Recombinant DNA

Power, Sex, Suicide: Mitochondria and the Meaning of Life

by Nick Lane  · 14 Oct 2005  · 369pp  · 153,018 words

, given the opportunity, human mitochondrial DNA really does recombine. But that is not to say that the recombinants will be passed on. No matter if recombinant DNA is formed in the muscles, it can only influence posterity if it recombines in the fertilized egg. Only then can the recombinant form be inherited

CRISPR People: The Science and Ethics of Editing Humans

by Henry T. Greely  · 22 Jan 2021

been raging for decades. This chapter looks at those discussions up to the disclosure of He’s experiment, in two parts: the early discussions of recombinant DNA technology, notably at the famous Asilomar Conference, and the more focused discussions after the development of CRISPR as a genome editing system. Along the way

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, it takes a look at some of the people, “CRISPR people,” although not “CRISPR’d people,” who were involved. Asilomar and the Ethics of Recombinant DNA Before the realization that DNA was the basis for human genetic inheritance and the knowledge, with Watson and Crick’s discovery of DNA’s structure

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knew how to edit the human germline genome—or anything’s genome for that matter. That changed, a little, in 1971 with the invention of recombinant DNA. Researchers learned how to move bits of DNA from one species into another using laboratory tools. The methods were crude. Stanford Medical School biochemistry professor

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cemented my relationship with Paul Berg, a crucial mentor for me. Berg did not immediately take the next step of then trying to move such recombinant DNA into a living organism. That was done first by two other Bay Area scientists, UC San Francisco (UCSF) professor Herb Boyer and Berg’s Stanford

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the same with DNA from a frog species.4 There has long been some dispute over who deserves how much credit for the invention of recombinant DNA.5 As with CRISPR, many researchers contributed. Some have argued that others were as or even more deserving of a recognition for inventing

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recombinant DNA as Berg, notably Cohen and Boyer or Berg’s fellow Stanford biochemistry department researchers, Janet Mertz and Ron Davis. This debate has, over the years,

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the departments over which should get credit. As it happened, in October 1980 Berg won a share of the Nobel Prize for Chemistry for inventing recombinant DNA. Berg shared the prize with Frederick Sanger and Walter (Wally) Gilbert, who were awarded half the prize money for inventing techniques to determine the sequence

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to recognize Sanger and Gilbert for sequencing—each had made substantial progress in very different ways—that left only a slot for one inventor of recombinant DNA if that accomplishment were to be awarded the prize that year. Ironically, exactly seven weeks later, the U.S. Patent and Trademark Office granted U

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universities; Boyer cofounded Genentech in part based on a license of that patent. You may well be wondering what this digression into the history of recombinant DNA, patenting, and Nobel Prizes—as interesting as its parallels to CRISPR may be—has to do with ethics, the topic of this chapter. As far

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another role that made him stand out from the rest of the recombinant DNA crowd. He was a leader, arguably the leader, in organizing a temporary moratorium on recombinant DNA research and in organizing and running the famous 1975 Asilomar Conference on recombinant DNA at which the moratorium was discussed. And the Asilomar Conference is an

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essential part of this story. The Asilomar Conference, or, to give it its full name, the Asilomar Conference on Recombinant DNA Molecules, was held on February 24, 25, and 26, 1975, at the Asilomar State Beach and Conference Grounds, an unusual unit of the California State

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Life Sciences of the National Research Council on this matter, propose the following recommendations. First, and most important that until the potential hazards of such recombinant DNA molecule have been better evaluated or until adequate methods are developed for preventing their spread, scientists throughout the world join with the members of this

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committee in voluntarily deferring the following types of [recombinant DNA] experiments . . . Additional recommendations advised caution with respect to some other types of recombinant experiments, asked the National Institutes of Health (NIH) to consider establishing an

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early in the coming year to review scientific progress in this area and to further discuss appropriate ways to deal with the potential biohazards of recombinant DNA molecules.” The letter was signed by the 11 members of the committee, with Paul Berg listed first, as chair. Among the others were Herb Boyer

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, Stan Cohen, and Ron Davis from the Bay Area’s recombinant DNA laboratories, as well as Jim Watson, codiscoverer of the structure of DNA, and a young biologist named David Baltimore, one of the discoverers of how

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, it actually was a three-day conference with about 140 attendees from around the world. The attendees were mainly scientists doing, or planning, research in recombinant DNA but there were several government officials, 12 journalists, and four lawyers.12 The meeting was held at the Asilomar Conference Grounds, located on nine acres

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publications as different as the New York Times, Wall Street Journal, Frankfurter Allgemeine Zeitung, Nature, and Rolling Stone.16 And the world was talking about recombinant DNA and about science’s effort to police itself. Asilomar does have some ironies. First, it focused on the physical safety risks of

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recombinant DNA research, the chance that a life-form with recombinant DNA could harm lab workers, the public, or the environment. It did not discuss broader questions—of playing God, designer babies, hubris

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enforceable (in the United States) by a government action almost immediately after the conference ended. Its recommendations were adopted by the NIH, acting through a Recombinant DNA Advisory Committee (RAC) that Donald Frederickson, then NIH director, had appointed shortly before the Conference. The RAC has had a long and shifting career, surviving

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the idea that this was self-regulation by Science was not wrong. Asilomar helped lead to the rejection of legislative efforts to restrict or stop recombinant DNA research, in the Cambridge, Massachusetts, city council and in the U.S. Senate. Regulation was left to the NIH, an organization dominated by scientists who

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human uses but specifically on human germline uses. Some, whom I am also not able to name, expressed the view that, since Asilomar and the recombinant DNA debates, Science had promised that the human germline would not be manipulated and that this was a crucial issue to confront. And it is the

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include some very important and well-respected scientists, such as Paul Berg, Nobel Prize winner and one of the parents of the Asilomar meeting on recombinant DNA; Emmanuelle Charpentier and Feng Zhang, two of the people viewed as among the most important inventors of CRISPR; Eric Lander, the director of the scientifically

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and Mark S. Frankel, eds., Designing Our Descendants: The Promises and Perils of Genetic Modifications (Baltimore: Johns Hopkins University Press, 2003). 2. The story of recombinant DNA has been told in many places, including, in detail, in a biography of Berg. Errol C. Friedberg, A Biography of Paul Berg: The

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Recombinant DNA Controversy Revisited (Singapore: World Scientific, 2014). A short description of the history is at https://www.sciencehistory.org/historical-profile/paul-berg. 3. Henry T.

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. 9. Maxine Singer and Dieter Soll, “Guidelines for DNA Hybrid Molecules,” Science 181, no. 4105 (1973): 1114. 10. Paul Berg et al., “Potential Biohazards of Recombinant DNA Molecules,” Science 185, no. 4148 (July 26, 1974): 303. 11. Daniel J. Kevles, The Baltimore Case: A Trial of Politics, Science, and Character, rev. ed

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get the chance, go. It is gorgeous and peaceful. 15. Paul Berg, David Baltimore, Sydney Brenner, et al., “Summary Statement of the Asilomar Conference on Recombinant DNA Molecules” Proceedings of the National Academy of Sciences 72, no. 6 (June 1975): 1981–1984. 16. Capron and Shapiro, “Remember Asilomar.” Some have speculated that

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many new members, held its first meeting on December 5 and 6, 2019; its future is not yet clear. 18. Donald S. Frederickson, “Asilomar and Recombinant DNA: The End of the Beginning,” in Biomedical Politics, ed. Kathi Hanna (Washington, DC: National Academies Press, 1991). 19. And, yes, Doudna’s name can be

Life as We Made It: How 50,000 Years of Human Innovation Refined--And Redefined--Nature

by Beth Shapiro  · 15 Dec 2021  · 338pp  · 105,112 words

virus and spliced the two virus genomes together. This created the world’s first “recombinant DNA”—a genome engineered to have combined (or, in the parlance of genetics, recombined) DNA from more than one organism. They intended to insert their recombinant DNA into the bacterium Escherichia coli, as lambda virus naturally infects E. coli. Before the

