© A. Barrington Brown / Photo Researchers, Inc.
Stumbling on Gold:Two Smart Alecks in Cambridge
by Victor K. McElheny
“A NAGGING YET PRODUCTIVE SYMBIOSIS”
By the fall of 1951, when Watson started talking with Francis Crick, who was as iconoclastic and determined as he was, Watson was already convinced that the clamorous marketplace of science was no place for secrets. Jim and Francis believed that you must be ﬁercely competitive, but in order to go fast, you must share information in the expectation of learning things rather than withhold it from fear of theft. Over the next year and a half, they served each other as teachers and devil’s advocates—impolitely, relentlessly. For them science was inherently interactive. Professional competence in isolation was not enough to get important results. They were sure that science has, inevitably, many elements of guessing and playfulness, even farce—one could be wrong so often and so much of the time; there were so many things staring you in the face that you and often your rivals didn’t see; a beautiful insight could solve a jigsaw puzzle even when the best solid evidence had been ignored....
Within half an hour of their meeting, the shy, tall 23-year-old biologist and the talkative 36-year-old physicist with the unruly eyebrows talked of “guessing” the structure of DNA. Independently, each was sure that DNA, as the site of genes, was the most important problem around. Having become frustrated with experiments on the genetics of bacteriophages, Jim “wanted to learn more about the actual structures of the molecules which the geneticists talked about so passionately.” Protein structure, which was what John Kendrew had brought Jim to Cambridge to work on, was out the window. For a time, Crick laid aside his thesis on the blood protein, hemoglobin, to work on DNA....
Jim and Francis, an odd pair, shared what Crick later described as a “religious” aim: “to try to show that areas apparently too mysterious to be explained by physics and chemistry, could be so explained.” But the “large and genial” Crick was “conﬁdent, ebullient, articulate,” while the “thin and angular” Watson, a loner, was “difﬁdent, his words...brief.” Nonetheless, Jim held to his convictions in spite of his collaborator’s “forceful arguments.” As they looked back years later, Jim and Francis both felt that the other was the ﬁrst person he had encountered who thought as he did. As Watson put it, “Before then I had been with lots of bright people and I couldn’t agree with any of them.” Now, in Francis Crick, Jim had met someone who wasn’t wasting time on secondary issues. “With Francis to talk to, my fate was sealed.” The following spring he would write Max Delbrück that Crick was “always the person to whom the best of us go if we wish to talk out a half-baked theory, since he is always ready to be both interested and yet devastating in his ruthless logic.” Theirs was “a nagging yet productive symbiosis in which neither could do without the special abilities of the other.”
Crick’s logical mind worked best when he could bring theory to bear on a factual problem. He later remarked, “There has to be a theory or logical structure or I just don’t remember it.” He always would look ﬁrst for a simple solution, Jim observed, “even if the problem [was] very, very difﬁcult.” The almost-daily conversations with Watson delighted Crick, who had few people to communicate with. Watson had “met all these people,” leaders in biology. For Francis, Jim was “the ﬁrst person in the outside world.” They shared, according to Crick, “a certain youthful arrogance, a ruthlessness.... [A]n impatience with sloppy thinking came naturally to both of us.” They admired each other: “I’ve always felt that Francis is much more clever than I,” Watson said. “His brain works much faster.” Late in 1951, Watson wrote Delbrück that Crick was “no doubt the brightest person I have ever known and the nearest approach to Pauling....He never stops talking or thinking.”
Although they lacked training for working on DNA structure, they also had few preconceptions, and they possessed much energy and persistence. As two historians, Franklin Portugal and Jack Cohen, put it: “It was precisely their lack of preconceived notions that gave Watson and Crick an advantage in ﬂexibility in considering many possibilities that might have been rejected in a more systematic and deliberate approach.” They were conﬁdent that “success means disagreeing with others on fundamental things.” Real scientiﬁc ability requires the “agnostic attitude” that rejects conventional wisdom.
