70 years ago, two young men made a groundbreaking discovery that led to global life sciences

Introduction

This year marks the 70th anniversary of the discovery of the DNA double helix structure. On April 25, 1953, two young men published a one-page paper in the well-known journal Nature, revealing the DNA double helix structure, which attracted widespread attention. Since then, biological research has officially entered the molecular era, opening up epoch-making changes and having a significant impact on drug production, crop variety improvement, disease treatment and other aspects.

Today, we are honored to invite Dr. Maoye Ji, CEO of Cold Spring Harbor Asia. Dr. Ji once worked at Cold Spring Harbor Laboratory in the United States and had many interactions with Nobel Prize winner James Watson. In 2008, Dr. Ji and Watson founded Cold Spring Harbor Asia in Suzhou, which is also the only overseas branch of Cold Spring Harbor Laboratory. Today, it has become a center for communication and learning among molecular biologists in China and even East Asian countries.

Today, we interview Dr. Ji about the discovery of the double helix structure and its impact.

01 How to prove that nucleic acid is genetic material?

Ye Shuisong: As early as 1869, scientists discovered the DNA molecule. But it was not until the 1930s and 1940s that the scientific community recognized that "nucleic acid is the genetic material of life." Can you briefly describe the process of discovering the double helix structure of DNA?

Ji Maoye: Life has a different characteristic from all other substances, which is that it is “passed down from generation to generation”.

Biologists, chemists, and physicists all ask this question: What substance supports this trait? Eventually, scientists discovered that there are four types of macromolecules that make up life. The first is protein, which can be broken down into twenty different amino acids; the second is lipids, which are fats; the third is sugar, which can provide energy; and the fourth is nucleic acid. Which substance supports the inheritance from generation to generation? From the perspective of molecular complexity, it is generally believed that protein is more likely to be the genetic material.

But by 1940, more and more experiments confirmed that nucleic acid might be the genetic material. The most famous experiment was conducted by Oswald Avery of Rockefeller University in New York. He found that after the nucleic acid of a pneumococcus was fused with toxicity, it could enter another non-toxic pneumococcus and make the pneumococcus toxic. This experiment strongly suggested that "DNA is the genetic material."

The experiment that ultimately proved that "nucleic acids are genetic material" was the Matha Chase experiment. This experiment was conducted at Cold Spring Harbor and is very famous in the history of biochemistry. The key point of the experiment was to label the virus with isotopes. The structure of the virus is a protein shell wrapped around nucleic acid. The Martha Chase experiment very cleverly used different isotopes to label the outer protein shell and the nucleic acid inside. This experiment also ultimately proved that "nucleic acids are genetic material, not protein."

02 How Watson became interested in DNA

Ye Shuisong: Why did Watson choose to go to Europe to study the structure of DNA?

Ji Maoye: In the 1950s, information dissemination was relatively slow, and research results were generally not known until half a year later. Watson often went to Cold Spring Harbor at that time. Because of the geographical convenience, he knew very early that genetic material was DNA. So he thought that as long as the molecular structure of nucleic acid was known, the structure of genes would be solved. After graduating with a doctorate, Watson clearly stated that he wanted to study the "molecular structure of DNA", so he went from the United States to Europe.

At that time, a technique was used to study molecular structure - X-ray diffraction. The principle of X-ray diffraction is that after irradiating highly purified DNA or protein with light, it will reflect and form photosensitivity, which can be developed on film. The developed image can be used to infer what the molecular structure is like.

At that time, Europe's X-ray diffraction technology was very good, especially the Cavendish Laboratory of Cambridge University. The director of the laboratory, Lawrence Bragg, won the Nobel Prize for this technology. At that time, many European research institutions used this technology to study biological macromolecules, proteins, etc., especially the University of Cambridge in the UK.

Lawrence Bragg

In the United States, there were no laboratories doing this kind of work at the time. So Watson went to Europe right after graduation. He took a "detour" and first went to Copenhagen, but later found that it was not the place he wanted to go, so he went to Cambridge after staying there for half a year.

Ye Shuisong: Was Watson very interested in the structure of DNA from the beginning?

Ji Maoye: Watson was interested in the molecular structure of DNA because he already knew that nucleic acid was the genetic material. So after graduating from his doctorate in the United States, he decided to understand the molecular structure of DNA. Once the molecular structure of DNA is understood, the structure of genes will be very simple and clear.