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sent a letter to the National Academy of Sciences and the Institute of Medicine, asking them to establish a committee to consider the hazards of recombinant DNA research. The letter underscored the potential of recombinant DNA experiments to advance science and improve human health but also raised concerns over the still-unknown outcomes of

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. A committee was formed, a temporary moratorium was declared on research creating recombinant organisms, and an international meeting was planned to decide the future of recombinant DNA research. While these measures were intended to assuage public concerns, they—unfortunately—had the opposite effect. Sensing that scientists feared the worst, protests began against

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recombinant DNA technology even before the technology could be evaluated. Jeremy Rifkin, who takes credit for starting the anti-GMO movement, raised money by frightening the public

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into believing that people were going to be cloned (recombinant DNA technology is not cloning). Concerned members of the public lobbied their government representatives to stop the research. By the time the meeting took place, a

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clear line had already formed between those who wanted recombinant DNA research to succeed and those who wanted to ban it from happening at all. The meeting to decide the future of

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was held in February 1975 at the Asilomar Conference grounds in Pacific Grove, California. Attendees included scientists, ethicists, and legal scholars. Most supported allowing recombinant DNA research to continue, but not without hesitation. They worried about what might happen if plant or animal genes were inserted into a bacterial genome. Could

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, however, on strict safeguards and containment protocols for potential biohazards. Participants left the meeting feeling as if they’d paved a way forward for safe recombinant DNA research. The conclusions of the Asilomar Conference were reported in both the scientific and popular press. The scientists who participated were pleased with the consensus

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as well. Not so. As before, anti-biotechnology activists exploited the risk-averse outcome of the meeting to further undermine public trust. Rumors spread that recombinant DNA technology would soon generate superbugs or be used to create superhumans. The division between supporters and opponents deepened. After Asilomar

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, recombinant DNA research recommenced under intense scrutiny. In Cambridge, Massachusetts, local politicians insisted that researchers use containment facilities designed for airborne infectious diseases, despite the fact that

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along with these restrictions, even though doing so reinforced public perceptions of the research as high risk. Despite these challenges, however, the practical power of recombinant DNA technology was indisputable. Bacteria could be coaxed to do new things, to express genes that humans engineered them to express. Scientists could use

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recombinant DNA technology to learn the functions of genes, accelerating the genome’s decoding. And by turning bacteria into living protein factories, the technology could reduce our

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to the human version produced by recombinant organisms. The era of synthetic biology had begun. RECOMBINANT PLANTS Although the medical industry was first to embrace recombinant DNA technology for its commercialization potential, the agricultural industry was not far behind. Before this could happen, though, scientists needed to discover a way to

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the Agrobacterium plasmid’s DNA are necessary for it to integrate into the plant genome. They also know which bits cause disease and, thanks to recombinant DNA technology, can cut these bits out (because they don’t want to make the plant sick) and insert other DNA in their place. Then they

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of these labs published manuscripts describing their approaches to engineer plant cells. The years following the 1983 Miami Winter Symposium saw huge investment in developing recombinant DNA technologies for agriculture. Academic and commercial labs worked to discover which plant genes cause what traits (What gene causes potatoes to turn brown?), to develop

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to keep alive and, unlike bacteria, can make proteins that are ready to use with little additional processing. Yeasts are also straightforward to engineer using recombinant DNA technologies. Since the 1980s, when yeast was first used to produce recombinant insulin, protein production using yeast has grown into a billion-dollar market. The

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vitamin-fortified GMO banana. Alliance for Science. Berg P, Baltimore D, Brenner S, Roblin RO, Singer MF. 1975. Summary statement of the Asilomar conference on recombinant DNA molecules. Proceedings of the National Academy of Sciences 72: 1981–1984. Butler D. 2012. Rat study sparks GM furore. Nature 489: 474. Carlson DF, Lancto

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

by Walter Isaacson  · 9 Mar 2021  · 700pp  · 160,604 words

, when Stanford medical professor Stanley Cohen and biochemist Herbert Boyer of the University of California, San Francisco, attended a conference in Honolulu that dealt with recombinant DNA technology, which was Stanford biochemist Paul Berg’s discovery of how to splice pieces of DNA from different organisms to create hybrids. At the conference

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them file a patent application. In 1974 they did, and it was eventually approved. It had not fully occurred to them that one could patent recombinant DNA processes, which are found in nature. It didn’t occur to other scientists either, and many were furious—especially Paul Berg, who had made the

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original breakthroughs on recombinant DNA. He called the claims “dubious, presumptuous, and hubristic.”3 * * * In late 1975, a year after the Cohen-Boyer patent application was filed, a struggling young

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time, he was living in a shared apartment, driving a beat-up Datsun, and surviving on cold-cut sandwiches. But he had read up on recombinant DNA and convinced himself that he had finally found a winning horse. As he went down his list of scientists alphabetically, the first one who agreed

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: a smiling Paul Berg on the telephone learning the news that he had, on that same day, won the Nobel Prize for his discovery of recombinant DNA.5 Detour By the time Genentech began recruiting Doudna in late 2008, the company was worth close to $100 billion. Her former colleague, who was

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DNA of a virus found in monkeys and splice it to the DNA of a totally different virus. Presto! He had manufactured what he dubbed “recombinant DNA.” Herbert Boyer and Stanley Cohen discovered ways to make these artificial genes more efficiently and then clone millions of copies of them. Thus the science

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Herbert Boyer and convinced them to file for a patent on the method they had discovered for manufacturing new genes using recombinant DNA. Many scientists, including Paul Berg, the discoverer of recombinant DNA, were horrified at the idea of patenting a biological process, but the royalties that flowed to the inventors and their universities

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let the issue become politically polarized. Asilomar In the summer of 1972, Paul Berg, who had just published his seminal paper on how to make recombinant DNA, went to the ancient clifftop village of Erice on the coast of Sicily to lead a seminar on the new biotechnologies. The graduate students who

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. It was followed in April by a conference organized by the National Academies of Science at MIT, which discussed how to prevent the creation of recombinant DNA organisms that could be dangerous. The more the participants discussed it, the less sure they became that any method would be foolproof. So they issued

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a letter—which was signed by Berg, James Watson, Herbert Boyer, and others—calling for a “moratorium” on the creation of recombinant DNA until safety guidelines could be formulated.7 This led to a memorable gathering that would become famous in the annals of scientists attempting to regulate

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’s own public involvement. After Baltimore set the stage by explaining why the meeting had been convened, Berg described the science that was at issue: recombinant DNA technology made it “ridiculously simple” to combine DNA from different organisms and create new genes. Soon after he had published his discovery, Berg told the

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planet, like what Michael Crichton described in his 1969 bio-thriller, The Andromeda Strain. During the policy debates, Berg insisted that the risks of using recombinant DNA to create new organisms were so hard to calculate that such research should be banned. Others found that position absurd. And Baltimore, as he would

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generally do throughout his career, sought to find a middle ground. He argued for restricting the use of recombinant DNA to viruses that had been “crippled” so that they could not spread.9 James Watson, true to form, played the cranky contrarian throughout. “They had

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of lawyers helped spur the scientists by warning that their institutions would likely be held liable if anyone in any lab ever got infected with recombinant DNA. The university responsible might then have to shut down. Later that night, Berg and Baltimore stayed up with a few colleagues eating takeout Chinese food

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question a central element of democratic political theory and practice: the commitment to equality of opportunity.” Preimplantation genetic diagnosis and Gattaca After the development of recombinant DNA in the 1970s, the next big bioengineering advance—and set of ethical issues—came in the 1990s. It resulted from the confluence of two innovations

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the process that led to the February 1975 Asilomar conference, the one that had come up with the “prudent path forward” guidelines for work on recombinant DNA. She decided that the invention of CRISPR gene-editing tools warranted convening a similar group. Her first step was to enlist the participation of two

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of the key organizers of the 1975 Asilomar conference: Paul Berg, who had invented recombinant DNA, and David Baltimore, who had been involved in most of the major policy gatherings, beginning with Asilomar. “I felt that if we could get them