The Watson of the DNA conversations was, in the eyes of the Nobel Prize-winning biologist Peter Medawar, a precocious genius with a style that could have led English schools to steer him toward literary studies. In fact, just then, British universities were producing a score of outstanding molecular biologists. Over all of them Jim “had one towering advantage,” Medawar wrote. “In addition to being extremely clever he had something important to be clever about.” Discovering the nature of the gene “was the most important objective in biology.” It was a good working hypothesis that “the gene was what provided the information for life.” It was clear that “the main challenge of biology was to understand gene replication and the way in which genes control protein synthesis.” Such problems, Jim was convinced, “could be logically attacked only when the structure of the gene became known.” He thought of himself as the only one in Cambridge who “lived solely to understand how DNA functioned as the gene, and who had ﬁrst-hand practical experience in using bacterial viruses to get close to the self-replication of the gene.” In that spirit of conﬁdence, he was willing to “learn enough facts so I could talk with [Francis].”...
[What followed was a two-year collaboration, outwardly at a leisurely pace—Watson later said he had been “slightly underemployed”— but intellectually increasingly intense and ﬁnally frenetic in the race to reach the ﬁnish line ahead of other scientists, such as Linus Pauling, who were also working on the problem. Watson and Crick relentlessly tracked down and integrated into their thinking clues from many ﬁelds, built several unsatisfactory models of DNA, and had even been ofﬁcially “taken off the project” by their Cambridge advisor. By February 1953, they were focused on building a model of DNA’s chemical structure in their Cambridge University ofﬁce.]
BASE PAIRING SATURDAY, 28 FEBRUARY 1953
Arriving at their ofﬁce before Francis, Jim cleared his desk to try forming base pairs with hydrogen bonds, using the cardboard cutouts. First, he tried more tinkering with adenine linked to adenine and so on. But it didn’t work. Then he linked an adenine to a thymine, and a guanine to a cytosine. The two pairs, linked by hydrogen bonds, were “identical in shape.” With hydrogens in ﬁxed locations, there was a stable complementary relationship between the two chains. DNA had the capacity to self-replicate.
Donohue entered, and Watson asked him if he had any objections to the linkups he had made. Donohue said no. Jim’s morale “sky-rocketed.” DNA’s “central role in cellular existence” had become “unambiguously clear.” Neither Jim nor Francis had ever “anticipated that the answer would come so suddenly in one swoop and with such ﬁnality.”... In one hour, he had gone from nothing to understanding the structure of DNA.
About 40 minutes later, as Francis came through the door Jim told him his astonishing news: he had a credible model structure of DNA. “Not by logic but serendipity,” as Crick put it, Watson had found base pairing that worked. He was using neither Chargaff’s rules, which, Donohue noted, he was still “cheerfully disregarding,” nor the crystallographic evidence that had moved Crick two weeks before. Yet not only were Chargaff’s ratios explained, but, even more exciting, the model also made possible a far better scheme for duplicating DNA than Jim’s like-with-like models. They had stumbled on what one scientist later called “a scientist’s dream—simple, elegant, and universal for all organisms.” Francis and Jim “became enormously excited.” The structure was informative about a basic mechanism of life. One could begin “to think of the gene in terms of chemical structure.” But Watson and Crick couldn’t claim to be wonderful scientists. “It wasn’t very difﬁcult science,” Watson reﬂected, “just a wonderful answer.” “We essentially guessed the structure,” but it would prove to be “as correct as evolution.”
Sure it was luck, as happens in most discoveries, Crick wrote, “but the more important point is that Jim was looking for something signiﬁcant and immediately recognized the signiﬁcance of the correct pairs when he hit upon them by chance.” By “trial and error,” Jim and Francis had pulled together an array of insights about DNA that had been accumulated over many years by [scientists such as] Levene, Todd, Caspersson, Avery, Hershey, Chase, Chargaff, Wyatt, Pauling, Corey, Perutz, Kendrew, Cochran, Crick, Vand, Stokes, Astbury, Bell, Wilkins, Gosling, Furberg, Franklin, Gulland —and Donohue. But, as two historians later commented, “It was far from being a trivial matter to bring all these factors together and satisfy them uniquely.”
In 1984, Watson recalled his reaction as “near ecstasy.” In 2000 he reported thinking at the time, “Boy, it was pretty. If it was right, it was going to be very important.”...
