Chapter 11 8 Life Sciences

a lot of money John Rockefeller was in trouble.Crude oil from his giant Lima field in Ohio was so high in sulfur that it smelled like rotten eggs.Everyone calls it skunk juice and no one buys it.His refineries couldn't get rid of that one stink, so Rockefeller was helpless in the face of tens of thousands of barrels of worthless crude. When a group of chemical engineers at his Indiana plant asked him to fund a way to get rid of the odor, Rockefeller declined because he didn't want to throw money into the water again.However, a few engineers continued to work on the problem in their spare time, and in 1913 they succeeded in finding a way to "crack" oil.This new process not only removed the stench, but also doubled the output of gasoline.Witnessing this achievement, Rockefeller suddenly realized, and almost overnight, he became a staunch supporter of science.

In his later years, the industrial tycoon often thought about how to dispose of the huge wealth accumulated over the years.Under his personal supervision, a large part of the huge charitable fund he established was invested in scientific goals and methods.Rockefeller was a Christian, yet a pragmatist who didn't want to give his money to those in need; he wanted to find the root causes of problems and eliminate them.He hopes that his investment can improve human life, and science is undoubtedly the most effective way in our time. In the 1920s, under the management of philosophy professor turned science advocate Wycliffe Rhodes, the Rockefeller Charitable Fund began to make large-scale funding for pure science.Rhodes' largest grant was for a telescope at Caltech's Mount Palomar Observatory in Hale, just one of many large grants from the Rockefeller Foundation to the school in the 1920s.Rhodes likes to throw a lot of money at once, and he prefers Caltech because he believes—like most scientists—that the best research is done by top scientists at a few elite institutions Yes, and the scientists themselves know better than fund managers how to spend the money.Rhodes' approach is to identify the most valuable centers for basic research, provide a large sum of money with few strings attached, and allow scientists to decide for themselves what to do with the money.There is a lot of money that needs to be distributed.By 1932, the Rockefeller philanthropy alone was funding American scientific research six times as much as all donations to science at the turn of the century.The history of science expert Daniel Kevries described Rhodes as "the central bank of science," and one of his favorite sayings, "to make the top of the mountain higher," has become the Foundation's unofficial motto.

Fueled by the largesse of Rockefeller and Carnegie, as well as private donations, private science centers such as Caltech, MIT, Columbia, Harvard, and Johns Hopkins grew rapidly in the 1920s— — not to mention the schools that Rockefeller supported, such as the University of Chicago and the Rockefeller Institute of Medicine in New York City.Not only has a large number of new infrastructure, teaching buildings and laboratories been newly built, but the strength and influence of the discipline have also been greatly improved.The alliance formed between government, business, and science during World War I—in the form of Hale and Millikan's National Council for Scientific Research—was further consolidated in the 1920s, forming a A scientific "clique" of academic authority and socialites: university professors, businessmen, government officials, charitable fund managers and wealthy councils, as well as the presidents of the National Academy of Sciences and the American Association for the Advancement of Science.They talked to each other at academic conferences, dined at each other's clubs, advised each other, provided each other with funding, nominated each other for greater office, and together charted the course of science between the two world wars.

This system is very beneficial to Caltech.For example, Hale, Noyce, and Millikan were all organizers of the National Council for Scientific Research and influential figures in the National Academy of Sciences.When the Carnegie Foundation, which funded Hale's Wilson Observatory, searched for a new chairman in 1919, Hale and Noyce made sure that their mutual friend and former National Scientific Research Council chairman John C. · Miriam can be nominated.As Noyce pointed out to Hale, "With this arrangement, you, me, and him can basically influence the policy of the Carnegie Foundation." Received a Carnegie grant: $200,000 for various chemistry research projects in the 1920s—one-third of the chemistry department's total yearly expenses.Some of the money funded Pauling's early scientific research.

Not surprisingly, James Cartel, then editor of Science, tartly likened this intricate connection to the astronomical problem of calculating the motion of planets involving several celestial bodies. "Where the Scientific Research Council belongs to the National Academies, or whether the National Academy belongs to the Scientific Research Council, or whether both are satellites of Pasadena, is a complex question involving three celestial bodies.  … Carnegie Corporation, Rockefeller Foundation and the National Scientific Research Council is another problem involving three celestial bodies."

By the late 1920s, grants from private philanthropic foundations became a vital source of Caltech's income—twenty percent of its total assets—with a large portion coming from the Rockefeller Foundation. Noyce had received a lot of money from the Carnegie Foundation to fund his physical chemistry program, and now he turned his attention to the Rockefeller Foundation, hoping to use it to expand the Department of Organic Chemistry.Organic chemistry is a weakness at Caltech.Noyce's only organic chemist in the department was a remnant of Tropp's time named Howard Lucas, whom Noyce considered less than brilliant.For Noyce, organic chemistry—the study of living molecules like carbides—was a cornerstone that could lead to his other long-cherished fields: biochemistry and medical research.Noyce believed it would be a major advance for his branch of science, an interdisciplinary field where chemistry could revolutionize biology, just as physics, with his help, had revolutionized chemistry.As early as 1922, he approved a project to try out insulin at Caltech, which he expanded with Carnegie funding in the following years; he even wanted to create a Research-driven medical school.