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Nature titled “Adopt a Moratorium on Heritable Genome Editing.” Zhang of course signed up, as did Doudna’s erstwhile collaborator Charpentier. So did Berg, whose recombinant DNA discoveries had prompted Asilomar forty-four years earlier. “We call for a global moratorium on all clinical uses of human germline editing—that is, changing

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halt to germline editing.10 Baltimore too expressed puzzlement. Lander had tried to recruit him to sign the letter, but as with the discussion of recombinant DNA forty years earlier at Asilomar, Baltimore was more interested in finding “a prudent path forward” for what could be a lifesaving advance rather than declaring

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, 1989. 6. Shane Crotty, Ahead of the Curve (University of California, 2003), 93; Mukherjee, The Gene, 225. 7. Paul Berg et al., “Potential Biohazards of Recombinant DNA Molecules,” Science, July 26, 1974. 8. Author’s interview with David Baltimore; Michael Rogers, “The Pandora’s Box Conference,” Rolling Stone, June 19, 1975; Michael

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Rogers, Biohazard (Random House, 1977); Crotty, Ahead of the Curve, 104–8; Mukherjee, The Gene, 226–30; Donald S. Fredrickson, “Asilomar and Recombinant DNA: The End of the Beginning,” in Biomedical Politics (National Academies Press, 1991); Richard Hindmarsh and Herbert Gottweis, “Recombinant Regulation: The Asilomar Legacy 30 Years On

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. Author’s interviews with James Watson and David Baltimore. 10. Paul Berg et al., “Summary Statement of the Asilomar Conference on Recombinant DNA Molecules,” PNAS, June 1975. 11. Paul Berg, “Asilomar and Recombinant DNA,” The Scientist, Mar. 18, 2002. 12. Hindmarsh and Gottweis, “Recombinant Regulation,” 301. 13. Claire Randall, Rabbi Bernard Mandelbaum, and Bishop

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, 267–69, 280 in China, 301 Kass Commission and, 280–81 moral questions concerning, see moral questions moratorium proposed for, 270, 272 patents for, 392 recombinant DNA, 98–100, 153, 232, 269–71, 274, 287, 330, 331 regulation of, 270, 278, 281 utopians and, 267–69 see also biotechnology; CRISPR-Cas9 gene

As Gods: A Moral History of the Genetic Age

by Matthew Cobb  · 15 Nov 2022  · 772pp  · 150,109 words

the Asilomar agenda. Two key issues that shaped subsequent decades – the commercial exploitation of genetic engineering and the terrifying threat of new bioweapons made with recombinant DNA – were both being actively developed at the time of Asilomar but were not discussed. They were known to only a handful of privileged delegates, and

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. However, those procedures were not globally binding – different countries have different biosecurity standards, some of which may lead to disaster in the future. Both the recombinant DNA and the H5N1 research pauses were widely accepted and observed. The most recent call for a research moratorium, focused on heritable human gene editing, has

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a paroxysm, pioneer molecular biologist François Jacob reached deep into our collective psyche to identify what he thought was the fundamental problem: The notion of recombinant DNA is tied to the mysterious and the supernatural. It rekindles the terror associated with the hidden meanings of monsters, the revulsion engendered by the notion

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synthesising proteins used in medicine. The Stanford University press release that announced the paper picked up on this last point, declaring to the world that recombinant DNA ‘may completely change the pharmaceutical industry’s approach to making biological elements such as insulin and antibiotics’.45 When Berg heard about what Morrow had

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became known as ‘the Berg letter’ called on scientists around the world to defer all experiments involving genetic engineering ‘until the potential hazards of such recombinant DNA molecules have been better evaluated or until adequate methods are developed for preventing their spread’.1 For the first time in history, scientists had publicly

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one of the most intensively studied moments in twentieth-century biology – the Asilomar conference of February 1975 and the global debate about the regulation of recombinant DNA research that it ignited. Scores of books, PhD theses, articles and memoirs have been published about the period, which saw protests, furious rows, complex legal

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had the support of the US scientific establishment. Its most striking part was the declaration that the signatories would defer experiments involving the creation of recombinant DNA, including the introduction of animal viruses into plasmid or phage DNA that could infect bacteria. The letter also called on scientists around the world to

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carefully weigh the implications of experiments fusing animal DNA with plasmids or phages, given that the outcome would be ‘new recombinant DNA molecules whose biological properties cannot be predicted with certainty’. Next, they called on the NIH – the main federal funder of US biomedical research – to create

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Molecular Biology Organisation (EMBO), which had expressed its support for the Berg letter.26 Quoted in The Times, Kendrew argued that the potential dangers of recombinant DNA ‘may lead us to question scientists’ common and generally unspoken assumption that the acquisition of new knowledge is always an absolute good, requiring no justification

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certainly will. In this field, unlike motor car driving, accidents are self-replicating and could also be contagious.34 Brenner opposed an outright ban on recombinant DNA research, suggesting instead that existing physical containment protocols might suffice, in particular if they were combined with the possibility of engineering the microorganisms so they

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people from conducting irresponsible or unnecessarily hazardous experiments’, the report concluded, before outlining a set of underwhelming recommendations. The most radical of these were that recombinant DNA work should be done by trained researchers (!), laboratories should have the basic equipment required for containing ordinary pathogens and that each institution should have a

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at the end. Whatever the case, a clear statement to this effect was eventually included, with only five votes against. The final declaration stated that recombinant DNA research could recommence so long as appropriate containment facilities and protocols were available (a rough description of these was included, together with a four-point

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Congress. There were also public meetings in several towns where universities wanted to set up high-level containment facilities. In the United Kingdom, regulation of recombinant DNA research not only involved trade union representatives but also saw the creation of statutory health and safety committees in universities and research establishments. In France

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could never be fully resolved because it involved all possible combinations of all possible genes, viruses and bacteria. As a result, even the advocates of recombinant DNA research remained concerned that one such combination might inadvertently – or deliberately – create a new disease. At a meeting held at NIH headquarters in Bethesda in

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guidelines appeared, Erwin Chargaff, a prominent and irascible 70-year-old biochemist, published a rambling and self-important letter in Science opposing the study of recombinant DNA. In typically curmudgeonly style, Chargaff unleashed apocalyptic predictions about ‘freakish forms of life’, warning of the coming of ‘something much worse than virulence’ when ‘the

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the arguments about genetic modification that took place over subsequent decades, right down to the present day. Some of the fears invoked by opponents of recombinant DNA were literally fictional. The historian Luis Campos has shown how Michael Crichton’s first technothriller – The Andromeda Strain, published in 1969 and turned into

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in a situation that was even less restrictive than that in the United States.46 During this period scientific societies increasingly argued against regulation of recombinant DNA.47 The American Society of Microbiology mobilised its 25,000 members to lobby their political representatives to oppose restrictions on the new technology.48 The

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regulations, which restricted work on recombinant human DNA except in the strictest containment facilities. Gilbert’s group soon hit another problem – the Cambridge row over recombinant DNA not only forbade them from pursuing key steps in their research programme, it also distracted them from laboratory work as they felt compelled to engage

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half of the 1977 Nobel Prize ‘for their discoveries concerning the peptide hormone production of the brain’. Then, at the November 1977 Senate hearings into recombinant DNA, Berg highlighted the still-unpublished Genentech research on somatostatin in his evidence, generously describing it as ‘extraordinary… astonishing… ingenious… elegant’.28 Berg also used the

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Genentech: The ability to isolate pure genes puts us at the threshold of new forms of medicine, industry, and agriculture. Tailor-made organisms produced by recombinant DNA methods could provide valuable diagnostic reagents, probes for studying the operational status and efficiency of gene expression in health and disease, vaccines to immunise individuals

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the pressure of competition and potential profit might drive scientists to make dangerous short-cuts, led to close questioning by the Senate Subcommittee that discussed recombinant DNA in November 1977. The senators particularly focused on what appeared to be a series of scandals involving systematic disregard for NIH guidelines at UCSF. Earlier

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companies they approached – US pharmaceutical giants Johnson & Johnson and Eli Lilly. Especially at an asking price of $80 million. With public and institutional fears about recombinant DNA evaporating and an increasing appetite for speculation as the US stock market rose, the Genentech founders abandoned the idea of selling to the highest bidder

