Chapter 13 10 Fibrous tissue and chain structure

female einstein Pauling was not the only scientist who used theoretical methods to study the molecular structure of proteins.Dorothy Lynch was struggling in the same way.In fact, she thought she had solved the problem. Lynch was born in Argentina in 1894 to a family of British engineers.She studied mathematics in England, then turned to philosophy, became a disciple of Russell, and became a minor celebrity in Russell's bohemian socialist circle.She married a physicist and became the first woman to earn a PhD in Science from Oxford University.After that, she stayed on to teach mathematics and published many papers.She was unconventional and ahead of her time: feisty, smoking, sharp-tongued, pursuing an independent career (she never published under her husband's name), and curious about everything. (In addition to her many academic achievements, she wrote a pamphlet of sociology on problems in families where both parents worked.) During her studies with Russell, she realized that all scientific progress Straight from mathematics and logic.She took this belief first to physics and then to

① Russell (Betrand Russell, 1872-1970), British philosopher, mathematician, logician, main founder of analytical philosophy, advocate of the world peace movement, won the 1950 Nobel Prize in Literature.This belief carried into biology. But she has been missed from major scientific discoveries.In the early 30s—nearing 40, divorced from her husband, with a young daughter—Lynch became an academic gypsy.In order to learn new fields of genetics, embryology and protein chemistry, she cut her teeth and practiced in biology laboratories all over Europe.She joined The Theoretical Biology Organization, a small informal group of leading British scientists, including protein crystallographers John Bernal and Dorothy Hodgkin.They believed that combining old disciplines in a new way would lead to another quantum leap in biology.Weaver is always looking for new talent to fund.He noticed the group, knew about Lynch, read her paper on applying mathematics to chromosome shrinkage.In 1935, he generously gave her a five-year research grant.

She got results quickly. In 1936, Lynch proposed a new and weird protein structure.According to her theory, amino acids are not just connected end to end, they may be connected to each other in a more complex way, so what may be formed is not a chain structure, but a protein fiber organization.She acknowledges that this type of bonding has not yet been demonstrated, but argues that so little is known about proteins that it is not unreasonable that there may be undiscovered forms of bonding. She's a mathematician, not a chemist, but her fiber structure fits perfectly with some experimental data.One of her most proud structures is a honeycomb-shaped hexagonal amino acid ring, which forms a closed birdcage structure by pinching six vertices—according to her topology calculations, it contains a total of 288 amino acids—many scholars This number is thought to represent the basic unit of many proteins.The structure, which she calls a "cycloalcohol," is the first to specifically explain a globulin other than fibrin, and it's sparked much buzz.

The initial reaction was yes.Lynch has published papers detailing the advantages of her cyclic alcohol structure, including how it explains the ability of proteins to form thin films on liquid surfaces (the cage, she says, can open to form a flat float), how Activation of antibodies in animals (the side chains of amino acids can protrude from the cage, providing reaction sites, she thinks), and so on.Protein experts read her article carefully.Astbury initially agreed with her model, because he proposed a chain-like structure of keratin folds that was similar to Lynch's hexagonal structure.

Lynch plunged headlong into the study of protein structure, teaching himself the basics of X-ray crystallography.She knocked on the door of the Cambridge Protein Laboratory, suggesting experiments and engaging everyone she met in an enthusiastic discussion of her work.Before long, her knowledge enabled her to make useful mathematical interpretations of X-ray patterns.Passionate, argumentative, and increasingly obsessed with her research.She tries to convince everyone she feels she should be persuaded to accept her ring alcohol point of view.She began to preach her ideas at scientific conferences, and newspapers began to pay attention to this extraordinary woman, who seemed to be close to the end of the mystery of protein structure.One newspaper even called her a "female Einstein."

The attention given to Lynch and her cyclic alcohols between 1936 and 1938 caused a certain antipathy among scholars in the field of molecular structure.The globulin expert Bernal noticed that Lynch had many flaws in her theory due to her lack of basic knowledge of chemistry and biology.Her hypothesis is of course very interesting, but it is only one theory among many, and there are many places that are open to debate.The four-way linkage of amino acids required in her model has never been seen by an organic chemist; while the possibility cannot be completely ruled out, there is no new evidence to support it.Lynch's retort—"Proteins are so different from other substances, so why not accept that there is no analogue to this structure in organic chemistry"—also failed to resonate with researchers. , because their understanding of the way peptide bonds are connected has long been confirmed by experiments.Lynch's personal style didn't help either; some felt that, as a scientist, she was restless, and as a woman, she was decidedly too much.She makes people think, but at the same time makes people uneasy.The small circle of protein scientists began to divide into two factions for her and against her.

