we like competition too much, but the facts do not support this claim. When we modeled with enthusiasm, we also taught Wilkins this method and even lent him the molds necessary to make the model. Of course, we may not have done enough (they have never used our molds), but this is not because of a competitive mentality, but because we are eager to know the details of the structure.

These, of course, are all favorable factors for us. I believe there are two more. Neither Jim nor I felt any external pressure that required us to solve this problem. This means that we can concentrate on studying this issue for a period of time and then put it aside for a while. Another advantage is that we have gradually formed a self-explanatory but very effective way of cooperation, which is not available in the London group. Between Jim and I, whoever proposes a new idea will be taken seriously, and the other will criticize it in an open, honest and harmless manner. In hindsight, this is very critical.

In the process of solving scientific problems, we almost inevitably fall into misunderstandings. I have listed some of the mistakes I have made. Now, let’s talk about some positive conclusions. Correctly solving problems often requires sequential logical steps. If one of the links is wrong, then you may be on the wrong track, getting further and further away from the correct answer. Therefore, it is very important not to fall into one’s own misunderstandings. How to do this? Intellectual cooperation can help you get out of these misunderstandings.

A typical example is Jim’s initial insistence that the phosphate group must be in the center of the structure. His reason is that the long basic side chains of histidine and nucleoprotein can penetrate deep into the center of DNA to contact the phosphate group. I strongly believe that this reason is very far-fetched and we should ignore it. One night, I said to Jim: “Why don’t we try to put the phosphoric acid group outside?” “Because that would be too simple.” (meaning that there are many possible models.) “Why not Try it?” I said. Jim walked away without a word. In other words, until then, we have not built a satisfactory model, so any acceptable model is progress, even if it is not unique.

The significance of this debate is that our attention has turned to bases. When the phosphate is inside and the base is outside, we don’t need to care about the shape and position of the base. And once we put the bases inside, we must study them more closely. A new discovery made me laugh: when we made the base model in proportion, although the shape was similar to what I thought, the size was much larger!

Therefore, there is no simple answer to how long it took us to solve the problem of DNA structure. At the end of 1951, we focused on modeling for a while, but after that, I was forbidden to do any more work in this area because I was still a graduate student. In the summer of 1952, I planned to do an experiment for a week or two to see if I could find evidence to support base pairing in solution, but because of my doctoral dissertation, I had to abandon this exploration in advance. The final solution to the structure of DNA, including the coordination information of the measurement model, took only a few weeks. Less than a month after this, our paper was published in the journal Nature. If only the last part of the work is counted, it is of course incredibly short, but of course the time spent on reading and discussion before should also be included, because it is these reading and discussion that make it possible for us to propose the final model.

Soon we discovered that our model had some detailed errors. We only have two hydrogen bonds between G and C, although we realize that there may be three. Pauling then eloquently argued why there are three hydrogen bonds between G and C, so after seeing the picture in my article on Scientific American, there are still two hydrogen bonds. This matter is indeed not my fault. In fact, the editors were too rushed (they usually do), and I never saw proofreading samples. In addition, the bases in the model are too far from the center. However, despite this and other errors, our model still captures all the key properties of the double helix: the double helix is ​​antiparallel, which is a property I inferred from Franklin’s data; the phosphate backbone is on the outside, and the nucleic acid Inlaid inside; most importantly, the pairing of specific bases.

There are several points that should not be ignored. This requires considerable courage (or reckless, depending on how you look at it), and a certain degree of expertise, to temporarily set aside the question of how to solve the double helix and reject the parallel structure. Soon after our model appeared in the journal, cosmologist Gamow proposed such a parallel model, and recently two authors have reiterated this idea. Allow me to fast forward to now to discuss these two models. According to their proposal, the double strands of DNA are not interlaced, but are parallel like two railroad tracks. They believe that such a structure will make the double strands easier to untie. Each chain does sway a bit, so, at first glance, the structure they propose is not much different from ours. They claim that these new models are also consistent with X-ray diffraction data and are also comparable to ours.

I don’t believe these models at all. I am also very skeptical of the diffraction pattern, because such a model will leave several bright spots in the blank area on the X-ray fiber pattern. In addition, their models look ugly, because their shapes are imposed on them by the modeler without obvious structural reasons.