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significantly, MITI promoted the grandly titled Next Generation Basic Technology (NGBT) project, which coordinated and developed the activities of fourteen companies, including the development of recombinant DNA technology. This was funded to the tune of ¥26 billion (around $100 million) over ten years.40 The United Kingdom was much less systematic in

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affair, President Carter had convened an eleven-person Presidential Commission to explore bioethical issues associated with gene therapy, in response to the growing power of recombinant DNA technology and the assumption that it would eventually be applied to humans. In 1982 the Commission published its conclusions – Splicing Life: A Report on the

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the CRISPR sequences came from bacteriophage viruses, suggesting that the bacteria had acquired these sequences after viral infection – CRISPR sequences were a natural form of recombinant DNA. Mojica thought about why such sequences might be so widespread and decided that CRISPR and their accompanying interspaced bits of DNA and the Cas genes

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for germline engineering and germline gene modification’ – inevitably invited comparisons with the 1974 letter signed by Berg and Baltimore that called for a moratorium on recombinant DNA research. But unlike the Berg letter, and unlike the Lanphier and Urnov article in Nature, the Napa statement preferred to merely ‘strongly discourage’ any clinical

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alone could decide how to regulate their national affairs. ✴ Many people drew the obvious parallels between the discussions of germline editing and the debates about recombinant DNA that took place around Asilomar. The Napa letter that effectively launched the Washington Summit suggested that the key feature of Asilomar had been the adoption

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to the ethical, social, and economic concerns of biotechnology.’33 Her critique continued: By failing to engage with the social, economic, and ethical issues surrounding recombinant DNA research and applications, the conference set a precedent for treating such issues as ‘outside the scope of regulation’. Despite Doudna’s claim, the public became

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involved in debates over recombinant DNA because they were suspicious of the reassurances from the scientists that emerged from Asilomar, not because the scientists invited them in. As Parthasarathy pointed out

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scientists, physicians and bioethicists involved in those discussions had been as clear and cautious as the NASEM gene-drive committee. As in the debates around recombinant DNA in the 1970s, worried scientists were more focused on technical issues associated with physical and biological containment than on the deeper question of whether the

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But the newspaper obscured these insights with claims that Soviet scientists such as Bayev shared the concerns of their US counterparts about the safety of recombinant DNA – the NIH regulations were adopted by Soviet laboratories and were prominently displayed when Western journalists or academics visited.13 Bayev was quoted as saying that

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Union appears to have used genetic engineering to develop new biological weapons during the twentieth century. The US programme was discontinued before the advent of recombinant DNA, there was apparently no interest from the British, while the French were quite content with their nuclear weapons.37 China, which was attacked with biological

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the methods involved might enable terrorists or biohackers to replicate experiments with potentially disastrous results. Janet Mertz told me that her 1972 breakthrough in assembling recombinant DNA molecules put the technique within the grasp of ‘a bright high school student’; in 1989, Commander Stephen Rose wrote of genetic engineering becoming a ‘cottage

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for AS GODS “A gripping, bawdy tale of science fiction morphing into business history. Exhaustively researched and beautifully written, As Gods provides the histories of recombinant DNA, biotech, GMOs, gene therapy, and cloning in a single lively, accessible account.” —Nathaniel Comfort, John Hopkins University “A lucid and vigorously insightful account of the

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primate virus that can induce tumours in mammalian cells, so once the focus of interest for cancer researchers. Subsequently used as a vector to introduce recombinant DNA into mammalian cells. Synthetic biology. A form of genetic engineering that involves redesigning organisms (usually microbes) according to engineering principles, in order to meet human

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Harbor Laboratory Archive, SB/1/1/414/4. http://libgallery.cshl.edu/items/show/63403 3 Friedberg, E. (2014), A Biography of Paul Berg: The Recombinant DNA Controversy Revisited (Singapore, World Scientific Publishing), p. 127; Berg, P. (2000), A Stanford Professor’s Career in Biochemistry, Science, Politics, and the Biotechnology Industry. An

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/25. http://libgallery.cshl.edu/items/show/74250 67 Rogers, Biohazard, pp. 70–1; Wade, The Ultimate Experiment, pp. 31–2. 68 Rogers (1975); Lear, Recombinant DNA, pp. 140–1. A decade later, Robert Sinsheimer had a rather different recollection: ‘Occasional monitory comments by the lawyers present received little attention’ – Sinsheimer, R

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. 206. 36 For an excellent brief summary, see Gibson, K. (1986), in R. Zilinskas and B. Zimmerman (eds), The Gene-Splicing Wars: Reflections on the Recombinant DNA Controversy (London, Collier Macmillan), pp. 55–71. For more extensive accounts, see Wright, Molecular Politics; Gottweis, H. (1998), Governing Molecules: The Discursive Politics of Genetic

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Center Report, December 1977, pp. 8–10. 43 US Senate, Committee on Commerce, Science and Transportation, Subcommittee on Science, Technology and Space (1978), Regulation of Recombinant DNA Research (2, 8 & 10 November 1977) (Washington, DC, US Government Printing Office). 44 Le Monde, 12 June 1975; Anonymous (1975), Nature 256:5; Robert, B

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Politics. 48 Abelson, P. (1977), Science 197:721; Halvorson, H. (1984), in R. Zilinskas and B. Zimmerman (eds), The Gene-Splicing Wars: Reflections on the Recombinant DNA Controversy (London, Collier Macmillan, 1984), pp. 73–91. 49 Wright, Molecular Politics, p. 334; Statement from EMBO, 30 November 1977, reproduced in Watson and Tooze

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Pergamon Press). For an analysis of the Wye College meeting, see Wright, Molecular Politics, pp. 341–51. 51 Stoker, M. (1979), in Morgan and Whelan, Recombinant DNA and Genetic Experimentation, pp. xix–xx, p. xx. 52 US House of Representatives, Committee on Science and Technology, Subcommittee on Science, Research and Technology (1978

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Quotes in this and subsequent two paragraphs from US Senate, Committee on Commerce, Science and Transportation, Subcommittee on Science, Technology and Space (1978), Regulation of Recombinant DNA Research (2, 8 & 10 November 1977) (Washington, DC, US Government Printing Office), p. 36. 29 Guillemin, R. and Lemke, G. (2013), Annual Review of Physiology

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. Oral History Program 4. David Baltimore and Wally Gilbert. Photo: Rick Stafford 5. Protestors at an American Association for the Advancement of Science forum on recombinant DNA, March 1977. Photo: Courtesy of the National Academy of Sciences (US) 6. City of Hope Hospital and Genentech researchers. Photo: Bettmann/Getty Images 7. Ananda

The Gene: An Intimate History

by Siddhartha Mukherjee  · 16 May 2016  · 824pp  · 218,333 words

cleaning it, changing it at will. To produce such genetic chimeras, Berg recalled, “none of the individual procedures, manipulations, and reagents used to construct this recombinant DNA was novel; the novelty lay in the specific way they were used in combination.” The truly radical advance was the cutting and pasting of ideas

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a strange chimera: genes from far branches of the evolutionary tree stitched together to form a single contiguous piece of DNA. Berg called the hybrids “recombinant DNA”. It was a cannily chosen phrase, harkening back to the natural phenomenon of “recombination,” the genesis of hybrid genes during sexual reproduction. In nature,

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matched in test tubes. Recombination without reproduction: he was crossing over to a new cosmos of biology. Figure adapted from Paul Berg’s paper on “Recombinant” DNA. By combining genes from any organisms, scientists could engineer genes at will, foreshadowing human gene therapy and human genome engineering. That winter, a graduate

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dish, would naturally select their hybrid plasmids. The transference of antibiotic resistance from one bacterium to another bacterium would confirm that the gene hybrid, or recombinant DNA, had been created. But what of Berg and Jackson’s technical hurdles? If the genetic chimeras were produced at a one-in-a-million

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select the hybrid DNA. Grow one such bacterial cell into its million descendants, and you would amplify the hybrid DNA a millionfold. You would clone recombinant DNA.” The experiment was not just innovative and efficient; it was also potentially safer. Unlike Berg and Mertz’s experiment—involving virus-bacteria hybrids—Cohen