Pauling was high on the list of people Lynch was trying to persuade.As early as the summer of 1936, Lynch wrote to Pauling: "I would very much like to have the opportunity to talk to you about protein theory." Pauling's response was enthusiastic; they exchanged research papers.Lynch wrote again to Pauling: "I am still eager to have a long conversation with you." In the spring of 1937, Pauling wrote: "She is a very intelligent person, and I approve of what she is doing now Theoretical speculation. No doubt, there are many facts in her theory." However, he doubted whether the hexagonal ring of amino acids proposed by Lynch was stable enough to replace the polypeptide chain, and he was very concerned about Lynch's completely mathematical method to study cyclic alcohols. Fifteen years ago, he also saw some crystal theories based purely on the mathematical logic of harmony and symmetry rather than experimental data, and he once proved some of them to be wrong.He argues that nature does not strictly follow mathematical theories, and even if they do, the theories are quite complex, allowing for a great deal of deviation and certain idiosyncrasies.Pauling came to realize that Lynch had been too preoccupied with creating a "perfectly symmetrical structure" rather than those that naturally arise from chemical laws.He sees no chemical reason for proteins to form cyclic alcohols.

By 1938, Weaver was also suspicious of Lynch.He asked some scientists for their opinions on Lynch, but the conclusions were not consistent-some people thought she was a genius; others thought her theory was absurd.Weaver himself began to see her as "a weird fish".Her value lies in sparking discussion, but she spends a lot of time cultivating her followers and very little time proving her theories.He wanted a definitive answer to the cycloalcohol question, and asked Pauling to help him, because Pauling "is one of the very few people who is not intimidated by Lynch's mathematical skills."Weaver arranged for the two to meet in January 1938, while Pauling was at Cornell.

However, before the two sat down face-to-face, Pauling already had a plan in mind.Pauling had just arrived at Cornell University in Ithaca, N.Y., when he saw a photograph in the New York Times of Lynch "addictively playing with her refined model of globulin" with the headline "Protein Molecule's architecture".Pauling judged from the fuzzy photos that the birdcage structure of Cycloalcohol was too fine and the interior was too empty, which did not conform to the known fact that the interior of globulin was very dense.Two months before the scheduled meeting, Pauling, Mosky, Max Bergman, and Weaver held a discussion of Lynch's work at the Rockefeller Institute for Medical Research.Weaver wrote in his diary that Pauling was not only convinced that Lynch's research relied too much on reasoning and pursued too much formal symmetry, but he also felt that Lynch's research was still in its early stages and should not be subject to such a large-scale publicity.Bergman added that she did not pay enough attention to the peptide bond; the consensus was that her proposed birdcage structure surrounded by strong covalent bonds would not be easily opened to explain the first stage of denaturation - Pauling thinks The process of denaturation reversal involves hydrogen bonding.The final conclusion was that Pauling would "try to understand precisely what clear results Lynch had achieved" when the two met in January.

Lynch came to the icy Ithaca, eager to interview Pauling.But the two-day, two-hour talks between the two only confirmed Pauling's thoughts.Pauling questioned Lynch's model structure and found that she knew a lot about mathematics and little about the empirical facts of chemistry. The confidential report he gave Weaver about the meeting completely discredited Lynch.Pauling said that Lynch studied this problem as a mathematician, "interested in the rigorous reasoning from the hypothesis, not the actual structure of the protein"; "she is interested in using experimental data to verify her theory and Not very enthusiastic"; "Dr. Lynch has the vocabulary of a chemist and a biologist deftly, but her arguments are sometimes weak and her information is superficial."