Urgently, even ruthlessly, the brash collaborators had pulled together and orchestrated the fragments of knowledge about DNA. The double-helix structure ﬁt the data, but was it the real one? Was it right?
Jim awoke on Sunday morning, 1 March 1953, feeling “marvelously alive.” Little did he imagine that in less than four years he would evolve from a scientist doing his own experiments to a scientiﬁc impresario who spotted key problems, selected people to work on them, and then pushed to get them accomplished with an intensity and an inﬂuence few scientists have matched. It was a much subtler and far more sustained effort than the extraordinary tour de force he and Francis had just pulled off.
As he walked to the Cavendish [Laboratory], he took delight in the beauty of King’s College Chapel and the newly cleaned Georgian-style Gibbs Building. The sight of the buildings and their green surroundings made him reﬂect “that much of our success was due to the long uneventful periods when we walked among the colleges or unobtrusively read the new books that came into Heffer’s bookstore.”
Francis felt less relaxed. Once he “saw the base pairs and their symmetry,” Jim recalled, “he gave up working on his thesis” and turned to the vital work of making sure the double-helix hypothesis held up. The ﬁrst metal model was “the key thing, because you could have the right base pairs and still not ﬁnd a satisfactory structure.” It took them about a week to be sure of the structure. A six-foot-tall version of their model was not ready until the beginning of April, when they sent their ﬁrst paper to Nature.
When Jim arrived at their ofﬁce that Sunday morning, an anxious Francis was already there, testing again, with the help of a compass and ruler, whether Jim’s cardboard base pairs—each with one purine and one pyrimidine—ﬁt within the sugar-phosphate backbone of the double helix. They did.
John Kendrew and Max Perutz came in to see if Francis and Jim still thought they “had it,” and Francis gave each a characteristically buoyant and booming lecture. Crick later recalled, “We did have a constant stream of visitors, so much so that Jim got sick of me because I was in a state of—somewhat of euphoria explaining all this, and Jim would have to go out of the room. He couldn’t bear to hear it all over again.” Jim rejoined, “It was so obvious. You didn’t have to talk about it.” As he would do often in the coming days during such lectures, Jim slipped out. He went to see if the Cavendish Laboratory’s workshop could hurry and ﬁnish the metal representations of the bases for the next, more precise, but still tentative stage of model building. It was ﬁnished in two hours. An hour later Watson ﬁtted the metal bases together, so that “they satisﬁed the X-ray data and the laws of stereochemistry,” forming a right-handed helix with one chain running opposite to the other.
Then followed a nerve-racking quarter of an hour. Now it was Crick’s turn to inspect the freshly fashioned model. Every time Francis frowned, Jim’s stomach felt queasy. But Francis couldn’t ﬁnd anything wrong. The next morning was easier. While Jim sat on top of his desk dreaming of the letters he would write, Francis kept busy tightening the metal model on its support stands. By Tuesday evening, the reﬁnements were ﬁnished and Jim and Francis were sure that the sugar-phosphate backbone would permit the base pairing they proposed. Jim and Francis still hadn’t seen the latest X-ray evidence from King’s College, London, but they told each other over lunch that “a structure this pretty just had to exist.” They could begin drafting their “note” for Nature.
Such modest conﬁdence still left Jim and Francis with many worries. It might be the biggest scientiﬁc event since Darwin’s Origin of Species, but had it been a ﬂuke? “We had done something very good. Now what do you do?” After such “fantastic good luck,” Watson “worried about whether I would be part of the next step.” They wondered how the double helix “could be deﬁnitively proved correct and then how we might determine the way in which the genetic information within it was used to order the amino acids within polypeptides.”
Invaluable then and later was Erwin Chargaff’s discovery of the 1:1 ratio of A to T and G to C, the ﬁnding he could not or would not interpret. When Chargaff died at the age of 96 in 2002, Watson commented, “The base composition was an essential clue for ﬁnding the structure of DNA; there’s no doubt about that. We could have come up with the answer, but no one would have believed it.”