Watson sketches the double helix structure of DNA

In fact, for scientists, the most important thing is not funding, technology, etc., but asking a so-called "important question". The question Watson and his colleagues asked at the time was, how to solve this problem (discover the structure of DNA)? In fact, the technology was already mature at the time, and the DNA structure problem could be solved in a few steps. But at that time, not many people knew to ask this question.

03 Contributions of Watson and Crick

Ye Shuisong: What are the contributions of James Watson, Francis Crick, Rosalind Franklin and others to the double helix structure of DNA?

Ji Maoye: As a younger generation studying genetic molecular biology, Watson, Crick, Rosalind Franklin, Maurice Wilkins, Ivory, and Linus Pauling are all our scientific predecessors. I think their contributions are very important. But I also have my own judgment on the events at that time. These judgments are based on the information Watson gave me and my own professional judgment. I think the term "DNA double helix" oversimplifies the DNA molecule. There are at least three important points about the double helix.

From left to right: Crick, Watson, Wilkins

Franklin

First, DNA is a double helix, which is its chemical structure, and its shape in the scientific sense is a double helix.

Second, it is not just a double helix, it is also a carrier of genetic material and genetic information that is passed down from generation to generation. All other biological macromolecules and biological substances do not have this function of being passed down from generation to generation. Therefore, DNA is an information carrier.

In addition to the double helix shape, information encoding is also very important. The information encoding includes A, T, G, and C pairing. The double-stranded information is complementary. After knowing the information of one strand, the second strand will naturally be clear;

The third point is that the pairing of A, T, G, and C does not affect the overall appearance geometrically. At that time, only Watson and Crick made these three points completely clear.

More importantly, DNA is a genetic material that is passed down from generation to generation. It is responsible for copying the information code of the arrangement and combination of A, T, G, and C and passing it on to the next generation. In this regard, Watson, as a biologist, naturally thought of these issues. But if we only regard DNA as a chemical structure, it does not really solve the whole problem. The information coding inside is more important.

Let me give you some more details. Watson and his colleagues already knew the double helix structure in February 1953, but they had not completed the entire work.

It was not until around 10 a.m. on February 28 that Watson cut out a model with cardboard in his own apartment and pieced together the chemical structure of A, T, G, and C. He found that the shapes of A and T pairing and G and C pairing were exactly the same, and would not cause the shape of the double helix to bulge out or indent on one side. At that time, he discovered the principle of base pairing.

Crick arrived after ten o'clock, and Watson showed him, "I have discovered this principle!" Crick was very excited at the time. Up to that moment, the double helix structure was complete. The two of them have a famous history. That day, when Crick went to the Eagle Bar in Cambridge for dinner, he loudly announced, "I have discovered the secret of life!"

04 Missing the Double Helix

Ji Maoye: There is another detail. The article (1953 paper) was signed by Watson first and Crick second. And this model is also called the "Watson-Crick model" in the scientific community. Why is Watson's name first and Crick's name second? The reason is that Crick's work was to infer the double helix structure of DNA after seeing the photo of Rosalind Franklin, while Watson's work was to discover base pairing, which is actually more important.

Rosalind Franklin and Linus Pauling of Caltech only considered DNA as a chemical problem. After Watson and his colleagues read Pauling's article, they found that Pauling proposed that "DNA is a triple helix", and they immediately thought that this was wrong. Because for them, how to copy and replicate the information in DNA and how to open and close in moderation is a very important issue. If the structure they proposed cannot open and close in moderation to copy and replicate the genetic code, then it must be wrong.

Pauling's proposal of the triple helix is ​​a very good illustration of "DNA is a molecule with very unique functions in life sciences". If biologists were not involved, it would take a long time for physicists and chemists to figure it out. Because they would not consider such a function of genetic information arrangement and combination, opening and closing in a controlled manner, and copying and replicating at any time. Watson also told me that Rosalind Franklin was a pure chemist and physicist. Her academic style was very rigorous, and she refused to speculate on data. She wanted the data to "speak". When the data did not "speak", she would not guess what it was. I think this is the biggest difference between Watson, Crick and Franklin.

Watson, Crick and others knew that they had to "go to the question with the answer". Watson knew very early that DNA was the genetic material, but it was not until the morning of February 28 that they completed the study of the structure of DNA when Watson completed the puzzle of A, T, G, and C alone without destroying the appearance and integrity of the double helix.

Ye Shuisong: Let's talk about Franklin's contribution. She made a DNA X-ray diffraction pattern in January 1951. Some researchers also said that she already knew that DNA was a double helix. But she was a chemist. Does this mean that she did not particularly understand the significance of the DNA structure?