However, such a rebuttal is not sufficient and can easily be attributed to my bias. These two groups of researchers keenly felt that they did not belong to the mainstream of scientific research, and authoritative experts even ignored their opinions. In fact, on the contrary, everyone, including the editors of Nature, pays special attention to giving them opportunities to express their opinions to show fairness.

At this time, a pure mathematician Bill Pohl (Bill Pohl) also participated. He was very right to point out that unless a new unconventional event occurs, the two DNAs produced by circular DNA replication will be linked to each other, rather than separated from each other. From this he inferred that DNA double strands cannot be linked to each other as we proposed, but must be parallel to each other.

I have had a long correspondence with him and also made phone calls. He also visited me later. He knows the details of the experiment quite well, but still insists on his point of view. In a letter, I told him that if nature does occasionally produce two circular DNAs that coil around each other, then a special mechanism must have evolved to untie the double strands. He thinks this is a strong argument that has not been confirmed by experiments, and he is not moved at all. Years later, people discovered that this is indeed the case. Nick Cozzarelli and his colleagues discovered a special enzyme called topoisomerase II. The enzyme can cut a double strand of DNA, bypass the other DNA, and then reattach the broken double strand. Therefore, it can untie two intertwined circular DNAs, even when the DNA concentration is very high, intertwined DNA will be produced in the separated DNA.

Fortunately, Walter Keller and Jim Wang have done a lot of outstanding work on the “number of interleaving” of circular DNA, showing that all these “parallel double-stranded” models (side- by-side models) must be wrong. The number of unwinding of the two circular DNAs is consistent with our model prediction. I think a lot about this question. In 1979, I specially wrote a review article with Jim Wang and Bill Bauer, entitled “Is DNA Really a Double Helix?” Double Helix), examined all relevant arguments in considerable detail.

However, I am not sure if this is enough to convince the staunch skeptic, although Bill Bor has already surrendered at this time. Fortunately, there are new discoveries at this time. The previous X-ray diffraction data alone cannot make a sufficient argument for two reasons: First, the information in the X-ray diffraction image is not complete after all; Second, we must first assume a temporary model, and then use fairly limited data to detect it.

By the end of the 1970s, chemists had invented an effective method to synthesize short-stranded DNA of known sequence. If you are lucky, these short strands of DNA can still crystallize. Through X-ray diffraction and other unambiguous methods (such as homomorphic replacement), people can unambiguously analyze their structures. In addition, the X-ray diffraction point image of this crystal has a higher resolution than the previous fiber pattern. Part of the reason is that the previous DNA fiber is a mixture of different sequences of DNA, which is the average of all the images, so it is more blurred.

Using such short-stranded DNA, Rich and his research team at MIT, as well as Dick Dickerson and his colleagues at Caltech, made an unexpected discovery. X-ray diffraction shows that the DNA is a left-handed structure that has never been seen before and looks quite distorted (zigzag). They are called Z-DNA. Its X-ray patterns are also very inconsistent with classic DNA models, so they are obviously a new type of DNA. Later, it was discovered that such Z-DNA is most likely to appear in a specific base sequence (purine and pyrimidine appear alternately). What are their functions in nature? This is still an active research topic. One guess is that it may have regulatory functions.

More conventional DNA quickly crystallized. The results obtained this time are very similar to the X-ray data of DNA fibers, but there are slight changes in different local base sequences, and the double helix is ​​also slightly different. This is also an active area of ​​research.

It was not until the early 1980s that the double helix structure of DNA was finally confirmed. Our model went from being more probable at the very beginning, to very probable (thanks to the meticulous work on DNA fibers), and finally to almost certainly correct. It took 25 years. Although it is correct as a whole, the specific details are still deviated. Of course, the work on the chemical and biochemical properties of DNA sequences, base complementary pairing (which is the core function of DNA) and the characteristics of double-stranded antiparallel have been determined long ago.

In the history of science, it takes a tortuous process to turn a theory into a “fact” (recognized by people). The establishment of the DNA double helix is ​​a good example. I guess that after 20 to 25 years, many people have a strong desire to overthrow traditional ideas. Every generation has new trends. In the case of the double helix, although the facts are there, it is difficult for the previous generation to accept this new model. In non-scientific fields, it is more difficult to reject such challenges, because new ideas tend to become popular because of their novelty. New is everything. Whether in scientific or non-scientific fields, new approaches always try to retain some of the traditional views, because the most effective innovations are always born out of established traditions.