THE HIDDEN FUTURE
Having found the elegant solution to the puzzle of how DNA duplicated itself, they knew they were now entering a different world. Instead of one question, they now confronted many—and for years afterward they would struggle to ﬁnd the right way to use molecular biology to ask and answer those questions. Instead of the elegant simplicity of the double-helix structure they now confronted the bewildering complexity of how the DNA is duplicated and how it directs cells to make proteins. How did the coded information, the instructions stored in the library “stacks” of the cell’s nucleus, get copied and reach the relatively distant manufacturing “suburbs” of the cell? DNA had two tasks, one strategic and the other tactical. The strategic job was that of faithfully making new DNA copies once in a cell’s life cycle. The tactical task went on constantly. This was the making and unmaking of the many thousands of different kinds of molecules the cell needed to carry out such business as digesting food and building the many structures inside itself.
To go forward and answer such questions, Jim and Francis realized that they would have to enlist skeptical biochemists, even though Chargaff kept sneering for decades that it was “a lot of nonsense.” Crick observed long afterward, “We had to get involved with the biochemists, but it wasn’t clear to the biochemists that they had to get involved with us.” And the topics of cell duplication and function were myriad. On his sixtieth birthday, in 1988, Watson reﬂected that the period after ﬁnding the double helix was “the most difﬁcult” in his life....
The community Watson and Crick had to reach ﬁrst was not large. “There weren’t that many people around who were that interested,” Watson commented in 2002; some “immediately said it was important, but many more said, ‘Let’s wait and see.’” Watson later estimated the audience for DNA at about 50 scientists: 15 in England, 5 or 6 in France, and the others scattered. Even of these 50, few were doing research that could have solved the structure. Most had not faced the fact that the standard genetics of the past wouldn’t arrive at the gene, whereas “molecular structure” would. Did the whole world stand up and cheer? Crick asked later. “Not a bit of it, not a bit of it!” Neither Watson nor Crick was ever asked to give a talk about DNA at Cambridge, Jim recalled. This was not just English reserve, but a kind of irritation. At this time, “[M]ost biochemists worked on proteins...Someone coming along and saying, ‘DNA is more important,’ was unpleasant.”
Delbrück’s fascinated reaction to the DNA structure was, “It was obviously right,” although the details of how the structure would code for genetic speciﬁcity were “still very, very obscure.” In the middle of April Delbrück wrote Watson: “The more I think of it the more I become enamored of it myself.” Although he was concerned about how the DNA unwound and opened up to do its strategic and tactical work, he thought that if the model was correct, “all hell will break loose, and theoretical biology will enter into a most tumultuous phase.” Many dead ends of classical genetics might open up again. The same day, he wrote his old mentor Niels Bohr in Copenhagen, “Very remarkable things are happening in biology. I think that Jim Watson has made a discovery which may rival that of Rutherford in 1911,” the year Rutherford formulated the nuclear theory of the atom.
ANNOUNCING THE DISCOVERY
About three weeks before Watson and Crick’s ﬁrst paper about the double helix was published, colleagues car-pooled over from Oxford to see their model against a white-painted brick wall in the basement of the Austin wing. One of them was Sydney Brenner. “The moment I saw it...I just knew this was the answer to things...Bang, there it was.” Looking back nearly half a century later, Brenner said the fashioning of the double-helix model was “when molecular biology actually started.”
The opening sentence of Watson and Crick’s paper in Nature on 25 April 1953 was very modest: “We wish to suggest a structure for the salt of deoxyribose nucleic acid. This structure has novel features that are of considerable biological interest.” Forty-seven years later, in the White House celebration that took place when the sequence of 3 billion base pairs of human DNA was nearly complete, President Bill Clinton declared that the second sentence, which he recited, was “one of the greatest understatements of all time.”
©2003 by Victor K. McElheny. Used by arrangement with Perseus Publishing. All rights reserved. Reprinted with permission.
From the Gene to the Brain
by Samuel H. Barondes, M.D.