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it was, we thought it might just work,” Berg recalled. The panel drafted a formal letter, pleading for a “moratorium” on certain kinds of recombinant DNA research. The letter weighed the risks and benefits of gene recombination technologies and suggested that certain experiments be deferred until the safety issues had been

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addressed. “Not every conceivable experiment was dangerous,” Berg noted, but “some were clearly more hazardous than others.” Three types of procedures involving recombinant DNA, in particular, needed to be sharply restricted: “Don’t put toxin genes into E. coli. Don’t put drug-resistant genes into E. coli,

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Academy of Sciences. It drew instant attention around the globe. In Britain, a committee was formed to address the “potential benefits and potential hazards” of recombinant DNA and gene cloning. In France, reactions to the letter were published in Le Monde. That winter, François Jacob (of gene-regulation fame) was asked

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, as Berg put it, was so “ridiculously simple” that even an amateur biologist could produce chimeric genes in a lab. These hybrid DNA molecules—recombinant DNA—could be propagated and expanded (i.e., cloned) in bacteria to generate millions of identical copies. Some of these molecules could be shuttled into mammalian

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and tempers flared quickly on the first morning. The main issue was still the self-imposed moratorium: Should scientists be restricted in their experiments with recombinant DNA? Watson was against it. He wanted perfect freedom: let the scientists loose on the science, he urged. Baltimore and Brenner reiterated their plan to

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. The NIH would be flooded with queries; all hell would break loose. The federal government would respond by proposing draconian regulations—not just on recombinant DNA, but on a larger swath of biological research. The result could be restrictions vastly more stringent than any rules that scientists might be willing to

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, “Science, in its pure form, is not interested in where discoveries may lead. . . . Its disciples are interested only in discovering the truth.” But with recombinant DNA, Berg argued, scientists could no longer afford to focus merely on “discovering the truth.” The truth was complex and inconvenient, and it required sophisticated assessment

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unpredictable regulators and find their work arbitrarily constrained—or they could become science regulators themselves. How were biologists to confront the risks and uncertainties of recombinant DNA? By using the methods that they knew best: gathering data, sifting evidence, evaluating risks, making decisions under uncertainty—and quarreling relentlessly. “The most important

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conference deliberately limit the scope of the concerns? . . . Others have been critical of the conference because it did not confront the potential misuse of the recombinant DNA technology or the ethical dilemmas that would arise from applying the technology to genetic screening and . . . gene therapy. It should not be forgotten that

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sufficiently advanced technology is indistinguishable from magic. —Arthur C. Clarke Stan Cohen and Herb Boyer had also gone to Asilomar to debate the future of recombinant DNA. They found the conference irritating—even deflating. Boyer could not bear the infighting and the name-calling; he called the scientists “self-serving” and

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Times. Cohen also received a quick baptism on the seamy side of scientific journalism. Having spent an afternoon talking patiently to a newspaper reporter about recombinant DNA and bacterial gene transfer, he awoke the next morning to the hysterical headline: “Man-made Bugs Ravage the Earth.” At Stanford University’s patent

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institutions, would also be part of that patent). Both Cohen and Boyer were surprised. During their experiments, they had not even broached the idea that recombinant DNA techniques could be “patentable,” or that the technique could carry future commercial value. In the winter of 1974, still skeptical, but willing to humor

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Reimers, Cohen and Boyer filed a patent for recombinant DNA technology. News of the gene-cloning patent filtered back to scientists. Kornberg and Berg were furious. Cohen and Boyer’s claims “to commercial ownership

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cold-cut sandwiches for lunch and dinner. The assigned ten minutes grew into a marathon meeting. They walked to a neighborhood bar, talking about recombinant DNA and the future of biology. Swanson proposed starting a company that would use gene-cloning techniques to make medicines. Boyer was fascinated. His own

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disparaged—that came to their rescue. Like most university laboratories with federal funding, Gilbert’s lab at Harvard was bound by the Asilomar restrictions on recombinant DNA. The restrictions were especially severe because Gilbert was trying to isolate the “natural” human gene and clone it into bacterial cells. In contrast, Riggs

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Yet no human insulin was in sight. In Boston, Swanson knew, Gilbert had upped his war effort—literally. Fed up with the constraints on recombinant DNA at Harvard (on the streets of Cambridge, young protesters were carrying placards against gene cloning), Gilbert had gained access to a high-security biological-warfare

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circular motion; visual space to subvisual space; motion on land to motion in air; physical connectivity to virtual connectivity. The production of proteins from recombinant DNA represented one such crucial transition in the history of medical technology. To understand the impact of this transition—from gene to medicine—we need to

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some of the most potent and most discriminating medicines in the pharmacological world. But to make a protein, one needs its gene—and here recombinant DNA technology provided the crucial missing stepping-stone. The cloning of human genes allowed scientists to manufacture proteins—and the synthesis of proteins opened the possibility

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the two separate chains used by Genentech were not “natural” genes, the synthesis did not fall under the federal moratorium that restricted the creation of recombinant DNA with “natural” genes. PART FOUR * * * “THE PROPER STUDY OF MANKIND IS MAN” Human Genetics (1970–2005) Know then thyself, presume not God to scan;

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hospital. It is important to conceptualize the transformation in genetics that occurred between 1971—the year that Berg and Jackson created the first molecule of recombinant DNA—and 1993, the year that the Huntington’s disease gene was definitively isolated. Even though DNA had been identified as the “master molecule” of

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would eventually come to a standstill. James Watson echoed the frustration with the pace of “single-gene” genetics. “But even with the immense power of recombinant DNA methodologies,” he argued, “the eventual isolation of most disease genes still seemed in the mid 1980s beyond human capability.” What Watson sought was the sequence

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the genetic code], with the discovery of the biological mechanism by which cells read the information contained in genes, and with the invention of the recombinant DNA technologies of cloning and sequencing by which scientists can do the same.” The sequence of the human genome, the project asserted, marked the starting point

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future of the future.” For a while, the “future of the future” seemed biologically intractable. In 1974, barely three years after the invention of recombinant DNA technology, a gene-modified SV40 virus was used to infect early mouse embryonic cells. The plan was audacious. The virus-infected embryonic cells were mixed

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wake of the Berg recommendations of the Asilomar meeting. Known for its tough oversight, the advisory committee was the gatekeeper for all experiments that involved recombinant DNA (the committee was so notoriously obstreperous that researchers called getting its approval being “taken through the Rack”). Perhaps predictably, the RAC rejected the protocol

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single gene using modern gene-mapping methods. Students protest a genetics meeting in the 1970s. The novel technologies of gene sequencing, gene cloning, and recombinant DNA raised anxieties that new forms of eugenics would be used to create a “perfect race.” The link to Nazi eugenics was not forgotten. Herb Boyer

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and Robert Swanson founded Genentech in 1976 to produce medicines out of genes. The drawing on the blackboard shows the scheme to produce insulin using recombinant DNA technology. The first such proteins were produced in enormous bacterial incubators under Swanson’s watchful eye. Paul Berg speaks to Maxine Singer at the Asilomar

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call: Details of Berg’s account of Asilomar come from conversations and interviews with Paul Berg, 1993 and 2013; and Donald S. Fredrickson, “Asilomar and recombinant DNA: The end of the beginning,” in Biomedical Politics, ed. Hanna, 258–92. The Asilomar conference produced an important book: Alfred Hellman, Michael Neil Oxman,

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.org/view/15021-The-moratorium-letter-regarding-risky-experiments-Paul-Berg.html. In 1974, the “Berg letter” ran: P. Berg et al., “Potential biohazards of recombinant DNA molecules,” Science 185 (1974): 3034. See also Proceedings of the National Academy of Sciences 71 (July 1974): 2593–94. “are specious”: Herb Boyer interview,

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1973): 5. “was to demonstrate that scientists were capable”: Paul Berg, author interview, 2013. “The public’s trust was undeniably increased”: Paul Berg, “Asilomar and recombinant DNA,” Nobelprize.org, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1980/berg-article.html. “Did the organizers and participants”: Ibid. “Clone or Die” If you