More importantly, he refuted an idea that could accommodate a structure of 288 amino acids.He writes that there is no known chemical force that limits protein molecules to this number; the approach of many proteins or protein components to this size is due to some pressure of evolution rather than the result of chemical inevitability u Pauling overturned this theoretical pillar of Lynch's and demonstrated her lack of knowledge of protein chemistry, concluding that Lynch's thesis was "disingenuous."Unfortunately, he went on, protein researchers "didn't know that her scientific attitude was very different from theirs, and were deluded into taking her work for real." The only positive thing about meeting Lynch, he said, was that he regained the strength to work on the protein problem: "After talking to Dr. There are too many elements; however, I think these speculations are superior to Dr. Lynch's theory." Weaver encouraged him to imagine boldly. As far as the Rockefeller Foundation is concerned, Pauling's report completely cut off Dorothy Lynch's financial resources.During the conversation, Pauling's severe criticism and thorough questioning made Lynch pale with fright.She returned to England dejectedly.There, she came under more attacks from Bernal and friends.Weaver's UK representative, W. E. Diesdale, wrote after reading Pauling's comments: "Lynch acted as a catalyst, but I do not know whether the catalyst survived the reaction after it had been catalyzed. necessary." After returning to Caltech from Cornell University, Pauling concentrated on the study of protein structure.He now has a well-equipped laboratory in the Klein Laboratory Building and a growing number of students and postdoctoral researchers.He began to take more X-ray pictures of natural proteins, hoping to find something valuable beyond Astbury and Bernal's work.At the same time he also began to use Zechmeister's chromatographic techniques to separate and purify the fragments of the fragmented protein, hoping that by solving the structure of these fragments, he could understand the structure of the whole protein, perhaps in terms of the order of amino acids in the protein chain. Rebuild whole protein. However, he still devoted his main energy to the study of amino acids, the basis of protein structure.Here, Corey's work on glycine and diketopiperazines is a bit of a surprise because they are so underwhelming.The structure of amino acids does not look much different from Pauling's imagination.Most importantly, the structure of diketopiperazine verified the double bond characteristics of the peptide bond predicted by Pauling—the atoms on both sides of the peptide bond are firmly fixed on the same plane in the form of double bonds and cannot rotate around each other.This proves Pauling's 1937 hypothesis for the structure of keratin.So why did the last effort fail?He asked Corey, Hughes, and their students to study more amino acids and small peptides, drawing more detailed structural diagrams.Perhaps the answer lies in these details. Pauling's 1936 paper on protein denaturation, co-authored with Mosky, hadn't made much of an impact for two years.Despite the convincing chemical arguments in the paper and the detailed experimental data, most protein scientists do not believe that a weak, nameless and uncertain force like hydrogen bonding can determine the precise shape of proteins.Acceptance of the hydrogen bond theory has been disappointingly slow.But Pauling was still convinced it was right.He started talking to his newly hired colleague, the protein scientist Karl Niemann, about ways to prove the existence of hydrogen bonds. Just as Pauling threw himself into this new battle, a startling event happened: Lynch found evidence for the existence of its cyclic alcohol structure.Rather than quietly withdrawing from the field after her talk with Pauling, she doubled down on it.She found a powerful new ally in the Nobel Prize-winning physical chemist (and co-leader of the theory of shared-electron pair bonding) Irving Langmuir.Langmuir's interest in molecular membranes led him to the cycloalcohol hypothesis. In the fall of 1938, she wrote to the Rockefeller Foundation that "a remarkable miracle has occurred."Dorothy Hodgkins takes new x-rays of the small globulin insulin.Although Croft says "the calculated form does not appear to have any direct connection to the cyclic alcohols or to the various chain structures," Lynch and Langmuir analyzed the data using new mathematical tools and found the ring Evidence for the presence of alcohol.Their results, especially given Langmuir's reputation, created a huge shock among protein scientists.Langmuir confidently told Weaver that everyone should now be convinced of the cycloalcohol theory.Earls Bohr's group in Copenhagen started to build cyclic alcohol cages.Lynch began to publish a large number of papers. Pauling ignored the stubble.He believed that the new vector analysis methods used by Lynch and Langmuir—an approach developed in collaboration with