When Watson and Crick hit upon the structure of DNA in 1953, it turned out to be much more informative than even they had imagined. Once they grasped that DNA is arranged in a double helix, with its strands held together by a speciﬁc pairing of its four constituent bases—adenine with thymine, cytosine with guanine—they also realized that such pairing could guide the replication of the strands. As they put it in a phrase that soon became famous: “It has not escaped our notice that the speciﬁc pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”
Nor did other implications of the structure escape their notice. In little more than a decade after their initial insight, Watson, Crick, and a few others proposed that the information in each gene is encoded in a particular sequence of bases; that the code can be transcribed into an intermediate messenger called RNA; and that particular groupings of three bases, called codons, are translated into particular amino acids of proteins (see illustration on the next page). By 1966, with the deciphering of this triplet genetic code, the main ideas suggested by the discovery of the double helix had been ﬂeshed out.
This series of ﬁndings solved one of biology’s great mysteries: how inanimate molecules encode and replicate the characteristics of living creatures. Although we have come to take these ﬁndings for granted, they were completely unexpected. Even Max Delbrück, the physicist who was a prime mover in the creation of molecular biology, was stunned. As he put it to science historian Horace Judson, “Nobody, absolutely nobody, until the day of the Watson-Crick structure, had thought that the speciﬁcity might be carried in this exceedingly simple way, by a sequence, by a code. This was the greatest surprise for everyone.”
The surprise led to many practical applications. But for several notable pioneers of molecular biology, applied science did not have the excitement of the search for the molecular basis of life. Instead, emboldened by their success, they cast about for another scientiﬁc mystery, preferably as tantalizing as the one just solved.
MOVING ON TO THE BRAIN
To Francis Crick, the choice seemed obvious. Having abandoned his graduate studies in physics after World War II, he had been attracted to two big questions, which he called “the borderline between the living and the nonliving” and “the workings of the brain…the mystery of life and the mystery of consciousness.” Finding the former easier to think about, he turned to research on DNA. But once he felt satisﬁed with his contribution there, he wholeheartedly embraced the second question.
Proteins are made from DNA through two intermediate processes—transcription and translation—that utilize the triplet genetic code. By discovering the structure of DNA, Watson and Crick laid the groundwork for deciphering this mechanism.
© 2003 Christopher Wikoff
Crick was not the ﬁrst of the molecular biology pioneers to identify mental mechanisms as the next great problem in biology, and to move from the gene to the brain. He was preceded by Delbrück, whose seminal work on the genes of viruses that attack bacteria (bacteriophage) helped set the stage for the discovery of the double helix. Even before that discovery, though, Delbrück had decided to study the brain and behavior. For him, this took the form of studying the movement toward light, or phototropism, of the tiny stalks of a fungus called Phycomyces. He chose this problem because phototropism is easy to manipulate and measure, and because the simple fungus seemed to be a good subject for genetic research. Just as he had helped revolutionize genetics by studying a bacteriophage, Delbrück hoped to revolutionize brain research by studying a fungus.
Other pioneers soon followed. Like Delbrück, they each selected a relatively simple experimental system. Seymour Benzer, who had made major discoveries about bacteriophage genes, started investigating the behavior of fruit ﬂies. Gunther Stent, another student of bacteriophage, turned to the leech. Sydney Brenner, who had contributed greatly to the discovery of messenger RNA, began working on a tiny worm whose nervous system has only a few hundred neurons (as compared to the hundred billion neurons in our brains). Marshall Nirenberg, whose laboratory I joined as a trainee in 1961, just as he was about to ﬁnd a way to decipher the genetic code, was even then planning to shift to neurobiology—in his case using cultured mammalian nerve cells.
Each of these newcomers energized brain research. Having successfully participated in one scientiﬁc revolution, they were eager to start another. By bringing novel approaches to the design of experiments, and by training students to use ﬂies, leeches, worms, and cultured cells to tackle neurobiological problems, they stimulated a string of important discoveries.
More signiﬁcant still were the tools created as a result of their early work in molecular biology. Once it became apparent that each gene is simply a bit of DNA that contains a speciﬁc sequence of bases, techniques were developed to isolate genes and modify them. Other techniques were developed to chop up the DNA of an organism into bite-size pieces, each of whose sequence could be copied and then analyzed by a machine, one nucleotide at a time. By the year 2000, the application of these automated techniques yielded complete sequences of the worm and fruit ﬂy genomes and big stretches of the human genome. Furthermore, with the ability to manipulate genes as simple chemical entities it became possible to swap modiﬁed versions of various animal genes for the originals. Such swapping became a popular means to study the effects of individual genes and their variants.