So, what are the contributions of Jim and me? If we have anything commendable, it is our relentless pursuit of problems and decisive abandonment of an idea when it does not hold water. Given that we have gone through so many detours and tried so many wrong models, some people think we are not very smart. But this is the only way for scientific discovery. Many efforts fail not because people are not smart enough, but because explorers are stuck in a dead end or give up halfway. It is often criticized that we do not have a comprehensive grasp of all aspects of the knowledge required to solve the double helix, but at least we try to master them, and these critics cannot see this.

Nevertheless, we don’t think it is that important. I think that Jim and I’s contribution lies in that we have chosen the right questions early in our research career and have continued to do it. We stumbled upon a gold mine, which is true, but it is also because we are looking for a gold mine. Both of us agree that the central problem of molecular biology is the chemical structure of genes. The geneticist Hermann Muller pointed out this as early as the 1920s, and since then, others have held the same view. And Jim and I feel that things may not be as complicated as they seem, and there may be a shortcut to solve the problem.

Interestingly, for me, part of the confidence lies in the detailed knowledge of protein. After all, we cannot see the truth directly, but we think this issue is very important, so we tirelessly invest a lot of time and think hard from all possible angles. In fact, no one is prepared to make such a large intellectual investment, because it not only requires mastering genetics, biochemistry, chemistry, and physical chemistry (including X-ray diffraction-who wants to learn it?), but also requires panning for gold , Remove the false from all kinds of data and keep the true. Such discussions are very demanding and sometimes seem endless, and it is simply a mental breakdown. If you do not have a strong interest in this issue, I am afraid that such intense thinking cannot be maintained.

However, other theoretical breakthroughs in history often reflect the same pattern. Compared with other colleagues in the entire scientific community, our thinking is not the hardest, but we think harder than most of our colleagues in biology. At that time, except for geneticists and people in the phage team, most people believed that biology lacked clear logic.

Of course, someone will always ask what would happen if Watson and I didn’t propose the structure of DNA. It is often said that historians do not appraise this kind of “hypothetical history” way of thinking, but if historians cannot give a reasonable explanation for such a problem, I really can’t figure out what else to study in historical analysis. If Jim was hit by a tennis ball and died, I can be pretty sure that I might not be able to solve this problem myself, but if it weren’t for us, who would it be?

Jim and I agreed that if Pauling had seen the X-ray data of King’s College, he would definitely be able to resolve the structure of DNA. But Pauling himself said that although he liked the structure we proposed at first glance, he thought for a while before finally realizing that his model was wrong. If he did not see our model, he would never have thought of it himself. Franklin was only two steps away from discovering the answer. She just needs to realize that the double strands are antiparallel, and that when the bases are in the correct conformation, they can pair in pairs. However, she was about to leave King’s College, terminate her DNA work, and study tobacco mosaic virus with Bernard (5 years later, she died at the age of 37). Wilkins announced to us before he knew our structure that he intended to study the question of DNA structure wholeheartedly. After our repeated persuasion, he decided to try the modeling method too. If Jim and I do not succeed, I think the discovery of the double helix will be delayed by only three to five years.

However, Gunther Stent asked more general questions and was supported by Peter Medawar (he was a particularly thoughtful thinker). The problem is that if Watson and I did not discover the structure of DNA, assuming that DNA was not discovered suddenly but revealed bit by bit, its influence would be much weaker. For this reason, Stent argued: People are often ashamed to admit that scientific discoveries are actually closer to art. Style is as important as content.

I don’t fully agree with this claim, at least not in the DNA example. Rather than saying that Watson and Crick created the double helix, I would rather say that it was the double helix that created Watson and Crick. After all, I was still unknown at the time, and Watson gave the impression that he was smarter than reliable. But I think this proposition actually ignores the inherent beauty of the DNA double helix structure. What is really fascinating is the DNA molecule, not the scientists who study it. The discovery of the genetic code did not happen overnight, but when the truth came to light, looking back, its influence was not inferior at all. Even if it was not Columbus who discovered the New World, what about it? More importantly, after people have discovered, they still have enough human and financial resources to make full use of this discovery. Regarding the history of the discovery of the DNA double helix, I think it is this aspect that is really worth noting, not the personal factors, no matter how interesting or inspiring this story is in the eyes of other researchers.