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know the question: Herbert W. Boyer, “Recombinant DNA research at UCSF and commercial application at Genentech: Oral history transcript, 2001,” Online Archive of California, 124, http://www.oac.cdlib.org/search?style=oac4

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Hidden in Our Genes. Oxford: Elsevier, 2013. Fox Keller, Evelyn. The Century of the Gene. Cambridge: Harvard University Press, 2009. Fredrickson, Donald S. The Recombinant DNA Controversy: A Memoir: Science, Politics, and the Public Interest 1974–1981. Washington, DC: American Society for Microbiology Press, 2001. Friedberg, Errol C. A Biography of

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Paul Berg: The Recombinant DNA Controversy Revisited. Singapore: World Scientific Publishing, 2014. Gardner, Howard E. Frames of Mind: The Theory of Multiple Intelligences. New York: Basic Books, 2011. ———. Intelligence

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Books, 2007. Kornberg, Arthur, and Tania A. Baker. DNA Replication. San Francisco: W. H. Freeman, 1980. Krimsky, Sheldon. Genetic Alchemy: The Social History of the Recombinant DNA Controversy. Cambridge: MIT Press, 1982. ———. Race and the Genetic Revolution: Science, Myth, and Culture. New York: Columbia University Press, 2011. Kush, Joseph C., ed.

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Rutgers University Press, 2012. Watson, James D. The Double Helix: A Personal Account of the Discovery of the Structure of DNA. London: Weidenfeld & Nicolson, 1981. ———. Recombinant DNA: Genes and Genomes: A Short Course. New York: W. H. Freeman, 2007. Watson, James D., and John Tooze. The DNA Story: A Documentary History of

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85 Arendt, Hannah, 124 Arieti, Silvano, 442–43 Aristotle, 22–24, 27, 70, 142 Asilomar conference (Asilomar I, 1973), California, 226–27 Asilomar Conference on Recombinant DNA (Asilomar II, 1975), California influence of, 230, 231–32, 234–35 moratorium proposal of, 230, 477, 502 range of attendees at, 229, 238 recommendations of

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contests, 85, 344 Bickel, Alexander, 268–69 Bieber, Irving, 370–71 biochemistry, 140–41 biohazards Asilomar I meeting on, 226–27 Asilomar II recommendations on recombinant DNA and, 231, 233 Berg’s research using SV40 and, 210 Biohazards in Biological Research (Hellman, Oxman, and Pollack), 227 biological information central dogma of,

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for manipulating, 292 impact of genetic engineering of, 222 information theory on formation of, 413 Miller’s “primordial soup” experiments to form, 411 recombinant. See recombinant DNA replication of, 179–80, 180n, 182, 288, 296 sequencing of. See gene sequencing Watson and Crick’s double-helix model of, 13, 150–51,

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circumstances, 177 gene cloning, 218, 220, 221, 292 Asilomar II conference (1975) on, 233 “Berg letter” on benefits and hazards of, 228 Berg’s recombinant DNA research involving, 208–09 of BRCA1 gene in breast cancer, 439 coining of phrase, 222 as conceptual shift, 294 concerns about using, 227, 230, 231

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Lederberg, Joshua, 236 legal issues gene cloning and, 230 gene patent controversy and, 308–09 proposed moratorium on use of genomic engineering due to, 477 recombinant DNA technology patent and, 237, 308 Lejeune, Jérôme, 262n Lenz, Fritz, 119 Leopold, Prince, Duke of Albany, 99 Lessing, Doris, 147n leukemia, 405 Levene, Phoebus,

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BRCA1 gene sequence, 439 for gene-fragment technology, 309 for Genentech’s insulin created in a test tube, 245 for genes, 308–09, 312 for recombinant DNA techniques, 237, 245, 308 Patrinos, Ari, 317–18 Patterson, Orlando, 348 Pauling, Linus, 164, 333n DNA structure research of, 148, 152–53 hemoglobin

A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution

by Jennifer A. Doudna and Samuel H. Sternberg  · 15 Mar 2017

ancestors of our species millennia ago. Following the first attempts at gene therapy in the 1960s, the field took off, thanks to a revolution involving recombinant DNA—a catch-all term for genetic code produced in a lab, not by nature. Using new biotechnology tools and new biochemical methods, scientists in the

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that scientists could deliver genes more gently, without using viruses to ram new DNA into the genome. By tricking a cell into thinking that the recombinant DNA was simply an extra chromosome that needed to be paired with a matching gene already in its genome, scientists could ensure that the new DNA

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up RNA or DNA molecules, just like the DNA-cutting function of restriction endonucleases. Given how useful the discovery of restriction endonucleases had been for recombinant DNA technology in the 1970s, it seemed very possible that, by digging deeper into these and other aspects of CRISPR, we might uncover a treasure-trove

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wild fish, could be considered a GMO. A more common definition of GMO, however, includes only those organisms whose genetic material has been altered using recombinant DNA technology and so-called gene splicing, in which foreign DNA sequences are integrated into the genome. Since 1994, when the first commercially grown GMO plant

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community and beyond. Then, as now, the cause of concern was a breakthrough in genetic engineering. In this earlier instance, it was the birth of recombinant DNA. And in this case, scientists had moved proactively—and, ultimately, successfully—to prevent their work from inadvertently causing harm. In the early 1970s, scientists made

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1973—eventually known as Asilomar I—focused on the DNA of cancer viruses and the risks they posed; it did not directly address the new recombinant DNA experiments Berg was considering. That same year, however, scientists held a second conference focused specifically on gene splicing. The concerns raised at this meeting led

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National Academy of Sciences establish a committee to formally investigate the new technology. Berg would serve as the chairman of this group, the Committee on Recombinant DNA Molecules, which met at MIT in 1974. Soon after the meeting, they released a notable report titled “Potential Biohazards of

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Recombinant DNA Molecules.” The “Berg letter,” as it’s often called, issued an unprecedented summons for a worldwide moratorium on experiments the committee deemed most hazardous—those

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any experiments designed to fuse animal and bacterial DNA; second, that the National Institutes of Health establish an advisory committee to oversee future issues surrounding recombinant DNA; and third, that an international meeting be convened so that scientists from around the world could review recent progress in the field and compare notes

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on how to deal with potential hazards. This last recommendation would result in the International Congress on Recombinant DNA Molecules, held back in Asilomar in February 1975. Much has been written about Asilomar II. Roughly a hundred and fifty people attended, mostly scientists but

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of the media. The debate was heated at times, with even the biology experts disagreeing with one another on the relative hazards of experiments involving recombinant DNA. Some argued against prematurely ending the moratorium, feeling that certain experiments should continue to be prohibited until much more was known about their risks; others

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scientists and the public and pave the way for the creation of a governmental authority known as the Recombinant DNA Advisory Committee, which became heavily involved in overseeing subsequent research and clinical applications of recombinant DNA. Some forty years later, in the early part of 2014, I decided that we needed to take a

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felt I needed to help initiate the discussion. Much as Berg and his colleagues had sounded the alarm when the risks of their work with recombinant DNA became clear, I would need to leave the comfort of my lab and help spread the word about the implications of our research. Only that

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of Berg’s; Baltimore had not only attended the MIT meeting in 1974 but also coauthored the resulting paper that called for a moratorium on recombinant DNA research, and he had played a pivotal role in the discussions at Asilomar II. Paul’s and David’s attendance meant that our meeting would

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through open-ended scientific research. The wonders of penicillin would never have been discovered had Alexander Fleming not been conducting simple experiments with Staphylococci bacteria. Recombinant DNA research—the foundation for modern molecular biology—became possible only with the isolation of DNA-cutting and DNA-copying enzymes from gut- and heat-loving

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Sweet ’Omics—A Genealogical Treasury of Words,” Scientist, April 2, 2001. “It was clear that we had uncovered”: S. Rogers, “Reflections on Issues Posed by Recombinant DNA Molecule Technology. II,” Annals of the New York Academy of Sci­ences 265 (1976): 66–70. many scientists considered reckless and premature: T. Friedmann and