With this technology the new breed of neurobiologists transformed the study of the brain and behavior. Before such tools became available it had seemed to many leading psychologists that the inner workings of the brain were so complicated as to be beyond the reach of science. Molecular biology provided new ways to identify the molecular components of these inner workings and their speciﬁc behavioral effects.
Evidence of this transformation now ﬁlls the journals devoted to neurobiology, neurology, and psychiatry. To illustrate the impact of DNA-based research on these ﬁelds I have selected three examples, each of which is representative of a great many others. The ﬁrst shows how studies of the genetic basis of a pattern of behavior in a relatively simple animal contributed to the understanding of its human counterpart; the second, how methods for studying the human genome were used to discover the genetic basis of a devastating brain disease; the third, how molecular biological techniques are being applied to develop new drugs for a prevalent behavioral disorder.
GENES THAT SHAPE BEHAVIOR
Even before the ﬂowering of DNA-based technology, the new breed of neurobiologists started making their mark. A stunning early success was the discovery of a gene that inﬂuences the daily rhythm of behavior. This rhythm, most apparent to us as our daily cycle of wakefulness and sleep, also operates in other animals. It is a manifestation of the workings of an internal clock, whose settings can be modiﬁed by the environmental rhythm of light and dark. But the clock’s periodicity of roughly 24 hours is innate, which suggests that it is under the control of genes.
In the late 1960s, Seymour Benzer and a student set out to ﬁnd the genes in fruit ﬂies that control 24-hour behavioral rhythms. They began by creating a large number of mutants—animals with a critical genetic modiﬁcation—by mating ﬂies that had been treated with a chemical that randomly damages genes in their eggs or sperm. Then they examined the behavior of each of the offspring in the hope of ﬁnding a mutant whose behavioral rhythm was abnormal.
Amazingly, they found three—and they were all different. The ﬁrst mutant has no regular behavioral rhythm, suggesting that its clock is broken. The second has a clock that runs too fast, with a period of 19 hours. The third has a clock that runs too slow, with a period of 29 hours.
To ﬁgure out how these three mutants are related, Benzer used a technique of gene mapping that had been developed in earlier studies of fruit ﬂies. This technique locates the positions of genes on chromosomes (each of which contains a speciﬁc portion of the creature’s DNA) by studying the frequency with which two mutations are inherited together. With this approach Benzer discovered that each of the three abnormal rhythms is caused by a particular change in the structure of the same gene, which was named period.
As methods for determining the sequence of DNA (the order of the four bases) became available in the 1980s, the sequence of period was ascertained, as were the sequences of its variants in the mutants. This provided direct chemical conﬁrmation that the change in the daily rhythm of each of the three mutants was caused by a particular structural change in the same gene. It was the ﬁnal proof that a single ﬂy gene can play a decisive role in the control of a complicated pattern of behavior. Just as the discovery of the double helix catalyzed further work on the molecular basis of life, the discovery of period catalyzed further work on the molecular basis of behavior.
In the years that followed, the same approach was applied to a study of the 24-hour rhythm in mice. This led to the discovery of several other genes that work together to inﬂuence daily rhythms, which explains why mutations in any one of them can alter the operation of the internal clock. Furthermore, members of this same class of genes were subsequently found in fruit ﬂies and other organisms. Although the details are not identical throughout the animal kingdom, there are many similarities. For example, in humans and mice there are three period genes that are all related to the one initially identiﬁed in fruit ﬂies.
These genetic similarities between humans and other creatures encouraged a continuing search for genes that inﬂuence behavior in ﬂies or mice. The great advantage of working with these animals is that they can be studied in ways that would be unthinkable in people. As with period, many of the genes that were identiﬁed in this search were subsequently shown to have similar effects in human brains. Because studies of genes in fruit ﬂies or mice can tell us so much about the functions of related genes in people, progress in human behavioral genetics has been greatly accelerated. Furthermore, human versions of many genes have been transferred into the DNA of experimental animals for a variety of purposes, such as those that I will soon describe.