However, the first step has to be organic chemistry.He needs to find a newcomer, a new scientific star with international reputation, so that it is possible to build a research team with him as the core.He started looking for funding to realize this plan.In the mid-1990s, Noyce persuaded the Rockefeller Foundation to provide a substantial sponsorship, including the cost of hiring a new organic chemist, but he could not find a suitable candidate.Organic chemistry is a specialty in Europe, especially Germany, and it is difficult to find first-class scholars in the United States. James Bryant Conant is the first person in the field of organic chemistry in the United States, but in 1927 he studied at the California Institute of Technology Two months later, an offer from Harvard University was accepted.Then Noyce's health began to deteriorate, distracting him. In 1930, this position was still vacant, and the Rockefeller Foundation gave Caltech a large amount of sponsorship: 200,000 US dollars, and guaranteed more funds for the development of natural sciences, including re-building the Gates Laboratory. A new organic chemistry building.

Noyce set his sights on Pauling.When Pauling applied resonance ideas to the molecular structure of benzene, Noyce asked him if he could consider changing his title to a professor of organic chemistry.For Noyce, the benefits were clear: In his new building he could have a recognized genius, a scientist with the cohesiveness needed to start a new department.But Pauling quickly declined.Pauling liked to think about biology—Noyce encouraged faculty members in the department to attend biology department seminars, and Pauling became acquainted with young men in the group of geneticist Morgan and even translated a German Genetics paper, and published his own opinion on it - but Pauling's main interests still revolved around crystal structure and chemical bonds.He believed that his structural method of quantum chemistry was the basis of all chemistry, including organic and inorganic chemistry.When promoted to full professor, Pauling insisted on changing his official title from Professor of Physical Chemistry to the more general Professor of Chemistry.Changing back to organic chemistry would be a step back.He doesn't want to be put into a certain category.

The name doesn't matter, what matters is what Pauling actually did.Noyce considered Pauling's work on the chemical bond to be the most significant advance in the discipline of chemistry, and organic chemistry was no exception.Only Pauling has the ability to promote a scientific research project.Either way, Pauling's group will take center stage in the new building.But it would be good if his research could be slightly biased towards biological topics. Pauling is a smart man, he can see the direction of the wind. In February 1932, Pauling applied to the Rockefeller Foundation and the Carnegie Foundation at the same time, requesting a grant of 15,000 U.S. dollars per year for five years to support "a series of studies on the structure of inorganic and organic matter, Including theoretical and experimental work".Much of the work he asked for funding involved topics in X-ray crystallography and electron diffraction, but he also described his growing interest in organic molecules—successful studies of the molecular structure of benzene. "I expect to solve the wave functions of simple organic crystals and molecules," he wrote, and use semi-empirical methods to "establish a set of principles of atomic radius and structure for distance, the general electronic state of any molecule, and its stability relative to other molecules. This knowledge will also be crucial for biochemistry, allowing for the determination of the structure of proteins, hemoglobin, and other complex organic matter .”

Weaver Pauling's proposal—especially on proteins—5; caught the attention of Warren Weaver.Just two months earlier, the Rockefeller Foundation had hired Weaver to distribute its grants for the natural sciences. As a scientist, Weaver is a second-rate character, but his knack for making friends is first-rate.One of his close friends was Max Mason, a professor of electrical mechanics at the University of Wisconsin who later became chairman of the Rockefeller Foundation.The other is Millikan.Millikan was so impressed with Weaver when he taught physics at the University of Chicago that when he went to Caltech, he offered Weaver a teaching position.Weaver spent three pleasant years as a junior professor in Pasadena before Mason asked him to return to the University of Wisconsin in 1920; when Weaver left, Millikan refused to accept his resignation, saying He should always think of himself as a Caltech faculty member.