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National Academy of Sciences of the United States of America 69 (1972): 2904–9. a notable report titled “Potential Biohazards of Recombinant DNA Molecules”: P. Berg et al., “Letter: Potential Biohazards of Recombinant DNA Molecules,” Science185 (1974): 303. Much has been written about Asilomar II: Institute of Medicine (US) Committee to Study Decision Making

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. E. Hanna, ed., Biomedical Politics (Washington, DC: National Academies Press, 1991); M. Rogers, Biohazard (New York: Knopf, 1977); P. Berg and M. F. Singer, “The Recombinant DNA Controversy: Twenty Years Later,” Proceedings of the National Academy of Sciences of the United States of America 92 (1995): 9011–13. Berg and his colleagues

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decided that most experiments should proceed: P. Berg et al., “Asilomar Conference on Recombinant DNA Molecules,” Science188 (1975): 991–94. gave rise to a consensus that allowed research to proceed with popular support: P. Berg, “Meetings That Changed the World

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, and the Politics of Deliberation,” Hastings Center Report 45 (2015): 11–14. creation of a governmental authority known as the Recombinant DNA Advisory Committee: N. A. Wivel, “Historical Perspectives Pertaining to the NIH Recombinant DNA Advisory Committee,” Human Gene Therapy 25 (2014): 19–24. “A Prudent Path Forward for Genomic Engineering and Germline Gene

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–3 Asilomar II, 203–4, 207 on CRISPR, 57, 84 Engineering the Human Germline, 192–93 IGI Forum on Bioethics, 206–10 International Congress on Recombinant DNA Molecules, 203–4 International Summit on Human Gene Editing, 219–22 controversies, 99 de-extinction, 146–47 gene drives, 149–52 gene-edited food, 126

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, 161, 167–71, 167 infection, blocking, 52 Innovative Genomics Institute (IGI), 156, 206 insects, gene-edited, 149–50 Intellia Therapeutics, 89, 177 International Congress on Recombinant DNA Molecules, 203–4 International Society for Stem Cell Research, 216 International Summit on Human Gene Editing, 219–22 I-SceI endonuclease, 28, 29, 30 IVF

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, 125, 200–201, 204–5, 206, 243, 244–45 public health, 154 Puck, Jennifer, 207 puppeteer function, 108 Q Qi, Stanley, 109 R recombinant DNA, 19, 201, 205, 207 Recombinant DNA Advisory Committee, 205 Recombinetics, 135 regulation of cloning, 191 of crops, 127–28 of gene-edited pigs, 133 of germline editing, 221, 235

Troublemakers: Silicon Valley's Coming of Age

by Leslie Berlin  · 7 Nov 2017  · 615pp  · 168,775 words

technological innovation of the past 150 years. In the space of thirty-five miles and seven years, innovators developed the microprocessor, the personal computer, and recombinant DNA. Entrepreneurs founded Apple, Atari, Genentech, and the pioneering venture capital firms Sequoia Capital and Kleiner Perkins Caufield & Byers. Five major industries were born: personal

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years, products from Silicon Valley companies such as Apple, Atari, and their competitors were reshaping how people worked and played. Insulin had been synthesized using recombinant DNA, and the Supreme Court had declared that genetically engineered life-forms could be covered by patents.9 Software companies were going public. Pension funds had

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also explained that because only commercial entities, not nonprofit research institutions and universities, would pay royalties, a patent would not restrict academic use of the recombinant DNA process. “Patents are intended to ensure that technological discoveries are not kept secret,” he liked to say. As for the concern about public funding:

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the claim near the end of the document, to minimize the need for retyping. With that addition, the patent application covered the use of recombinant DNA in applications as varied and broad as possible. While Rowland drew up the application, Reimers worked to convince the National Science Foundation and the American

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for Biologically Functional Molecular Chimeras.” It was a patent of notable breadth, claiming title to what the Stanford biochemist Paul Berg (who had done pioneering recombinant DNA work himself) later criticized as “techniques for cloning all possible DNAs, in all possible vectors, joined in all possible ways, in all possible organisms.”

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mentioned it at a scientific conference. Within days, concerned conference organizers had asked the National Academy of Sciences to create a committee to assess the recombinant DNA process. “New kinds of viruses with biological activity of unpredictable nature may eventually be created,” they cautioned. “Certain of these hybrid molecules are potentially

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workers and the public.”53 One year later, the National Academy of Sciences committee, whose members included Cohen and Boyer, recommended a moratorium on certain recombinant DNA experiments until the risks were better understood.54 In February 1975, 150 top scientists from thirteen countries, along with a number of invited journalists and

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scientists, possibly influenced by a panel of attorneys who had presented the previous afternoon, proposed a set of guidelines for minimizing safety risks when conducting recombinant DNA research. Rolling Stone, which dubbed the Asilomar meeting the “Pandora’s Box Congress,” claimed that the safety guidelines marked the first time that scientists

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public knowledge, but a patent, by definition, is restrictive. The scientists also raised another objection, again familiar to Reimers from his conversations with Cohen: the recombinant DNA process built on research by many more scientists than just Cohen and Boyer. (To this day, Berg calls the patent claims “dubious, presumptuous, and hubristic

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university technology licensing officer in the country,” attributed much of Reimers’s success to “his aggressive, outgoing personality.”67 A few years after filing the recombinant DNA patent application, Reimers claimed, with evident frustration, that there were “over 28,000 unused patents that the government has accumulated mainly due to a lack

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executives at Xerox about PARC’s personal computer. There were pockets of backlash against violent video games. Protests and research bans followed reports about the recombinant DNA process, some people mistakenly fearing that it threatened the very existence of humanity. Reimers’s patent application was criticized for its potential to undermine the

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to consider selling Atari, and the United States celebrated its bicentennial with fireworks and song, Niels Reimers tracked the country’s rising fears about the recombinant DNA process he was trying to patent. Scientists’ decision, made a year earlier at the Asilomar “Pandora’s Box” conference, to regulate their own research,

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“the A-bomb, nerve gas, biological warfare, [and] the destruction of the stratospheric ozone layer by fluorocarbon sprays.” The magazine further noted that, thanks to recombinant DNA, “the spreading of experimental cancer may be confidently expected.”1 Time ran a cover story called “Doomsday: Tinkering with Life,” almost as colorful a title

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Defense Fund and the Natural Resources Defense Council called for public hearings on genetic engineering. The Sierra Club adopted a resolution opposing “the creation of recombinant DNA for any purpose” outside a few carefully regulated government labs.4 The mayor of Cambridge, Massachusetts, asked the National Academy of Sciences to investigate whether

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requiring that some research be conducted in special facilities with air locks, the scientists garbed in outfits that resembled spacesuits. Thirteen bills aimed at regulating recombinant DNA were introduced in Congress.7 Senator Edward Kennedy called congressional hearings, proclaiming that “Scientists must tell us what they are capable of doing, but we

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Department of Health, Education, and Welfare to launch a years-long review of its policies around institutional patent agreements.11 One historian has claimed that “recombinant DNA patenting caused so much controversy that it threatened to torpedo federal patent policy.”12 And Reimers still faced objections within his own university. Faculty members

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“I kept thinking about the potential for good,” he later said. He was particularly encouraged by the thought that new medical treatments might arise from recombinant DNA.14 He knew that although the Stanford faculty objected, the press hyped public hysteria, and patent attorneys in Washington debated, the scientific community had concluded

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that recombinant DNA posed no more significant risks than many other types of research.IX The shift gave him hope.15 Planning for a day when Stanford would

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license, he noted, would come with “the potential for both income and controversy.” He preferred to focus on the income.16 Drug companies could use recombinant DNA to develop pharmaceuticals, chemotherapy medications, synthetic hormones, and vaccines that did not rely on killed or weakened viruses that could potentially cause disease. Chemical companies

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sustained attention. During one long brainstorming lunch, Nobel Laureate and University of California professor Donald Glaser, a cofounder of and consultant to the company, mentioned recombinant DNA as an arena that Cetus might explore. No one else in the meeting was interested—not the two other company founders and not Tom Perkins