GENES THAT UNDERLIE HUMAN BRAIN DISEASES
While knowledge accumulated about the genes and proteins that control brain functions, the new DNA-based technology was also being used to address an urgent practical neurobiological problem: the genetic basis of certain brain diseases. Physicians already knew that many of these diseases run in families, and that some are transmitted from a parent to children in a pattern that indicates the disease is caused by an abnormal variant of a single gene. Using techniques that worked with fruit ﬂies, human geneticists began to look for these variants in the DNA of their patients. If they could understand how molecular abnormalities give rise to a disease, new treatments might be possible.
By the mid-1990s, they had a string of successes. Among the most momentous was the discovery of gene variants that determine the onset and course of Alzheimer’s disease. Several of the gene variants were found in the DNA of families of patients whose disease comes on unusually early, generally before the age of 50 (early-onset Alzheimer’s disease). Another was found in the DNA of the more typical patients who became demented at a later age, generally after 60 (late-onset Alzheimer’s disease).
The discoveries about early-onset Alzheimer’s disease have opened some exciting new doors because they suggest that the dementia is attributable to a pathogenic substance called A-beta (also known as beta-amyloid peptide). This substance, which is a fragment of a normal brain protein called amyloid precursor protein (APP), is usually produced in small amounts by the cleavage of APP by several brain enzymes. Studies of the DNA of some patients with early-onset Alzheimer’s disease have identiﬁed mutations in the gene that encodes APP—mutations that affect the cleavage of APP by the enzymes in ways that increase the formation of A-beta. Further studies of such patients turned up mutations in two other genes, each of which encodes a protein component of an enzyme that cleaves APP to make A-beta. Inheriting certain variants of either the APP gene or one of the enzyme genes has the same disastrous effect: accumulation of large amounts of A-beta, which damages nerve cells. Not unexpectedly, transferring these gene variants into the DNA of mice leads them to develop a mouse version of Alzheimer’s disease.
Now the search is on for drugs that can block the actions of the enzymes that make A-beta, and that can prevent the brain abnormalities in the genetically engineered mice with Alzheimer’s disease. Recognizing the great prevalence of Alzheimer’s disease, pharmaceutical companies are investing billions of dollars in this quest. If the accumulation of A-beta can be stopped, we may have a treatment not only for the relatively rare cases of early-onset Alzheimer’s disease but for the vast number of people who develop the disease later in life.
Genetic studies of late-onset Alzheimer’s disease have also been informative—in this case by implicating a variant of the gene that encodes a protein called apolipoprotein E (APOE). This protein, which plays a role in the metabolism of cholesterol, exists in three common forms, each encoded by a different gene variant. Inheriting the gene variant called APOE-4 greatly increases the risk of developing late-onset Alzheimer’s disease. An important distinction must be made here. Unlike the gene variants that invariably produce early-onset Alzheimer’s disease, the APOE-4 gene variant only increases the risk of getting Alzheimer’s disease; it does not invariably cause it. In individuals who inherit this susceptibility, the balance may be tipped by other gene variants and by environmental factors.
The discovery of a gene variant that increases susceptibility to the commonest form of dementia has inspired a search for the gene variants that inﬂuence susceptibility to other brain disorders such as schizophrenia and bipolar disorder. In these illnesses, susceptibility appears to be inﬂuenced by the combined action of several gene variants. This has made it difﬁcult to identify any one of them. But the prospects for success improve as knowledge about the human genome grows.
As the gene variants that participate in the development of these and other illnesses are identiﬁed, inexpensive DNA tests for these variants will be developed, so that this information can be used to help patients. Such DNA tests are already being used as an aid in the diagnosis of Alzheimer’s disease. When good medications for Alzheimer’s disease are discovered, DNA tests will also be used for prevention—by identifying genetically susceptible people so that treatment can be initiated before symptoms appear. In the not very distant future, large-scale DNA screening will become available for the many other gene variants that put people at risk for a variety of diseases, so that appropriate preventive interventions can be considered.