one of Pauling's former students, David Hacker—was too limited to provide a real proof.Even after Harker wrote to tell him that he believed Lynch and Langmuir's analysis to be correct, Pauling remained unmoved. Pauling is not alone in this attitude.In Britain, Bernal and others, including Willie Bragg, stepped up their attacks on Lynch. In January 1939, Nature published a series of short articles.For molecules as complex as proteins, vector analysis can only provide "vague and provisional" conclusions, Bragg wrote.Bernal, for his part, said Lynch's theory about insulin was "clearly wrong."After Lynch's rebuttal, Bernal struck again, writing that "there is no X-ray experiment to support the cycloalcohol model; virtually all X-ray evidence so far is against this model." Lynch felt Betrayed; she privately called Bernal, a fellow man she had befriended in the Theoretical Biology organization, "jealous, savage, betrayer." Langmuir defended Lynch's views in published articles as well as in private.He collaborated on papers with Lynch, took her and Huck to conferences—it was especially meaningful to have support from Pauling's own students—and persuaded Mosky that the denaturation process might proceed in steps close to those predicted by the cycloalcohol theory.With Langmuir's help, the cycloalcohol theory was brought back to life. Pauling was very confused and angry that so much attention was being paid to a theory he believed to be false.This not only deviated from the exploration of the real problem of protein, but also attacked Pauling's hydrogen bond theory, slandered his reputation as an authoritative scholar of protein, and challenged his view of nature.He felt it was time to strike back firmly and bring him to an end. In the early spring of 1939, Pauling and Niemann co-authored a paper to verify and refute the main arguments for the structure of cyclic alcohols point by point.It took them several weeks to complete the paper, "Protein Structure," which was published in the July issue of the Journal of the American Chemical Society.Among Pauling's attacks on different theories, the language of this paper is the most violent.The main weapon they wield is chemistry, specifically bond energy data.Pauling believes that these data clearly show that the cyclic alcohol structure is less stable than the polypeptide chain, so the possibility of existence is very small.Purely from the energy point of view, Pauling and Niemann wrote: "Our rigorous argumentation concluded that cyclic alcohols cannot be the main structure of proteins, even if such structures exist (this is unlikely, because Compared with the polypeptide chain, its energy is at a disadvantage), and the proportion of amino acid residues with this structure will not exceed 3 percent." (The original text uses a different font to emphasize this conclusion.) In discussing their opinion After Lynch and Langmuir's other major contradictions and mistakes, Pauling and Niemann came up with their own ideas on protein structure.Compared with the paper on protein denaturation published by Mosky and Pauling three years ago, there is not much new content: a protein is a polypeptide chain, connected into a certain shape by some known links, hydrogen bonds, sulfur-one Sparse bonds and "similar inter-primary interactions" are intermingled.What a certain shape is, no one knows.The only thing that can definitely be ruled out seems to be the cyclic alcohol structure. The article "Protein Structure" was devastating and immediate.Todd wrote after reading: "I must admit that I was very happy after reading the article of Pauling and Niemann'exposing Lynch's true face'! It is time to draw a conclusion on the theory of cycloalcohols. I believe that at least all the chemistry here Everyone would welcome that move. As far as I'm concerned, the conclusion is irrefutable, and I'd be quite interested in whether Lynch would react in some way." Ironically, a few weeks before Pauling and Nieman submitted the paper, Lynch decided to abandon protein research.Injured by the hostility of Bernal and the Cambridge research group, she fled England for the United States in the spring of 1939.She told Weaver that the data she was getting in the insulin study was not mature enough, and she dropped further work.The timing of Pauling and Nyman's paper could not have been worse.Lynch is seeking a teaching position for herself and a home for her daughter; she has to fight back in order to save her face and get a job.She stormed into the Harvard office of Arthur Lamb, editor of the Journal of the American Chemical Society, and demanded her rebuttal.Lamb explained