But Weaver wasn't good at lab work."I lacked that wonderful spark of creativity that a great researcher needs," he said. "I never had a first-rate original thought." So, like many scientists frustrated at the bench, he turned to teaching. and administrative work.He formed good relationships with all kinds of people, and soon rose to become the chair of the mathematics department at the University of Wisconsin. He settled down and seemed set to spend the long years in Wisconsin.Suddenly, in early 1932, Mason called him, this time to the New York offices of the Rockefeller Foundation.Wycliffe Rhodes was gone, Mason explained, and so was his generous way of giving; the Great Depression had changed that, and now those trustees of the Rockefeller Foundation wanted to be clear before giving away large sums of money. Find out what the money will be used for.The trend now is to allocate smaller grants to specific research projects led by a single scientist.Directors want to see results.Of course, this means that the fund manager will supervise the project more strictly, and can accurately pick the winner from the many scientists who participated in the competition.Mason trusted Weaver's judgment.This, he explained to Weaver, was why he wanted Weaver to run the natural sciences department. Weaver was too surprised to say a word.The prospect of this work dazzled and fascinated him.At 38, the good-natured, bright-faced experimental loser and midlevel academic executive was tapped to run the world's most important science-funding agency.He will have the power to open up new fields of research, make or break a career, allocate millions of dollars in funding, and even change the course of scientific history. He couldn't wait to take the job. Weaver himself may have few original ideas, but he is good at discovering the ideas of others.He was particularly passionate about a new kind of biology.Although he himself was not educated in this area, he believed that a scientific revolution was brewing there, which would give birth to a new method that could greatly improve human life.Like Noyce, he believed that the methods of the more "successful" natural sciences—mathematics, physics, and chemistry—if applied to biology would bring about a revolution in the discipline.He called this "the friendly invasion of the biological sciences by the physical sciences." He didn't even use the word "biology" when referring to his thinking in the early 1930s, calling it "the process of life" before inventing a proper name in 1936: molecular biology.It will change the way we think about the living world, he told the trustees of the Rockefeller Foundation.Whereas old biology was concerned with whole organisms, molecular biology was concerned with the unknown world within a single cell, the processes of metabolism and the structure of individual proteins.Quantitative measurements will support qualitative observations.Using universal laws of nature derived from chemistry and physics, biology will move from the field to the laboratory.Here, a new generation of scientists will use unimaginably powerful experimental equipment, such as X-ray crystallography instruments, ultra-high speed centrifuges and increasingly powerful microscopes, to discover the origin of life. Weaver isn't alone in his enthusiasm. In the late 1920s, H.G. Wells and Julian Huxley published a bestseller, The Science of Life, which provided a popular overview of the science in this area, representing a small group of like-minded British and Thoughts of American scientists.Before long, they wrote, "biological science armed with theoretical and practical knowledge beyond our imagination" could "ultimately dictate the development of mankind."Scientists will "operate directly on genetic material to make future eugenics a possible reality".At that time, man will improve any species, including himself, just as he improved the varieties of wheat and corn. Weaver took this idea a step further.Lab-based work on biology and psychology will help "people rationalize their behavior" by uncovering the molecular structures that lead to violence, depression, perversion and sexual problems, he told the Rockefeller Trustees.From now on, he said, the Rockefeller Foundation should devote itself to using the most powerful emerging scientific techniques to unravel the mysteries of the human body and brain.The trustees, mostly conservatives, were struck by the idea that they could uncover the root causes of social unrest.They entrusted Weaver with carte blanche to carry out his