USING GENES TO MAKE DRUGS FOR MENTAL ILLNESS
Genetic information and DNA technology are also being used to aid in the development of new drugs for mental illness. Most of the drugs now used for this purpose can trace their origins to the serendipitous discovery, in the early 1950s, of the antipsychotic effect of chlorpromazine (Thorazine). Although not on the scale of the Watson-Crick breakthrough, chlorpromazine’s discovery set off its own small revolution. Its impact was augmented by the unanticipated ﬁnding of the antidepressant effects of imipramine (Tofranil)—stumbled upon in the course of a hasty search by pharmaceutical companies to ﬁnd a competitor for chlorpromazine—and by the realization that the therapeutic actions of both drugs stemmed from their effects on neurotransmitters, the brain’s chemical messengers. This drug revolution was further impacted by the chance discovery that benzodiazepines, such as Valium, relieve anxiety and that this, too, rests on speciﬁc effects on neurotransmission.
Coming, as they did, at a time when the hereditary characteristics of all living things could suddenly be accounted for by simple interactions of the four chemical components of DNA, the discoveries of relationships among drugs, neurotransmitters, and mental processes encouraged equally simple explanations. Among them was the proposal that psychosis is due to excessive neurotransmission by dopamine (which is inhibited by chlorpromazine), and that depression is due to inadequate neurotransmission by norepinephrine or serotonin (both of which are augmented by imipramine). Although these proposals have been shown to be naive, they stimulated research on the behavioral roles of each neurotransmitter. This, in turn, led to the creation of improved psychiatric medications such as ﬂuoxetine (Prozac) and risperidone (Risperdal).
The search for still better psychiatric drugs is now being guided by studies of the genes that encode the brain proteins that serve as the receptors for various neurotransmitters. DNA technology has been employed to identify many of these receptors and to study their distribution to particular brain curcuits. This information is being used to create drugs that target speciﬁc receptors, and that have more selective behavioral effects than those currently available.
Consider, for example, the ongoing redesign of benzodiazepines. These drugs, which were discovered in the late 1950s, are prescribed to treat two different ailments: anxiety and insomnia. Both therapeutic effects are due to binding of these drugs to specialized sites found on certain receptors for a neurotransmitter called gammaaminobutyric acid (GABA). But, useful though both effects are, there would be value in separating them, to create a new pill that relieves anxiety without making people sleepy.
That goal is being realized by studying the effects of benzodiazepines on genetically engineered mice whose GABA receptor genes have been modiﬁed in various ways. Using this approach, the proteins involved in the anti-anxiety effects of benzodiazepines have been distinguished from those involved in the sedative effects. Several pharmaceutical companies are now testing drugs that selectively bind the relevant proteins and that relieve anxiety without causing sedation.
In addition to its great value in designing these and other new medications, DNA-based research is being used to identify the reasons that people respond differently to the drugs already available. In some cases this is due to genetic differences in drug metabolism. For example, certain people are unusually sensitive to ﬂuoxetine (Prozac) because they have a defective variant of the enzyme that destroys the drug. Other people have an unusual variant of a protein that the drug targets. As DNA tests are developed for the gene variants responsible for such individual differences in enzymes and other proteins, they will be used as aids in the selection and dosage of medications.
THE NEUROBIOLOGICAL LEGACY OF WATSON AND CRICK
While the lights ignited by their discovery of the structure of DNA were illuminating biology, Watson and Crick went their separate ways. But now they ﬁnd themselves again on some common ground, this time as passionate proponents of brain science.
For Crick, this is a continuation of the attraction he ﬁrst felt as a graduate student. Perched in his study at the Salk Institute in California, he still tries to understand how the inanimate molecules that make up a person work together to generate the experience of consciousness. In Watson’s case, brain science is a more recent interest, and a more practical one. Building on the success of the systematic sequencing of the human genome, which he helped initiate and orchestrate, Watson has turned his attention to the genetic basis of human behavioral disorders. From the shores of Cold Spring Harbor on the other American coast, where so much of early molecular biology was conceived, he uses his considerable inﬂuence to promote neurological and psychiatric research.
The issues that now interest both these men are a great deal more complicated than those that brought them together at the Cavendish Laboratory in Cambridge, England, half a century ago. They must surely be gratiﬁed that even such issues can be fruitfully addressed with the knowledge and tools that continue to ﬂow from their discovery of the double helix.