that he can publish any correction of fact or new development of relevant research, but the journal will not consider publishing platitudes.A few weeks later, Lynch sent a 21-page challenge article, refuting Pauling and Nyman's point of view bit by bit, and the final conclusion was; "People who object to the cycloalcohol hypothesis Based on plausible facts (caused by errors of logic), their experiments are irrelevant ... or insignificant." As usual, Lamb sent Lynch's manuscript to Pauling and Nieman, and asked them to comment on this for the reference of reviewers. Pauling and Erman refuted Lynch's point of view paragraph by paragraph, and the words were more violent: "... how can this specter continue to wander in the literature of organic chemistry?" I repeat the old rhetoric of imagining," "What we see is more hope than reality." Lamb sent these smoke-filled articles to two arbitrators, but their conclusions were quite different, and Lamb had to resubmit the entire article. to the other two arbitrators.Everyone who reads these articles is horrified by the vitriol on both sides of the argument; everyone's solution is different.Lamb and one arbitrator considered publishing Lynch's article together with Pauling's and Nieman's responses after both parties had reviewed the final draft; A debate; another likened the debate to a signal flare for the start of a world war and suggested delaying the process to "give both sides a chance to calm down". Lynch then discovered that Pauling and Niemann had made an error in their calculations of the energy required for protein formation; correcting this error reduced the difference in energy between the chain structure and the cyclic alcohol structure by about a third.She pointed this out in a letter to Pauling, who, however, replied that the change was so insignificant that it would not affect their conclusions, and therefore "we do not consider it worthwhile to correct this error in writing". Lynch then tried to hit Pauling from another angle.She was offered a temporary position at Johns Hopkins University, where she spoke with David Harker, who works there.Huck had friction with Pauling when he was a student.Lynch told him how Pauling attacked herself and how she prevented her from publishing her own opposition articles, and Huck expressed deep sympathy.At the same time, Huck also talked to Lynch about his views on Pauling. He felt that Pauling used resonance to explain all phenomena of chemical bonds, which was a bit arbitrary and far-fetched.Eventually the two collaborated and published a short letter in the Journal of Chemical Physics in the spring of 1940, proposing a new way to study chemical bonds without using resonance theory.Although the letter only mentioned Pauling in a footnote, it clearly challenged Pauling's most basic scientific methods. Pauling wrote back to Huck in the tone of a betrayed father. "I just noticed that letter from you and Dorothy Lynch again working together...I think it shows that you need to take some advice. The general tone of the letter is a criticism of the research work here. Even if this criticism has Certain basis, the college's kindness to your cultivation should also make you think twice about your own behavior." After making some specific criticisms, Pauling finally said: "Although careless readers may mistakenly think that your letter is is a small contribution to scientific understanding, and I do not feel the need for a reply to correct this error in understanding ...I think you should have better things to do and better partners. ’ He then wrote to the editor of the journal that it would be wiser to send the manuscript to Huck Lynch for his review before publishing it. Pauling goes around flaunting his might, and that's what Huck hates.He wrote back: "I have heard rumors from time to time of your unjust treatment of Dr. Lynch and of preventing her from publishing her theories. I have always held—and declared—that such a course of action would be impossible for you.  … If I It would be extremely regrettable to have to believe such rumors." Nineteen months after Pauling and Niemann's original paper, Lynch's abridged rebuttal was finally published in the Journal of the American Chemical Society.At this point, however, both the cycloalcohol theory and Lynch's academic career were over.Weaver informed her that the Rockefeller Foundation would stop funding her, and that five years was long enough to convince her colleagues of the cycloalcohol theory.She lost her financial resources and was unable to express further criticism of Pauling.In a letter to a friend in late 1940, she wrote: "I am utterly hopeless because I live in a system of power, like Hitler's Germany, where only the powerful survive...  