project called "Science of Man."Since then, the Rockefeller Foundation has stopped sponsoring mathematics, physics, and chemistry that are not directly related to the life sciences. Weaver knew that the success of the new project depended on finding chemists and physicists who could apply their skills to new fields.Pauling's ability in chemistry is obvious to all, and he has recently begun to be interested in biochemical issues, so he is a suitable candidate.As director of the Natural Sciences Department of the Rockefeller Foundation, one of the first things Weaver did after taking office was to allocate $20,000 to Pauling for two years—enough for Pauling to pay the salaries of five postdoctoral fellows and a full-time assistant, with some money left over. It can be used to purchase instruments, test tubes, crystals, film, transformers, and other necessary specialized equipment.This even exceeded Pauling's lost research funding due to the Great Depression, and it also marked the beginning of a long-term mutually beneficial cooperative relationship between the two men. As far as Caltech is concerned, the Rockefeller Foundation's focused funding program has both advantages and disadvantages.The new arrangement means that most research projects in astronomy, geology and mathematics, physics and chemistry - disciplines unrelated to biology and psychology - will lose access to funding.According to Weaver, not a penny.Not even Millikan could convince the Foundation to sponsor his cosmic ray research.But Morgan's genetics research would receive generous funding from Rockefeller, as would Pauling's. Shortly after joining the Rockefeller Foundation, Weaver visited Caltech and made a good impression.Noyce carefully arranged for him to visit the Gates laboratory building, and introduced him to the long-term plan for the development of organic chemistry - which he cleverly called bioorganic chemistry - and his own talent pool, especially mentioning Pauling.That night, Weaver wrote in his diary: "Noyce said to me that even if the entire chemistry department were left with Pauling alone, it would still be one of the most important chemistry departments in the world. He hoped that I would not This remark is considered a common Californian compliment." As soon as Weaver met Pauling, he began to believe that Noyce might be right.In Caltech's other chemistry labs, only one or two graduate students were silently completing the tasks assigned by the professor, while Pauling's lab in the Astrophysics Building was full of life.There were nine postdoctoral fellows and five graduate students in the room, and they were discussing enthusiastically with each other.Here, ideas exchanged freely and openly, a bit like Lewis's Berkeley Lab.Original ideas are scrawled on blackboards, sparking heated debate and laughter.Weaver thought it was a bit like a European-style center for theoretical chemistry—an academy within an academy, with Pauling running everything.After his visit to Caltech, Weaver evaluated Pauling as "a genius with first-class thinking ability, amazing analytical ability, and a close and fruitful connection with experimental science.  …Harvard University, Massachusetts The Provincial Institute of Technology and the University of Michigan are competing for high salaries, and he is almost recognized as the leader of theoretical chemistry in the world." The only flaw is that Pauling doesn't study the life sciences—at least not yet.In the interview, Weaver touted his molecular biology approach, emphasizing that the Rockefeller Foundation was much more interested in the structure of biomolecules than in sulfides.They had a long talk in Pauling's office, and he encouraged Pauling to use his structural chemistry ideas to unravel the mystery of life. But that message doesn't seem to be having an effect on Pauling.A few months later, when Weaver visited Caltech for the second time in October 1933, Pauling's first two years of funding were nearly exhausted.Of the more than twenty papers bearing Pauling's name from 1932 to 1933, only the one on benzene and two or three other papers on small carbon-based molecules are on organic chemistry, and almost one paper on molecular biology nor.All other papers dealt with Pauling's interest in inorganic crystals or with quantum theory problems in general.Pauling knew that Weaver had other plans, so he specially prepared a six-page report for his patron, explaining to him how he spent the Rockefeller Fund and his future plans.He said that the focus of his current scientific