Copernicus and Darwin demoted man from his bright glory at the focal point of the universe to be merely the current head of the animal line on an insignificant planet. In the mirror of our newer knowledge, we can begin to see that in truth we are far more than another ephemeral form in the chain of evolution. Rather we are an historic innovation. We can be the agent of transition to a wholly new path of evolution. This is a cosmic event.
Sinsheimer’s vision of “genetic change, specifically of mankind,” was fueled by the successful elucidation of the universal genetic code. The beauty of the double helix had immediately suggested how DNA could replicate itself, each strand unzipped becoming the template for a new daughter strand. Kornberg won the Nobel Prize for identifying the key enzyme, DNA polymerase. But with the genetic material now reduced to atomic detail, the big question in biology became: what is the code that governs how the instructions inscribed in DNA are communicated and translated into proteins?
During the course of the 1950s, the work of Crick, Watson, Sydney Brenner, and others established the central dogma. A messenger RNA facsimile ferries instructions from the cell’s data center (the nucleus) to the protein-manufacturing sites in the heartland (the cytoplasm). But what about the code itself? Proteins are made up of twenty different amino acids, whereas the DNA alphabet only has four letters. A two-base code would only yield a maximum of sixteen building blocks (4x4), whereas a triplet code (4x4x4) could in principle give rise to as many as sixty-four building blocks.
In 1959, Marshall Nirenberg, a biochemist at the NIH, developed a cell-free system to synthesize proteins in a test tube by mixing the raw ingredients—DNA, RNA, enzymes, and radioactively labeled amino acids. His colleague Bruce Ames felt the project was “suicidal.” With Nirenberg traveling in California, his German student, Heinrich Matthaei, found himself alone in the lab after midnight on a Saturday morning (May 27, 1961). Thirty-six hours earlier, President John Kennedy, inspired by Alan Shepard’s achievement in becoming the first American in space, asked Congress to commit to “landing a man on the moon and returning him safely to the earth.”
Here in the late-night tranquility of an empty lab, Matthaei was poised to crack the first clue in the genetic code that governs life on earth, propelling the field of genetic engineering into orbit. He pipetted a synthetic strand of RNA made up entirely of just one base (uracil, U) into his cell-free solution. The resulting peptide was composed entirely of one amino acid—phenylalanine. Clearly some combination of U’s provided the necessary code for phenylalanine. The first square in the 64-square genetic code bingo card—UUU—had been filled. Soon they had a second letter: CCC corresponded to proline.
That summer, Nirenberg delivered a lecture at a major conference in Moscow. His initial talk was attended by only a smattering of scientists, but Crick arranged for Nirenberg to give an encore performance in a plenary session. Nirenberg was heartily congratulated by Crick and other scientific legends afterwards and felt a bit like a rock star. An American literature student, who had spent the day touring art museums, was electrified hearing about Nirenberg’s results from his roommate. That student, one Harold Varmus, would later win the Nobel Prize for cancer research and become the director of the NIH.
The following year, Crick and Watson received their Nobel Prizes. By this time, Crick had proven that the genetic code was indeed made up of 64 triplets. “We are coming to the end of an era in molecular biology,” Crick said in his Nobel address. “If the DNA structure was the end of the beginning, the discovery of Nirenberg and Matthaei is the beginning of the end.”
In August 1967, Nirenberg wrote a guest editorial for Science magazine, entitled “Will society be prepared?” The implications of the revolution in biochemical genetics, as he called it, and the prospect of “genetic surgery” were weighing heavily on him. Nirenberg believed that scientists were going to be able to reprogram cells—initially microbes, but eventually humans. And that made him nervous. He wrote:
[M]an may be able to program his own cells with synthetic information long before he will be able to assess adequately the long-term consequences of such alterations… and long before he can resolve the ethical and moral problems which will be raised. When man becomes capable of instructing his own cells, he must refrain from doing so until he has sufficient wisdom to use this knowledge for the benefit of mankind. I state this problem well in advance of the need to resolve it, because decisions concerning the application of this knowledge must ultimately be made by society, and only an informed society can make such decisions wisely.16
The following year, it was Nirenberg’s turn to win an all-expenses paid trip to Sweden. His students, one of whom was an ambitious physician named William French Anderson, hung a banner in his lab that read “UUU are great Marshall.” Back home in Germany, however, Matthaei could only reflect on the Stockholm snub. Unlike Rosalind Franklin, he was still alive and eligible when the call came. But Nirenberg shared the stage with two others, and in Nobel math, four into three doesn’t go.
By this time, some scientists were seeing a different side of genetic engineering—the concept of gene therapy. One of the first to do so was yet another Nobel laureate, Joshua Lederberg. The son of a rabbi, Lederberg graduated from Stuyvesant High School in New York at the age of fifteen. He was barely twice that age when, in 1958, he won the Nobel Prize, for discovering the transmission of genetic material between bacteria, including the process of transduction, involving phages. Sharing the prize that year were Lederberg’s former supervisor, Edward Tatum, and George Beadle. (There was no mention of Lederberg’s wife, Esther, who performed many of the crucial experiments and coauthored papers with her husband.) Lederberg went on to become the president of the Rockefeller University and a NASA consultant who coined the term “exobiology.” Some believe he was the model for the hero in Michael Crichton’s debut novel, The Andromeda Strain.
At a symposium on “The Future of Man” in London in 1962, Lederberg expressed sympathy with the “noble aims” of eugenics while noting it had been “perverted to justify unthinkable inhumanity.” Advances in biology ultimately “could diagnose, then specify, the actual DNA composition of ideal man.” But Lederberg proposed a new term, “euphenics,” meaning the developmental engineering of organs as opposed to genetic engineering of the germline.17
In 1966, Tatum predicted that viruses could be used in “genetic therapy” via the introduction of new genes into defective cells of particular organs. He went on to describe what we now call ex vivo gene therapy. “The first successful genetic engineering will be done with the patient’s own cells,” he declared. The desired new gene would be taken from a healthy donor and transferred into the patient’s cells. “The rare cell with the desired change will then be selected, grown into a mass culture, and re-implanted in the patient’s liver.”18
In a commentary for the Washington Post in January 1968, Lederberg launched a trial balloon for his idea of gene therapy—using viruses for vaccination. Drawing inspiration from Kornberg’s demonstration of DNA replication in a test tube, Lederberg suggested that by screening enough natural viruses, it might be possible to isolate a virus that had naturally captured a medically important human gene, such as insulin or the gene encoding the missing enzyme in phenylketonuria.19 He even considered “extracting DNA molecules that code, say, for insulin and chemically grafting these to the DNA of an existing tempered virus,” forming the basis for virogenic therapy in man. Lederberg thought his idea of somatic gene therapy was more practical and palatable than genetic engineering, or “direct tackling of the germ line.”20