This new Pauling system beats me. He's a guy who couldn't be more dangerous. . . . even a man of integrity would dare challenge him. He's smart, quick, merciless in countering, and I think all Fear him. Only poor me pointed out his error: no one else would have dared to do so. Lynch would spend the rest of his life in scientific obscurity.She remains relentless, outspoken, and still believes in her ring alcohol theory.She talked about her beautiful protein structure to everyone who was interested, and accused Pauling and his cohorts of suppressing themselves.The Lynch incident made everyone involved feel bad.It destroyed Lynch's career, ending her academic ability in a wide range of disciplines with a failed research project.It deepened the rift between Pauling and Harker, making it difficult to reconcile years later.This fueled rumors that Pauling was a bully who would ruthlessly knock dissidents to the ground.The semi-public scientific debate also baffles one man from whom no one wants to alienate: Weaver.In a letter in late 1939, the Rockefeller Foundation manager quietly expressed his displeasure, apparently directed at Pauling: "It seems to me that so far there has been much active theoretical research on the protein problem." There is a useful purpose in even some heated debates; what is more important now is to obtain a wider and more reliable system of facts. No high-sounding words are more convincing than silent facts." Lynch later attributed her encounter to sexism.She told her friends, "Oh, it's the Y chromosome. If I had a Y chromosome, people wouldn't talk to me like that in the public press." Sexism was definitely the bane—science at the time This phenomenon is common in the world, and it is even more common at Caltech.But for Pauling, this effect is not great.Under the influence of Eva Helen, Pauling was the most "open" as the times allowed; he respected the research results of several other female scientists in this field, such as Dorothy Croft Hodge gold.His attack on Langmuir was no less violent.But Langmuir was on solid ground and unaffected, while Lynch was vulnerable. In fact, every protein scientist who has been in contact with Lynch has already had a similar idea, and Pao Lin just expressed this idea more completely and strongly in written form. The Y chromosome also doesn't make the cycloalcohol theory correct. However, the Lynch incident also revealed a darker side of Pauling's character.The facts on both sides of the debate are weak - as Lynch pointed out, it is impossible to assert that the cycloalcohol structure does not exist.In fact, in the 1950s, another scholar discovered a similar protein structure to cycloalcohol in certain ergot alkaloids - Lynch tried to use this discovery to win sponsorship for a re-examination of all other protein structures, but did not succeed.Playing the role of a science father who yells at his rowdy kids, Pauling closes the debate on a non-questionable note. The polemic showed Pauling's newfound power at this time.In the years since winning Caltech's chair of chemistry and chemical engineering, Pauling has become a well-known protagonist in the power structure of the chemistry community.Like Noyce before him, he served on the editorial boards of several journals, nominated for various positions, selected winners, offered advice, and lectured.He was invited, consulted, honored, and respected.He drank the wine of success.Yet fame and acclaim also brought to the fore some negative elements of his character, which intensified as his power increased: he was self-righteous, possessed absolute control over situations and debates, and had no regard for those with whimsical ideas. Stop it softly. serologist The debate with Lynch strengthened Pauling's belief in the hydrogen-bonding chain model of proteins proposed by him and Mosky - a belief that led him into a new and completely unexpected field of research. In the spring of 1936, after a presentation on hemoglobin at the Rockefeller Institute for Medical Research, Pauling received a note: Could you please spend an hour or two before leaving New York to discuss some mutually interesting research topics?Signed Karl Landsteiner. ①Landsteiner (Karl Landsteiner, 1868-1943), Austrian-American immunologist and pathologist, discovered A, B, O, AB blood group and MN blood group system, RH factor, won the 1930 Nobel Prize in Medicine . Pauling knew the name.Landsteiner was a well-respected Austrian medical researcher with an international reputation.Five