research is to solve the structure of organic molecules, and then specifically mentioned to Weaver that he would study chlorophyll and hemoglobin in the future.These hints and promises did not satisfy Weaver.He liked Pauling and thought he had a bright future, but he had to convince the foundation directors to accept Pauling's point of view.He told Pauling frankly that it was impossible to get money for structural work in general organic chemistry; only work that was directly related to biology could be funded. Pauling was all ears.When he formally applied for a three-year extension of his sponsorship in 1933, he mentioned biomolecules prominently in his report.Weaver thought he should be sponsored, but since Pauling had little to no biology-related research output, Weaver found it difficult to get the board to make up his mind.Finally, he likens Pauling to Louis Pasteur, whose abstract interest in chemical structure in the 1850s eventually led to major discoveries in biology and medicine.Even then, the council only approved a one-year extension of the sponsorship.Weaver calmly broke the news to Pauling, telling him that economic conditions made long-term funding "unwise," and reaffirming the Rockefeller Foundation's expectations: "If your work can directly involve chlorophyll, hemoglobin, and other biologically significant substances, then your application will be given priority consideration." Biology was interesting, but Pauling didn't intend to enrich his academic career around it.His background in organic chemistry was limited, and he hadn't taken a single biology class in his life.He was confident of his ability to solve almost any problem, but turning to biology would take him out of the realm of success into an unfamiliar place with different expectations, and have his success judged by another group of scientists.This would be a big risk.In addition, he felt that with a little more time and money, he would soon discover the general laws that determine the structure of sulfide minerals. In early 1934, he asked the Geological Society of the Penrose Fund of the United States to fund his research. He was rejected, which surprised Pauling, who felt that it was a double blow to his research plan and personality.He suddenly realized the importance of the Rockefeller Foundation.Pauling expanded his lab with funding from the Rockefeller Foundation, and the assistants, postdocs, and graduate students he recruited with the money prompted him to develop a new style of work.He first proposes new ideas or problems to be solved, asks students to conduct experiments, and then helps them analyze the results and co-write the paper.This way allowed him to get out of the laboratory, concentrate on his study, and carry out his best theoretical thinking; this expanded his research field and enabled him to think about the topics he was interested in at the same time.The papers he published in 1934 were all cooperative, and the salary of the general collaborators or the experimental equipment used were provided by the Rockefeller Foundation.The Great Depression was far from over, and it was impossible to get big money from other sources. Pauling was after money.He wrote: "Obviously, unless I develop an interest in chemistry related to biology, it will be difficult for me to continue to receive support from the Rockefeller Foundation." He gave up some research work in mineralogy to focus on biomolecules.He later resignedly said: "The above experience shows that sponsoring institutions can influence the scientific process." blood Pauling may have started late in organic chemistry and biomolecules, but once he did, he threw himself into the work with his usual energy and imagination.On the theoretical side, he and his student Weiland applied their resonance ideas to important organic matter structures, such as carboxyl groups in organic acids and aromatic-free atomic groups.Lawrence Brockway's electron diffractometer was already in operation, and a series of papers began to appear on the structure of small organic molecules, one of which described the structure of a sublayer of hemoglobin. Hemoglobin is an ideal subject for laboratory research for several reasons.First and foremost, it is the most important type of molecule in the body.Hair, horniness, and feathers, skin, muscle, and tendons are all proteins, as are the most important parts of nerves and blood.Enzymes that catalyze certain reactions that people have yet to explain are proteins; so are antibodies and large parts of chromosomes—matters