After all, “how to evaluate the double helix structure” is a question of the history of science. Naturally, there is no simple answer to historical questions. The benevolent sees benevolence, and the wise sees wisdom, and views will change over time. However, there is no doubt that the double helix structure has a considerable impact on a group of active and influential scientists quite quickly. Thanks to Max Delbrück, the first three papers were immediately distributed to all participants at the 1953 Cold Spring Harbor Symposium, and Watson was also invited to give a report. Later, I gave a report at the Rockefeller Institute in New York. I was told afterwards that this sparked people’s interest. Part of the reason is that I also demonstrated my enthusiasm for the subject and a fairly calm assessment of experimental evidence.

The clue of the story is roughly the article published in Scientific American in October 1954. Brenner had just received his PhD under the guidance of Hinschelwood at Oxford University, and he became our spokesperson in Cold Spring Harbor. He took a lot of effort to explain to Milislav Demerec (the director of Cold Spring Harbor at the time) what the double helix was about (Brenner was planning to move from South Africa to Cambridge in 1957. After that, we became the closest partners and shared the laboratory with me for 20 years). But not everyone agrees with this discovery.

Barry Commoner insists that physicists’ understanding of biology is too simple (which actually makes sense). When I visited Chakov from 1953 to 1954, he told me in a consistent tone of insight that our first “Nature” paper was a bit interesting, but the second one was lackluster. In 1959, the distinguished biochemist Fritz Lipmann (Fritz Lipmann) invited me to Rockefeller to give a series of lectures. When I talked with him, I realized that he did not grasp our understanding of the DNA replication mechanism. Understand (I also realized that he talked a lot with Chakov). However, by the end of the series of lectures, when he made his concluding remarks, he gave a very good overview of our theory.

Biochemist Arthur Kornberg once told me that when he first started to study the biochemical principles of DNA replication, he did not believe in the mechanism we proposed, but his excellent work convinced himself, Turned to join our camp. You know, he has always been a very cautious and demanding scientist. His work provides evidence for the first time that the double strands of DNA are antiparallel. In any case, in my opinion, we have received considerable attention, luckier than Avery, and luckier than Mendel.

What is it like to live under the halo of the double helix? I think we immediately realized that we might have made important discoveries by mistake. According to Jim, I walked to the Eagle Bar (opposite the place where we had lunch every day) and told everyone that we had discovered the mystery of life. I have no impression of this, but I do remember telling Audell that we might have made a major discovery when I returned home. Years later, she told me she didn’t believe it at all. “You say that every day when I go home, I won’t take it seriously after a long time.” Prague caught a cold at the time and happened to be out of the laboratory. Later, when he saw the model and understood the basic concepts, he became very excited immediately. The unpleasantness of the past faded away, and he became our strongest supporter.

There was an endless stream of people visiting our laboratory, including a delegation from Oxford (Brenner was one of them), so that Jim quickly became impatient with my tireless enthusiasm. In fact, he once became a little retreat, suspecting that this was just a dream, but the experimental evidence from King’s College excited us. By the summer, most of our suspicions have dissipated, and we can finally look at the double helix calmly and distinguish between accidental features (these are somewhat inaccurate) and which are fundamental (these can stand the test of time).

In the following years, our lives were very peaceful. I named my residence in Cambridge “Golden Spiral” and erected a simple copper spiral at the door. It is just a single helix, not a double helix. Its original intention is only to symbolize spiral, not to symbolize DNA. The reason why the word “gold” is used is to express its beauty, similar to how Apleyius called his story the “Golden Ass”. People sometimes ask me if I plan to plate it with gold, but we just dyed it yellow.

Finally, people may ask a personal question-am I satisfied with this discovery? I can only answer this way: I have enjoyed the whole process of exploration, no matter the high tide or the low point. Of course, this helped me a lot in my future publicity work to uncover the genetic code. But to be honest, I can only quote a few years ago painter John Minton (John Minton) talked about artistic creation in a speech in Cambridge, “The important thing is that when the painting is drawn, I am there.” This, in my opinion, is part of luck, and the other part is good judgment, inspiration and perseverance.

(source:internet, reference only)

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