years ago, he won the Nobel Prize for discovering the ABO blood type, which made it possible for humans to transfuse blood safely for the first time, thus saving countless lives.Landsteiner came to the United States in his later years to continue his research on blood, especially on the mediators in serum that make up the immune system.Pauling took a keen interest in the invitation and the man.The next day, he came to Landsteiner's laboratory and was welcomed by a seemingly noble scientist: Landsteiner was outstanding, with short gray hair, tall and straight, with a mustache, and He retains an air of elegance and confidence developed in his early years in Vienna.In slightly accented English, he invited the guests to sit down, and then told Pauling about a mystery he was trying to solve. It has to do with antibodies, specific protein molecules that help the body fight off infection, Landsteiner explained.Pauling's report on hemoglobin made him realize that perhaps Pauling could help him explain some of his observations.For example, the body can produce tens of thousands or even millions of antibodies with different specificities, and each antibody can recognize and lock a target molecule, or antigen.For example, antibodies against pneumococcus can only recognize and adsorb antigens with a specific structure, but not antigens specific to streptococcus, and vice versa.Landsteiner performed experiments using man-made chemicals acting as antigens, and demonstrated that this specificity was very precise: In some cases, antigens that differed by only a few atoms responded exactly to an antibody. different. Of course, no one has yet understood this specificity; enzymes, for example, are quite specific in their action on the target molecule of their substrate.But an enzyme has only one corresponding substrate.Various specific antibodies, including man-made chemicals, can be produced against thousands of targets.Landsteiner said something bothered him.For example, what is the chemical mechanism by which antibodies acquire specificity?How do protein molecules such as antibodies tell the difference between different antigens?What is the force that binds antibodies and antigens to each other?How is the body able to make so many antibodies with such precision?How does the body know how to shape antibody proteins for synthetic targets it has never been exposed to? Pauling knew nothing about these questions—but his first reaction was that the answer must have something to do with the structural form of the molecule.But he liked Landsteiner, finding him a fascinating thinker with wide-ranging interests (“a marvelous man,” he would tell people shortly afterwards).He was fascinated by Landsteiner's research work.The new field of immunochemistry, in which Landsteiner worked, may provide powerful tools for studying protein structure and specificity.At the end of their meeting, Pauling told Landsteiner that he would think about these issues and would meet with him again. But first he'll have to get a little crash education in the field.He promptly bought a copy of Landsteiner's latest book on immunology and read it on the train back to Pasadena.He was intrigued from the first pages of the book.Landsteiner writes: "The morphological characteristics of plant and animal species form the subject of a descriptive natural science and at the same time they serve as criteria for the classification of species. But until recently it was realized that, as in the category of crystals, differences in chemical properties correspond to differences in structure." Pauling found a thinker close to himself, one who could combine biology, chemistry, and crystallography in two sentences.He became fascinated by Landsteiner's research on the human body, such as how the immune system enables each animal to recognize chemical differences between self and non-self substances. The farmland outside the car window swept back quickly, and Pauling was immersed in Landsteiner's book.Landsteiner studied chemistry with the great Emil Fischer, making the study of the immune system an independent chemistry discipline and perfecting systems for producing and measuring antibody activity based on known organic compounds.这一工具可以产生两方面的作用：第一，抗体可被用作精细的探针，来辨别紧密相关的有机分子的结构差异，其中也包括蛋白质；第二，挑选的抗体可以作为探针来研究抗体的结构。由于无人知道抗体的结构以及抗体是如何与目标结合的，这一领域充满着未知数、自相矛盾的发现以及令人困惑的实验结果。多数免疫学家来自生物学或者医药领域，似乎缺乏化学知识或怀有偏见。换句话说，开拓免疫学领域的时机已经成熟。 在回到帕萨迪纳的时候，鲍林已经决定将一部分时间投入免疫学研究。他和莫斯基正在给他们的蛋白质变性理论作最后的修饰，鲍林开始将抗体与他关于蛋白质是由氢键联结起来的分子长链的思想联系起来。他理所当然地认为，抗体和所有分子一样，其性质是由其结构决定的。能不能设想它们的构造是为了迎合某一特定的抗原，就像手套紧密地套在手上一样？形状互补是一个早就存在的思想，最初是由保罗·埃尔利希在19世纪末提出的——他运用的词汇是锁和钥匙——其后又有人对这一理论作了改进。