that carry the genetic code and are a tangle of proteins and nucleic acids.Proteins are involved in every reaction and are an essential building block of any organ in the body.It is believed that the secret of life can be found in proteins. In the early 1930s, no one knew the properties of proteins, or even what proteins looked like.Proteins, however, are the engines that drive life's processes; it's at these molecular levels that those cold chemicals become living, breathing organisms.Uncovering the secrets of what Weaver calls "the giant protein problem" will be one of the most important elements of the life sciences program. In practical terms, however, studying proteins is a nightmare.Early data showed that they were huge molecules, sometimes comprising hundreds of thousands of atoms—much more complex than any molecular structure Pauling had ever solved.They are difficult to purify and are perishable.Just a little heat or treatment with an acid or base is enough to change a protein's natural shape and inactivate it—what's known as "denaturation."As experience with beating eggs shows, stirring an egg white a little with a fork is sometimes enough to denature it. At least hemoglobin is not so fragile.Large quantities of pure hemoglobin are readily obtained from the blood of cattle or sheep.Its greater advantage is that it crystallizes, meaning it has a regular, repeating structure.As long as a substance can be crystallized, it is at least possible to analyze its structure by X-ray diffraction. Hemoglobin can also be broken down and studied piece by piece.It is a protein that binds to other non-proteins, in this case to a ring-shaped molecule called a porphyrin.Porphyrin is combined with an iron atom, and the iron atom is combined with oxygen, so that hemoglobin can carry oxygen throughout the body.When Pauling visited Harvard in 1929, Conant introduced some of his research work on porphyrin to him, which aroused Pauling's interest.Porphyrins are of interest first because of their curious shape—a large ring made of many smaller rings—but more importantly, because they are found everywhere in nature, in the chlorophyll of plants. Combined with oxygen, it is also combined with oxygen in the hemoglobin of many animals.At the molecular level, porphyrins seem to represent the idea of ​​molecular biology with the universal significance of life: where there is life, there is porphyrin, and it plays similar roles in different organisms. Porphyrins consist of four pyrroles strung together in a ring.Pyrrole is a ring of atoms bonded alternately by single or double bonds, known as a "protein and non-protein binding" structure.Pauling discussed the chemical properties of this structure in a paper on the nature of chemical bonds.To study hemoglobin, pyrrole is a natural starting point.From here, Pauling can study more complex structures step by step: four pyrroles combined to form a porphyrin ring; a porphyrin ring plus an iron atom to form a hemoglobin; each hemoglobin and a globular protein to form a Hemoglobin unit; four hemoglobins make up a hemoglobin molecule.The resulting structure is unimaginably large: a sphere containing tens of thousands of atoms.Pauling quickly concluded that the structure was too complex to study directly by X-ray crystallography, although some optimistic British researchers funded by Rockefeller were planning to do just that.Maybe he could break down the hemoglobin molecule into its component parts, figure out the structure of each sublayer, and put them back together. Pauling began reading everything he could find on hemoglobin, including a paper that delved into how the molecule binds to oxygen.There is a mystery here.The researchers found that when oxygen binds to the four hemoglobins in hemoglobin, they don't appear to work in isolation.When the first oxygen atom is combined, the remaining three oxygen atoms are easier to combine, and when the first oxygen atom is lost, the remaining three oxygen atoms are easier to lose.There appears to be some form of communication between the hemoglobins.This could be used to explain how hemoglobin carries oxygen in the lungs and unloads it in the rest of the body, yet the communication between molecules is difficult to explain chemically. However, after several weeks of thinking, Pauling came up with a clever way.He designed a formula that could describe the data collected by predecessors on the binding of oxygen atoms, and then performed mathematical analysis on the various spatial relationships among the four hemoglobins, and