Ji Maoye: Wilkins, Watson and Crick shared the Nobel Prize in 1962. The details about the photo (Photo 51) and the history are mainly that Wilkins and Franklin were colleagues and there were big conflicts between them. When Watson went to London, it was Wilkins who showed Watson this photo.

Photo No. 51

On the plane from Suzhou to Beijing in 2010, Watson personally revealed a detail to me. He said that "Photo 51" had been in Franklin's drawer for "at least eight months"! Watson told me that he felt it was "amazing" that such an important photo had been in Franklin's drawer for eight months without any movement or follow-up work.

If what Watson told me is true, then I can infer from this that Franklin at least did not realize the importance of this photo at the time, or she thought the photo was not perfect enough. Franklin published the article in 1953 under the "urging" of Watson and his colleagues to publish the article. Before that, Franklin had not made any move. Franklin's research team gave up the issue of DNA as a spiral at that time.

05 Is the identity of the discoverer of the double helix controversial?

Ye Shuisong: You had very close communication with Watson. I wonder what he said to you when he talked about that past event?

Ji Maoye: Now on the Internet, whether in China or the West, there is a voice of "crying out for Franklin". But I think this is not really a matter of fact. I think it may require a very deep professional background in DNA, chemistry, and biology to deeply understand this issue. Many people cry out for Franklin because they think that in the social environment of the 1950s, women were in a disadvantaged position. I can understand this very well.

But in fact, Watson and Crick were also in the disadvantaged group at that time. Maybe many people in China do not understand this point. They think that Americans go to Britain and Europe with a very arrogant attitude. In fact, this is not the case at all. Watson's family background is not rich, and he himself did not come from a prestigious school. To go to Britain, he had to "behave with his tail between his legs" to some extent. Watson was very poor when he went to Britain. It was only with the scholarship provided by the National Science Foundation of the United States that he was able to stay in the Cavendish Laboratory in Britain and "hang out" with Crick for a few months.

At that time, he had to "keep his head down" in terms of social medicine and science. In the laboratory, the two of them were often scolded by the laboratory director, William Lawrence Bragg. After the end of World War II, Crick switched from physics to biology to study hemoglobin, but did not achieve any results. His previous research on fluid viscosity and flow dynamics also ended in failure.

One was a 36-year-old doctoral student, and the other was a young, marginalized country boy. They were both placed in a room at the end of the corridor in the Cavendish Laboratory. They were completely disadvantaged. In fact, I think some people in society now add some of their own understanding and speculation, as if Watson and Crick "bullied" Franklin. In fact, Crick and Franklin had always had a good relationship, even after the publication of the article on April 25. Watson and Franklin's relationship also improved later, and they could get along very politely. If Franklin thought that the two guys had "stole" her things very unkindly, then these people would never have maintained such a friendly relationship.

06 The significance of the discovery of the DNA double helix

Ye Shuisong: Can you comment on the discovery of this structure and its contribution to the development of life sciences, such as genetic engineering, genomics and gene editing?

Ji Maoye: I think the major discovery of the DNA double helix can be called a "defining moment" in history. From then on, biology became an information science.

In addition, as Crick said, they discovered the "secret of life". I think the discovery of the DNA double helix has elevated human understanding of the essence of life to an unprecedented level. It turns out that our lives are encoded by "language" (gene language). I think it is very wonderful. At least all life on our planet, from viruses to bacteria, plants, animals, and even the spirit of all things - humans, are all written in the same "language". The creatures on the earth are completely unified. We are different works written in the same "language".

Darwin's theory of evolution was limited to the animal or plant kingdom at the time, and the scope was not that wide. The significance of the discovery of the double helix is ​​that our understanding of life has changed since then. We have risen to a philosophical level, and all life is written in the same "language". I once said in an interview that we humans can be planned as walking "strings" to a certain extent, with 3 billion codes. You, me, and everyone in the world are composed of DNA sequences.

Therefore, life has risen to an abstract level, and this is the great significance of the discovery of the double helix. In terms of technology, medicine, forensics, and social learning, the double helix has a profound impact on our contemporary human society, and even continues to influence aesthetics and art.

This article is a work supported by Science Popularization China Starry Sky Project

Team/Author: Deep Science

Reviewer: Tao Ning, Associate Researcher, Institute of Biophysics, Chinese Academy of Sciences

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.