但是，鲍林的思路是全新的，是从变性的角度出发的。新塑造的抗体分子是否可能像一个变性分子，其氢键断裂，长链展开成一条直线？如果它与一个抗原接触，两个分子将会受到一股微弱而又不确定的力的吸引——范德瓦尔斯力及抗原和抗体上电荷相反区域之间的静电引力。能量因素将会使抗体和抗原之间产生最大的接触；当抗体的带电原子靠近抗原表面带相反电荷的区域时，自由能最少，而范德瓦尔斯力最大。抗原和抗体结合得越紧密，这种微弱而又不确定的力就会使更多的抗原和抗体相结合，这一配对的系统也就越稳定。抗体将会自然地根据抗原的形状来塑造自己，就像一团湿泥压在硬币上会留下印记一样。回到加州理工学院后不久，鲍林就完成了一篇有关抗体形成过程的论文初稿。 接着他把这篇论文放到了一边。首先得完成同莫斯基合作的那篇论文。随后诺伊斯去世了，鲍林和密立根之间的麻烦也开场了。鲍林并没有完全忘掉免疫学——他开始阅读有关的资料，并且对互相矛盾的研究结果越来越感到不满——但是他并没有在免疫学上花费过多的时间。 兰德施泰纳又将他拉了回来。鲍林在1937年11月以贝克讲座主讲人的身份在康奈尔大学讲学时，惊喜地又一次见到了他。这位老人是专程到伊萨卡来看望鲍林的。免疫学并非是他见鲍林的唯一目的——兰德施泰纳还想向鲍林探听一下自己到加州理工学院任职的可能性——但是他们一旦开始讨论抗体，就再也停不下来了。鲍林回忆道，兰德施泰纳将短暂的访问变成了“在一个复杂领域里人们所接受过的最佳讲座”。在四天集中的小型免疫学讨论班上，兰德施泰纳回答了鲍林的种种问题。鲍林在过去的一年里在所阅读的资料中发现了许多彼此矛盾的研究结果，兰德施泰纳一一澄清了他提出的疑问。鲍林将兰德施泰纳称为“免疫学之父”，热切地建议密立根邀请他到加州理工学院来工作。 但是，他的这一愿望没能实现——密立根抱怨说，接受每一个希望退休后来南加利福尼亚的阳光下安度晚年的前诺贝尔奖金获得者代价太高了——而且鲍林的注意力又岔到了别的事情上。在1938年和1939年，他仍然思考着、谈论着抗体——实际上，他对抗体的高涨热情促使生物系的一些学者开始制造果蝇基因的抗体和基因产品——但是克莱林实验室正准备开张，他的新房正在建造，贝克讲座需要继续，多萝西·林奇需要声讨，还有《化学键的本质》需要写作。同时由于他手下没有一个人了解如何进行免疫学方面的实验，所以他对于全力以赴地进入这一全新的领域还有些犹豫不决。 1939年7月，兰德施泰纳又一次向他发出了信号。这回，他在《科学》杂志上发表文章，将鲍林和莫斯基的蛋白质结构理论和抗体的形成联系在一起。在解释抗体的特异性时他写道：“可考虑的一种想法是，以不同的方式来折叠同一条多肽链。” 这与鲍林不谋而合，他开始对自己的理论作发表前的最后雕琢，以免别人抢得先机。已经有一些免疫学家陆续发表论文，认为抗体以抗原作为自己成型的模板，但是他们一般的想法是，这一过程是在不断加长的蛋白质链上按次序排列氨基酸，而鲍林认为这一方法过于复杂。他关于一成不变的蛋白质链扭曲成特定形状的想法更为简便易行， 这一理论还能解释困扰一些学者的一个问题，即抗体是“两价的”，能够同时与两个抗原结合，将它们聚合在一起。测试抗体的一个一般性试验是将抗体同抗原混合，看它们能否形成浑浊的沉淀物。如果有沉淀产生，则说明抗原和抗体结合到了一起。鲍林熟知，在有些情况下，分子首尾相连，形成化学沉淀物，他推测抗体同样如此。能够与两个抗原相结合的抗体是形成抗原一抗体一抗原一抗体沉淀物的最容易的一种方式。 在鲍林的脑海中一幅图像开始成形：一个“变性的”新抗体开始从一个抗体生产细胞中生长出来。长出的一头会和一个抗原接触，并与之结合。链的中段会往复折叠成一堆馅饼的模样，形成一个类似于球体的形状，这可以满足表明抗体是球蛋白的那些数据。氢键将这一堆馅饼联结在一起。接着刚刚从细胞中脱离出来的抗体链的另一头会和另一个抗原相结合，形成一个“两价的”抗体结构。这一简单的方法巧妙地解释了无数抗体是如何从一种简单的蛋白质结构中生成的，沉淀物是如何产生的，合成化学物质的抗体是如何形成的，当然还能解释通过形状互补，不确定的弱力体系如何促成抗体与抗原相互结合的。 1940年1月，芝加哥大学免疫学的一位青年助理教授丹·坎贝尔获得一份奖学金来到加州理工学院，鲍林让他做一些验证性的实验，而自己则对抗体理论作发表前的最后定稿。还有一些问题有待解决。他这一理论的威力不仅在于简单，而且还因为通过它可以作出一些具体的可以验证的预测。比如，按照鲍林的理论，一个抗体分子的两端可以和一个抗原上的同样的反应点相结合，可以和同一个抗原上的两个不同的反应点相结合，也可以和两个完全不同的抗原相结合。然而这一类双重反应的抗体，一个可以同两个不同的抗原反应的分子，从来没有被发现过。兰德施泰纳的实验结果与这一构造相距甚远。坎贝尔来校之后，鲍林和兰德施泰纳在那年春天互相邮寄血清和抗体样本试图解决这一难题，但是没有任何进展。 两人之间的通信使鲍林认识到，他和自己免疫学的导师在思考问题上的方法并不一致。鲍林回忆说：“我发现兰德施泰纳和我在对待科学研究的方法上迥然不同。兰德施泰纳会问，'这些实验观察到的结果会迫使我们如何认识世界的本质呢？'而我会问，'哪一种最为简单、通用和令人满意的世界观可以涵盖这些观察结果，并与它们并行不悖？'”在这一点可以得到确认之前，鲍林决定暂不发表自己的论文。当验证工作被证明相当棘手时，他决定将研究工作继续深入下去，寄希望于新的实验会支持自己的想法。 第二项预测具有更为深远的意义。如果鲍林的理论是正确的，那么就有可能在实验室中人工制造出抗体来。先小心地将普通的血红蛋白变性，然后在抗原的作用下将其复原。由于动物和人的血清血红蛋白非常容易获得，有可能廉价、纯净、安全地大量生产针对任何危险病原的抗体来。面对一个垂死的患肺炎的病人，医生可以从冰箱中取出一小瓶针对这一特定细菌的抗体来，有效地治愈病人。鲍林想象着以工业规模制造出种种灵丹妙药。人造抗体将给医药行业带来一场革命。有人会因此而一夜暴富。他让坎贝尔同时对这一问题展开研究。 1940年春天，鲍林期待着实验的结果。他对发表自己的观点尚缺乏信心，因而开始在科学会议上分发阐述自己思想的论文手稿。每个人似乎都对他的理论很感兴趣，尽管在确切的实验结果出来之前没有人会完全接受他的思想，连兰德施泰纳对他的抗体形成理论也只是抱谨慎的乐观态度。 坎贝尔的研究工作于事无补。尽管他的实验证明了鲍林对抗体二价性的认识，但是最关键的部分——双重抗体试验和人造抗体——没有取得令人信服的结果。但是鲍林觉得自己已经等得够久了。实验结果并没有证明自己的理论，但是同时也没有推翻自己的理论。他的论文毕竟只是一篇理论文章，是对进一步实验的指导，而非最终的定论。1940年6月，鲍林将自己关于抗体形成的论文送交《美国化学学会学报》。 这篇论文看来是又一个令人振奋的成功之作。论文体现了鲍林惯有的简洁和自信的风格。文章一开始就回答了鲍林提出的几个问题：“哪一种最为简单的分子结构可以用来解释观察到的抗体的性质？形成这样一种分子，最简单、最合理的过程是怎样的？”鲍林令人信服地指出，两价的抗体分子，每一头与一个抗原的某一表面互补，对解释沉淀反应来说既是充分的，也是必要的。他描述了蛋白质链的折叠如何能使抗体获得具有某一特异性的形状。他解释说，通过几个相对较小的力的共同作用——带正电和带负电区域之间的静电引力，氢键，范德瓦尔斯力——就可以形成将抗体和抗原结合在一起的“胶水”。而这一点正是他的理论最令人着迷的一面。抗体，这些结构最为精确的蛋白质，是通过自然界中这种最弱和最不确定的连接方式获得其特异性的。 对于自己的理论在很短的时间内取代了以往的模板理论，并成为抗体成形最主要的理论，鲍林又惊又喜。他欣喜地收到几百封请求将他的论文复印的信函，这超过了他以往的任何一篇论文。 他再次进入了一个新的领域，将威力无穷的结构化学带进了免疫学研究中。他再次高奏凯歌。 就在鲍林将抗体论文送交发表前，他在校园里散步时遇见了马克思·德尔布吕克，一个专攻生物学的物理学家。这位对新生物学的奥秘感兴趣的跨学科学者同样受到洛克菲勒基金的资助；鲍林十分欣赏这位德国移民，他认为德尔布吕克通过病毒这样最简单的生命形式展开生物学研究是“很有道理的”。德尔布吕克知道鲍林近来对抗体情有独钟，就建议他阅读一下帕斯卡·约尔丹最近几年的一些文章。这位德国学者在这些文章中提出，两个一样的分子在量子力学共振的作用下，会彼此吸引。他认为，这一现象可以帮助解释诸如基因和病毒——照他的说法，甚至还包括抗体——那样的分子为什么具有精确地复制自身的本领。鲍林对此产生了极大的兴趣，他和德尔布吕克一起到图书馆中将约尔丹的这些论文找了出来。德尔布吕克记得，在研究了五分钟之后鲍林就宣称，约尔丹的理论是“胡扯”。几天后，鲍林对德尔布吕克说：“我就此问题给《科学》杂志写了一个短笺；你我联合署名如何？”德尔布吕克对这篇文章没有做任何实质性的工作，但是他不想失礼，因而同意签上自己的名字。 鲍林的“短笺”后来被证明具有预言的性质。他和德尔布吕克合作的“生物工程中分子间作用力的实质”在1940年夏天发表在《科学》杂志的讨论栏中。文章首先用鲍林典型的直截了当的语言反驳了约尔丹关于共振是相同分子间引力基础的观点——“我们的结论为，约尔丹运用这一理论的方式是错误的，他以此为出发点来解释生物现象的做法是不可取的”——接着鲍林陈述了自己的观点：“我们……觉得在对分子间引力和分子的酶综合作用的讨论中，应当着重考虑互补性。”互补的形状就像冲模和硬币的关系，正是这种关系造就了生物学中的特异性。鲍林特别强调了在分子复制自身的情况下这样一个概念的重要性，即“互补性也许就是一致性”。 除了打击了约尔丹之外，这篇短文在浩瀚的文献中几乎没有泛起一丝涟漪。直到多年之后，它才被重新发掘出来，并被科学史专家颂扬为一门新科学的奠基之作，是“分子生物学的宣言”。DNA将成为互补性和一致性合二为一的一种分子。 连续几个月，鲍林向韦弗表达了自己对免疫学日益高涨的兴奋之情，特别还说明这是人工制造抗体的机会。鲍林在1941年初提出了一项非正式的资助申请：每年两万美金，用以全面开展免疫化学研究的一个项目。这笔钱将使加州理工学院能够雇用三个研究助理，三个研究生助手，一个访问教授，一屋子的实验用动物，一个用最好的仪器配备起来的实验室。这笔钱相当于鲍林为整个结构化学所作的预算，韦弗在2月份访问加州理工学院期间，告诉鲍林他的要求“太过分了”。鲍林将申请数额压缩了几乎一半。韦弗首先请教了这一领域内的一些知名学者。兰德施泰纳和其他人告诉他说，人工制造出抗体将具有“革命性”的意义。在韦弗的积极游说下，洛克菲勒基金同意在三年中每年向鲍林提供一万一千美金以资助他的免疫学研究工作。这笔钱使鲍林能够永久地雇用坎贝尔，给一位前途远大的青年博士后戴维·普莱斯曼提供资助，并添置了足够的设备、兔子和注射器以开展实验工作。 在韦弗接触过的众多科学家中，唯一的稍带警告口气的意见来自尖刻的英国生物化学家诺曼·皮里。韦弗在笔记中写道，皮里希望“鲍林不要在一些假设之上再堆砌另一些假设，不要坚持针对每一种可能的情况作出这一假设，现在应该静候实验的证据。”换句话说，皮里希望鲍林不要“重蹈林奇的覆辙”。