finally came up with a direction that fit the binding curve.The most likely orientation of the four hemoglobins is at the corners of a planar square, he said.His idea was later proved wrong, but when he first proposed it in 1935, it caused a heated discussion among the vast majority of medical researchers and biochemists among hemoglobin researchers.They had never seen such a research method in this field.Apparently, a new talent with new ideas has emerged. Pauling made his point, showing Weaver that he was serious about his new research project.However, his other studies on the hemoglobin molecule did not go well.He tried to apply the new X-ray technology to porphyrin, but soon found that this method was too complicated to be effective in the short term.Pauling gave up the effort, telling Weaver that he was not the kind of chemist who could spend two years performing an exhaustive crystallographic analysis of a compound.Solving the problem of the structure of hemoglobin eventually took 20 years, countless mills, countless X-rays, and will eventually win someone else a Nobel Prize. Pauling's one-year Rockefeller Fund was about to expire, so he applied for funding again for more basic research work.Weaver had trouble securing any Rockefeller grants for nonbiological work, but he had a bright idea.He suggested that Pauling use potential Rockefeller funding as a springboard to get Millikan to spend about $5,000 on basic research.Support from his own school, combined with Pauling's recent advances in hemoglobin research, might persuade the Rockefeller Foundation trustees to extend the sponsorship to three years.Pauling took Weaver's advice and added a threat of his own: If Millikan didn't agree, he would accept another university's offer.He got five thousand dollars a year.Pauling telegraphed Weaver the good news; Weaver quickly wrote back that the board had voted to extend his $10,000-a-year grant for another three years. In three years, Weaver and Pauling had grown from sponsors and sponsored persons to accomplices and friends. After the source of funding is stable, Pauling is free to try other methods to study hemoglobin and satisfy his interests in other fields. In 1935, after three years of hard work, he and one of his former students, the current postdoctoral Brett Wilson, compiled the lesson preparation notes of Pauling wave dynamics into a textbook: "Introduction to Quantum Mechanics and Its Application in Chemistry" Applications".Although sales were modest in the first few years after publication—quantum mechanics was not yet accepted as a required course for chemists—the book would have far-reaching consequences.Over the course of 30 years, this textbook has been reprinted, teaching generations of students the importance of new physics. Also in 1935, Pauling had a sudden inspiration to publish a paper on the problem of "irregular arrangement"-the theory of water molecules that explained the ice at absolute zero.It was a purely theoretical study dating back to his days of studying with Tolman. Thirty years later, advanced computers performed a thorough check on these formulas, proving that Pauling's theory was correct.This theory, now known as "Proton Irregularity," is, according to a student in the field, "the greatest American contribution to modern crystallography of water." These studies, however, are just sidetracks: hemoglobin is the destination. Pauling began to discover that biology was almost as interesting as chemistry.Pauling spent most of the summer of 1935 at Caltech's Institute of Marine Biology in Coronado, extracting hemocyanin, a related substance from limpets, and cooperating with Albert Taylor, a young biology professor at Caltech, became friends.Taylor is trying to figure out the mechanism of autosterility in sea urchins.This research work further stimulated Pauling's interest in why life can recognize itself and others, and why molecules respond differently to themselves and others.Maybe there's some kind of chemical connection here.Pauling was always on the lookout for new ideas, and brought this problem to his head. After Pauling returned to Pasadena, he came up with a new method of studying hemoglobin—examining its movement in a magnetic field.鲍林的推理过程为，当氧和血红蛋白中的铁原子结合时，也许是以一种共价的形式——反应将是特定和相当强烈的——这意味着至少它的一个孤电子将成对，而且其顺磁性——具有一个或更多的孤电子的分子的一种特性——将下降。如果他能够测出顺磁性的变化，他就有可能回答氧是如何与血红蛋白结合的问题。 为了进行其他的研究工作，他先前从海耳的私人实验室里借过一大块水冷式磁铁。1935年秋天，他请查尔斯·科耶尔，一位刚出炉的，精力旺盛、干劲十足的加州理工学院博士来进行这项工作。他们设计的实验相当简单：一个装有牛血的小玻璃试管被悬挂在磁铁的两极中，一头用一根线栓在一个敏感的天平上。当磁铁的电源被接通后，顺磁性物质将被吸引至一个方向；天平能够测出磁性变化的程度。 