In 1968, Nirenberg’s medical student French Anderson, decided to add his name to the chorus of those advocating for gene therapy. “In order to insert a correct gene into cells containing a mutation, it will first be necessary to isolate the desired gene from a normal chromosome. Then this gene will probably have to be duplicated to provide many copies. And, finally, it will be necessary to incorporate the correct copy into the genome of the defective cell.”21 Anderson’s ideas were too fanciful for the New England Journal of Medicine, which rejected the manuscript after some lively internal debate. One editorial member judged Anderson’s proposal to be “a worthwhile adventure in pure speculation.”
I. Perhaps inspired by Crick’s auction windfall, Watson auctioned off his Nobel medal. It was bought by Russian oligarch (and part-owner of Arsenal) Alisher Usmanov. After meeting Watson in Moscow and learning that he wanted to use the proceeds for charity, Usmanov agreed to loan the medal back to Watson. It was returned to Cold Spring Harbor in an armored truck.
II. Sinsheimer wanted to leave his mark on UCSC but he was also hoping to save a $36 million pledge from the Hoffman Foundation for a space telescope that had been fully funded by the Keck Foundation. Sinsheimer didn’t get his genome institute but UCSC would go on to play a major role in the completion of the first draft of the human genome.
CHAPTER 10 THE RISE AND FALL OF GENE THERAPY
It took more than twenty years for French Anderson’s worthwhile speculation to become a clinical reality. But the first tentative steps, albeit misguided, began shortly after his spurned manifesto. Stanfield Rogers, a physician at the Oak Ridge National Laboratory in Tennessee, had long been advocating the use of viruses to transmit genetic information. He had found that researchers handling the Shope rabbit papillomavirusI had lower levels of arginine than normal people, suggesting they were picking up the virus and supplemental activity of the viral enzyme called arginase, which breaks down the amino acid. Rogers had reported high levels of arginase in warts on the skin of rabbits infected with the virus, and speculated that the virus was a therapeutic agent in search of a disease. “The possibility of tying specific synthetic DNA information on to the genome of passenger viruses, thereby using viruses as a vector, could prove to be a useful technique,” he suggested.1
Rogers got his chance after reading a report in the Lancet about a pair of young, mentally retarded German sisters who had a rare inherited disease called argininemia—excess arginine in the blood caused by arginase deficiency. Believing he could supplement the missing enzyme using the Shope virus, Rogers persuaded the girls’ pediatrician to let him try a ludicrously premature experimental procedure—the first human genetic engineering experiment. In 1970, Rogers flew to Germany and injected small doses of the virus into the two girls, hoping to boost levels of the enzyme. There was no response. Later a third sibling received the virus, only to develop an allergic reaction. His reckless gene therapy adventure over, Rogers went back to studying plant viruses.
Two years later, Theodore (Ted) Friedmann and Richard Roblin published a commentary in Science entitled “Gene Therapy for Genetic Disease?”2 Friedmann, a physician, is widely credited with coining the term “gene therapy.” Friedmann was born in Vienna but fled with his family to the United States in 1938 to escape the Nazis. At the University of Pennsylvania, he attended lectures by Colin MacLeod, who with Oswald Avery had proven in 1944 that DNA was the genetic material. He later trained with Fred Sanger in Cambridge before joining the NIH.
Friedmann worked on Lesch-Nyhan syndrome, a debilitating, sex-linked genetic disorder in which affected boys suffer retardation, abnormal movements, and self-mutilation. Friedmann was able to correct cells from Lesch-Nyhan patients using gene transfer by replacing the DNA that codes for the key enzyme. The experiment was terribly inefficient—only about one cell in a million was corrected—because Friedmann was using a full genome’s worth of DNA (this was years before the ability to isolate specific genes).
Friedmann admired the work of Renato Dulbecco, who had just discovered that a tumor virus did exactly what gene therapists wanted to do, “taking a foreign piece of genetic information, a foreign DNA, and inserting it into a cell and forever changing that cell.”3 Viruses could indeed be used to ferry normal copies of genes into cells carrying a broken version of the same gene. Friedmann helped popularize the concept of using modified viruses for gene therapy, while warning of the ethical dangers of pushing ahead too quickly. “Gene therapy may ameliorate some human genetic diseases in the future,” he wrote. The idea of gene replacement therapy using viral vectors had just received a major shot in the arm.
This approach was exciting but why be content to just add a healthy gene, papering over the cracks in the genome as it were, rather than actually trying to repair the broken sequence? In 1978, the same year as he won the Nobel Prize, David Baltimore offered one approach to this medical milestone. A patient with a blood disease like hemophilia or sickle-cell could be treated by transferring a normal gene into the patient’s bone marrow stem cells that ultimately give rise to blood cells. This would allow a normal protein to replace (or be made alongside) the faulty protein and cure the patient’s disease. “It is likely to be the first type of genetic engineering tried on human beings, and might be tried within the next five years.”4
“The concept of repairing a defective gene such as the sickle-globin gene is appealing,” wrote one physician, “however, existing technology cannot direct a site-specific recombinational event. Therefore, the concept of gene-repair in a genome as complex as that of man is for the moment impractical.”5 The author of those words was a UCLA hematologist named Martin Cline.
In 1979, Cline proposed treating patients with beta thalassemia with gene therapy, but a UCLA review committee insisted on additional animal experiments. Frustrated, Cline looked overseas, and in June treated two young women—a twenty-one-year-old at Hadassah Hospital in Jerusalem and a sixteen-year-old in Naples, Italy, a few days later. The process involved extracting some of the patient’s bone marrow, transfecting the cells with the beta-globin gene, and infusing about 1 billion treated cells back to the patient following irradiation of their femur. Cline told the women that the chances of success were slim, but he felt compelled to try. “When do you consider animal experiments adequate?” Cline asked. “When do you feel ready for a transition [to man]? Here’s a patient who has a life-threatening disease with a limited life expectancy and no options with modern treatment. Is now the time to try an experimental treatment?”6
In the opinion of the NIH and most of Cline’s peers, the answer was emphatically no. Cline had taken it upon himself to conduct the first recombinant genetic engineering experiments on humans. Following censure by the NIH, UCLA’s dean of medicine accepted Cline’s resignation as chief of the oncology department in February 1981. He chastised Cline for conducting an unprecedented experiment on two patients without the necessary institutional approval. Although no medical harm had been done, he continued, “the freedom to conduct experiments of benefit to mankind is jeopardized by failure to act in accord with the relevant regulations.”7 Hematologist Ernest Beutler called the Cline episode tragic “because it interrupted the efforts of a highly talented, productive scientist who was in too much of a hurry to see patients benefit from the marvels of modern molecular biology.”8 Beutler softened his criticism when he judged that the patients were probably more at risk from the three hundred rads of ionizing radiation they received than the therapy itself.