在测试了含氧血、缺氧血以及各种控制手段后，他们发现鲍林的预测是正确的：结合的氧失去的孤电子参与了与铁原子结成的共价键。这就迈出了重要的～步，证明氧并非如一些研究者认为的那样，不分青红皂白地吸附在铁原子上。但是鲍林和科耶尔也发现了血红蛋白分子一些令人惊异的行为。他们的实验显示，血红蛋白中的铁原子在和氧结合的时候，也发生了根本性的变化，它与卟啉的化学键从离子键变成了共价键。鲍林写道：“在增加了氧原子后，血红蛋白分子结构会发生如此极端的变化，令人又惊又喜。如此紧密联系在一起的物质的化学键类型会如此不同，这种现象至今为止只在血红蛋白衍生物中发现过。” 鲍林和科耶尔在1936年发表的这篇论文进一步提高了鲍林的知名度。他们想出了一种巧妙的办法来解决一个古老的问题，并表明物理化学家在生物化学领域同样能够作出有价值的工作。他逐渐被原先专业领域外的科学家所知晓。他进入了一个新的领域，并很快开始征服它。 毛发和兽角 到现在为止，鲍林的工作都是围绕分子的血红素进行的，然而与此同时，鲍林努力思考着分子的其他部分——珠蛋白部分，即蛋白质部分。蛋白质化学还是一个庞大而又支离破碎的领域，鲍林用他惯常的方式开始自学，一面广泛地阅读科学文献，一面寻找着合适的切入点，以便用自己擅长的化学知识来提供深刻的见解。他发现蛋白质是由称为氨基酸的材料构成的。氨基酸的种类相对较少，20种左右，但都具有关键的相同点：每一个氨基酸都具有由三个原子组成的骨架，碳—碳—氮。碳的一头是羧基的一部分，氮的一头是氨基的一部分。各种氨基酸唯一的区别在于与中间碳原子相连的支链。伟大的德国有机化学家埃米尔·费歇尔在20世纪就证明，氨基酸可以通过头尾相连，即把羧基和氨基相连而构成较长的链，费歇尔把这一共价键称为肽键。他将构成的较长的分子称为多肽。到了30年代，尽管并不是每一个人都认为所有蛋白质都包含多肽链，但至少有一部分蛋白质是包含多肽链的。 鲍林觉得费歇尔的理论很合理，他开始用这个理论去认识蛋白质，将其视作由肽键联结的氨基酸所构成的长链。但是如何用这一长链的构造来解释蛋白质的多样性，如何解释蛋白质在肌体中令人眼花缭乱的功能呢？所有蛋白质都是由多肽链的不同排列构成的呢，还是存在着别的基本结构？ 和以前一样，结构仍然是鲍林研究的重点。他相信，蛋白质的构造方式决定了它的活性。然而要发现它们的构造却几乎不可能。直接用电子衍射或Ｘ射线晶体衍射难以解决蛋白质复杂的构造问题。例如，瑞典科学家西奥多·斯韦德贝里刚刚证明，血红蛋白是一个庞然大物，包含数十万个原子。其他的蛋白质也差不多大小。 不过，仍然有一些实验室试图通过Ｘ射线来获得对蛋白质结构的初步认识。最著名的两个实验室都在英国。在利兹，威廉·阿斯特伯里正在调查羊毛和其他纤维蛋白质，如毛发、角质、羽毛和肌肉纤维的分子结构。他的研究成果——出乎许多科学家的意外——清楚地显示出这些蛋白质具有一种规则的重复结构，一种晶体结构。 阿斯特伯里认为，他能够解释羊毛为什么可以被拉长而不会断裂，为什么又能缩回到原来的长度。羊毛同兽角、指甲和人的头发一样，统称为角蛋白。到了30年代初，阿斯特伯里也确信，角蛋白是由环状的多肽链组成的长链。他将其称为“分子毛线”。他的Ｘ射线照片显示，当羊毛被拉长时，分子发生了变化。尽管照片很模糊，他难以确定单个原子的位置，但是仍然可以从中推断出，角蛋白被拉伸时——他称其为乙型——多肽环被拉长了，而未被拉伸时的形态，或甲型的多肽环则是折叠在一起的。他的测量还表明，折叠发生在两个方向上，而不是三个方向上——就像在桌面上将甲型中的多肽环折叠成锯齿形状。进一步的研究显示，肌肉纤维具有同样的基本形状。 这是一项重大的进步，对蛋白质的特性作出了分子上的解释。 阿斯特伯里认为，也许这些分子的折叠同样能够用来解释肌肉和染色体的收缩。他开始将角蛋白视为“所有蛋白质的祖父”，这一基本结构也许可以解释所有其他蛋白质的运动。 但是，他有些高兴得太早了。Ｘ射线衍射还不足以用来解决羊毛角蛋白中多肽链的结构，因为每一根链中包含上万个原子。无法精确地了解角蛋白的构造，而且将其固定的力量仍然是一个不解之谜。尚无法证明角蛋白是由多肽链组成的——阿斯特伯里的研究工作只是表明有这种可能性。 鲍林对阿斯特伯里的工作进行了仔细的研究。 阿斯特伯里关注的是角蛋白这类纤维蛋白质，而另一组英国科学家关注的是球蛋白的分子结构。这类蛋白质在体液中会溶解，如血红蛋白、抗体和酶。这里主要的问题是获取良好的晶体。球蛋白并非不能结晶——比如科学家们长期以来就知道，血红蛋白在干燥后会结晶——但是在进行Ｘ射线衍射时，它们只能形成一片模糊的图像。这使一些蛋白质化学家推测，球蛋白没有内部结构，只不过是氨基酸随意的聚合，而肌体真正的活性组织——非蛋白质分子，如维生素和荷尔蒙——是自由定位的。 直到1934年，剑桥大学晶体学家约翰·伯纳尔证明了另一种理论。伯纳尔发现，球蛋白就像水母：需要借助液体环境来保持原来的结构，失水后，结构就会遭到破坏。伯纳尔将其悬浮在液体中进行Ｘ射线衍射，得到了一些实用的图形。到了30年代末期，以他为中心的一个小组致力于揭开球蛋白结构之谜。他和同事们——其中包括多萝西·霍奇金和在维也纳受过培训的青年化学家马克思·佩鲁茨——对一些球蛋白进行了提纯、结晶和Ｘ射线衍射分析：胰岛素、血红蛋白和糜蛋白酶。这是在极端艰苦的环境中取得的巨大成就。在佩鲁茨的记忆中，剑桥实验室是“在一幢破旧灰色大楼底层的几间灯光昏暗的脏屋子”，但是怕纳尔成功地将其变成了“神话中的城堡”。他们发现，他们研究的所有球蛋白都具有规则的结构，而且无一例外地异常复杂——当鲍林看见在剑桥实验室中拍摄的照片时，他的第一个反应是，如果直接用Ｘ射线分析这类蛋白质结构是可行的话，那也至少要花费几十年的时间。阿斯特伯里和伯纳尔的研究工作引起了越来越多的人的注意，其中也包括韦弗。他在30年代中期开始资助他们的工作。在洛克菲勒基金的支持下，三个中心开始围绕蛋白质精确的结构展开联合科研活动。前两个中心分别由阿斯特伯里和伯纳尔领导。两人都是物理学家，都认为只有通过不厌其烦的、直接的Ｘ射线衍射分析才能揭开整个蛋白质的结构之谜。第三个中心在帕萨迪纳，由鲍林领导。他寻求以理论的形式，在对结构化学的深刻认识基础上寻找一条捷径。在1935年，三个中心的不同之处在于，英国科学家从其Ｘ射线工作中得到了许多实际数据，而鲍林还没有发表过一篇关于蛋白质结构的论文。 氢键 鲍林很快意识到，要对这些奇怪的巨大蛋白质分子作实验，一定需要借助外界的帮助。 洛克菲勒医学研究所的一个研究小组正好具备鲍林缺乏的这种专长。两位洛克菲勒科学家，阿尔弗雷德·莫斯基和莫蒂默·安森最近所作的实验表明，在某些情况下变性可以被逆转；例如，血红蛋白在受热后会改变形状并丧失携氧的能力，然而如果被小心地冷却，至少一部分分子会恢复原来的形状和特性。结构和功能的这一联系令鲍林眼睛一亮，但是洛克菲勒小组的实验技能更让他心动。鲍林在1935年春天到纽约拜访了莫斯基，两人一见如故。鲍林直截了当地请莫斯基到加州理工学院工作几年，令莫斯基又喜又惊。他结结巴巴地说，这是一个不坏的主意，但是过于突然，所长西蒙·弗莱克斯纳不会答应的。鲍林说，他觉得所长可能会同意。他找到了所长办公室，说服秘书立即安排他和所长会面。他不仅要求弗莱克斯纳同意放莫斯基，还要求洛克菲勒医学研究所支付一切费用。弗莱克斯纳是洛克菲勒基金理事会成员，从韦弗那里对鲍林早有耳闻。他对这位青年科学家的坦率感到好笑，同时对他将化学技巧运用到生物学上感到十分有趣，最终答应了鲍林的要求。 莫斯基在夏天刚开始的时候来到了帕萨迪纳，马上开始对蛋清、肌肉和其他蛋白质的变性过程做了一系列的实验。鲍林让莫斯基负责实验室工作，同时彼此探讨变性的化学含义——弄清楚这一过程对蛋白质的结构造成了哪些实际的影响。莫斯基和安森收集的实验数据表明，变性过程可以分为两个层次，这让鲍林产生了浓厚的兴趣。第一个层次由相对较弱的热量和酸引起，往往是可逆的。而第二个层次，由较高的温度，较强烈的化学环境或是与破坏蛋白质的酶发生的反应所引起，通常是不可逆转的。根据这些数据，鲍林很快地用化学键理论作出了自己的解释。两个层次的变性意味着有两种类型的化学键，第一类涉及到相对较弱的化学键，很容易被打破或重建；第二类涉及到较强的化学键，难以打破，也难以重建。鲍林对打破第二类较强的化学键所需的能量进行了测定，数据表明这一类化学键为共价键；这反过来也验证了蛋白质是由氨基酸与共价的肽键结合而成的长链的观点。第二层的变性基本上将蛋白质撕裂成了碎片。 鲍林对较弱的化学键的研究更富有成果。他很快意识到，打破第一类化学键所需要的能量符合他所知的称为氢键的奇怪的化学键类型。在1935年的时候，鲍林是全美为数不多的理解并认识到氢键重要性的科学家之一。这一理论认为，氢在某种情形下，可以不形成一般的共价键或离子键，为两个原子所共有，在两者之间形成一座桥梁。鲍林认识到这一理论可以运用到他的化学键构想中：一方面，氢原子要靠近一个电负性很强的原子——比如说氧原子，或是氟原子——氢原子的孤电子被吸向这一原子，电荷集中在两个原子之间的区域中，在这一边形成一个小的负电荷。结果，在氢的另一边电子出现的机会较少，形成了一个小的正电荷，这样就与附近带负电的原子或分子形成了静电键——氢键。鲍林早在1928年就撰文讨论过氢键的概念，在1934年自己的共振理论中也融入了这一理论，并在1935年关于冰的摘值的论文中集中运用了这一理论。 现在莫斯基的变性实验使鲍林进一步确信，氢键是蛋白质结构中一个重要的成分。1935年秋天，他们两人根据鲍林的思路初步提出了一种新理论。他们写道：“我们对一个自然的蛋白质分子（表现出一定的特性）的认识如下。分子包含一个多肽链，在整个分子中连续不断（或者在某些情形下，包含两条或更多的多肽链）；这一多肽链被折叠为由氢键键合的唯一的结构。……”换句话说，所有蛋白质都包含氨基酸环，以及可能以阿斯特伯里认为的原始蛋白质角蛋白形式存在的多肽链。强肽键使整个链成为一个整体，但是各部分之间较弱的氢键折叠之后使整个链成为其最终的形状。这最终的形状对蛋白质的功能是至关重要的；分子除非保持这一形状，不然难以完成其功能。稍微受热之后，氢键断裂，整个链条伸长，并像针线盒中松散的纱线那样纠结在一起。然而，只要整个链还是一个整体，在合适的条件下，氢键能够重建，蛋白质也能恢复原先的形状和活性。较强的处理将使链本身断裂，打破肽键，并不可逆转地使蛋白质变性。 1936年7月，这篇名为“论自然、变性和凝结的蛋白质结构”的论文发表在《国家科学院学报》上，很快就被公认为是本领域中一项重要的进展。鲍林对化学键的认识一举对蛋白质变性和蛋白质活性的纷繁复杂的观察数据提出了一个统一的解释。韦弗大喜过望：尽管鲍林的思想最终被接受尚要假以时日，但是他向解决韦弗的“巨大的蛋白质问题”迈进了一大步。 然而，当论文在1936年6月1日到达《国家科学院学报》编辑部后的两天，鲍林的生活经历了一场巨变，原因与蛋白质没有丝毫的联系。