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with biologists. Without a scientific expert, Swanson could not have a company. For his part, Boyer had been privately thinking about commercial applications for recombinant DNA for months, ever since a pediatrician had tested Boyer’s young son’s growth hormone levels.33 The boy was fine, but the doctor happened

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microorganism” and could move forward as a “fully operational company” with its own manufacturing and laboratory facilities. Boyer, using photos, spoke about the science behind recombinant DNA. Kleiner and Perkins, both with limited knowledge of biology, did not know what questions to ask, so they ran through generic, but important, ones: What

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a technology.64 No company would make an investment if other companies could just copy the product. But this case was different. Not only was recombinant DNA important enough to merit wide licensing, he felt, but more practically, two star members of Stanford’s faculty, including coinventor Stan Cohen, were consultants

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receiving drafts of Reimers’s evolving plans for a nonexclusive license.66 The two men recognized that they were well matched in their vision for recombinant DNA. Recombinant DNA dominated the bicentennial summer for Reimers. In the space of four months, he spoke with the patent counsel at the Department of Health, Education,

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technology could revert to Stanford.67 After attorney Bert Rowland told Reimers that the federal patent office was not going to allow products made with recombinant DNA under the original patent application, the two men filed a follow-up application.68 Reimers needed to provide regular progress updates to Stanford’s

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to his earlier requests, he wanted to be kept apprised of the patent’s progress. Cohen told Reimers, “The complex scientific and political considerations involving recombinant DNA experiments, the moratorium on potentially biohazardous studies, etc. have made the cloning and the patent the focus of considerable attention. Thus, I am at some

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IX. In 1977, several signatories of the original moratorium letter drafted a new version, never sent, to explain that they now felt less concerned about recombinant DNA. That Flips My Switch  MIKE MARKKULA One Saturday in the fall of 1976, Mike Markkula broke his Mondays-only rule for seeing entrepreneurs and drove

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Perkins was trying to convince Genentech cofounders Bob Swanson and Herb Boyer to take the company public. Three-year-old Genentech had successfully used the recombinant DNA technique to synthesize human insulin and now supplied small batches of the hormone to large pharmaceutical companies such as Eli Lilly. These companies would manufacture

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awarded the Nobel Prize in Chemistry. The Nobel Committee cited him for his “fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA.” Berg shared the prize with Frederick Sanger of the MRC Laboratory of Molecular Biology in England and Walter Gilbert, the Harvard researcher whose team had

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wanted all universities automatically to have the same rights Stanford had won piecemeal. The patent in place, Reimers turned to refining the terms of the recombinant DNA license. The beauty of the Cohen-Boyer process—its simplicity—also meant that as the patent application sat in limbo for six years, scientists

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 NIELS REIMERS In 1983, Stanford earned more than any other university from technology licensing: $2.5 million ($6.1 million in 2016 dollars).1 The recombinant DNA patent generated almost 60 percent of this amount. Niels Reimers, with his inspirational messages to himself and his dogged persistence, was among the first people

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different choice.13 Even as he was leaving, the Office of Technology Licensing was proving the success of Reimers’s leadership and vision. Three inventions—recombinant DNA, FM sound synthesis, and a patent fundamental to developing the magnetic resonance imaging (MRI) machine—were bringing in more than $1 million each in

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’s lab and in Herb Boyer’s lab at the University of California, San Francisco, inspired Niels Reimers to file for a patent on the recombinant DNA process on behalf of the two universities. Courtesy: Genentech Genentech cofounders Herb Boyer and Bob Swanson shortly after they launched the company. Courtesy: the

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National Institutes of Health Protestors interrupt a National Academy of Sciences forum in March 1977. The forum discussed the merits and dangers of recombinant DNA research. Courtesy: PARC, a Xerox company The main beanbag meeting room at Xerox PARC. Left to right: Jim Mitchell, Ed Fiala, Terry Roberts, Vikki

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Courtesy: Carolyn Caddes/Department of Special Collections, Stanford University Libraries. Regis McKenna, around 1985. McKenna helped introduce the world to the microprocessor, personal computer, and recombinant DNA. He was also instrumental in launching Silicon Valley’s presence in Washington, DC. Courtesy: Mike Markkula The Apple executive team celebrates Mike Markkula’s fortiethth

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. Genentech GenenLab notebook at http://blog.zymergi.com/2013/01/origins-biotech-genentech.html. 21. Boyer’s lab learned that EcoR1 could be used in recombinant DNA after reading Janet E. Mertz and Ronald W. Davis, “Cleavage of DNA by RI Restriction Endonuclease Generates Cohesive Ends,” Proceedings of the National Academy

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Maxine Singer and Dieter Soll to Philip Handler, July 17, 1973, at http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CDBBCG. 54. “Potential Biohazards of Recombinant DNA Molecules,” Science, 26 July 1974, letter reprinted in James D. Watson and John Tooze, The DNA Story: A Documentary History of Gene Cloning (San Francisco

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and Co., 1981): 206. Vellucci quoted in “Test Tube Laboratory Fine, but Build It Somewhere Else,” Palo Alto Times, June 16, 1976. On Harvard Yard: “Recombinant DNA: Cambridge City Council Votes Moratorium,” Science, July 1976. 6. Gene Bylinsky, “DNA Can Build Companies, Too,” Fortune, June 16, 1980. 7. “Gene Splicing Sheds

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but Want More Safety,” Science, January 1977; “Gene-Splicing: At Grass-Roots Level a Hundred Flowers Bloom,” Science, Feb. 11, 1977. 10. “Who Should Control Recombinant DNA?,” Chronicle of Higher Education, March 21, 1977. Jeremy Rifkin led the protesters, who called themselves the People’s Business Commission. Chant detail is from Jeffrey

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the propriety of our proceeding as planned and authorized,” that prompted the review. Robert Rosenzweig to Distribution, June 30, 1976; Rosenzweig to Those Interested in Recombinant DNA, June 4, 1976; Rosenzweig to Donald Frederickson, June 18, 1976; Rosenzweig to Joseph Califano, Jr. Feb. 15, 1977, SUOTL. 12. Doogab Yi, The Recombinant

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Lederberg, and several Stanford administrators, quoted in Yi, The Recombinant University: 209. 14. Niels Reimers, interview by author, May 15, 2015. 15. See also Cohen, “Recombinant DNA: Fact and Fiction,” statement prepared for a meeting of the Committee on Environmental Health, California Medical Association, Nov. 18, 1976, and “The Nobel Letters,” Watson

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and “OTL Income and Other Figures (2013),” SUOTL. 80. Niels Reimers to Arnold, Feb. 17, 1978, SUOTL. 81. Niels Reimers to File, “Various Conversations Regarding Recombinant DNA,” July 15, 1976, SUOTL. 82. “Flashback to 1970,” recollection by Sally Hines, in 40 Years of Discovery, Office of Technology Licensing anniversary publication. Genentech held

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successfully combines the DNA of two different organisms.” The description of Cohen’s work: “1973—First Expression of a Foreign Gene Implanted in Bacteria by Recombinant DNA Methods,” http://med.stanford.edu/about/highlights.html. 22. Christensen, “Gene Splicers Develop a Product.” 23. Stan Cohen, ROHO interview. 24. Herb Boyer, quoted

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inspiration. Abbate, Janet. Inventing the Internet. Cambridge, MA: MIT Press, 1999. Berg, Paul and Janet E. Mertz. “Personal Reflections on the Origins and Emergence of Recombinant DNA Technology.” Genetics 184 (2010): 9–17. Berlin, Leslie. The Man Behind the Microchip: Robert Noyce and the Invention of Silicon Valley. New York: Oxford University

Genentech: The Beginnings of Biotech

by Sally Smith Hughes

Dedicated to the memory of Janet Wentworth Smith (1910–2007) and to my children, Dylan, Amy, and Casey Contents Cover Copyright PROLOGUE ACKNOWLEDGMENTS 1 INVENTING RECOMBINANT DNA TECHNOLOGY Two Scientists on Converging Paths The Collaboration Patenting and Politics Steps toward Commercialization 2 CREATING GENENTECH Bob Swanson Founding Genentech Legal and Political Obstacles

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Robert Swanson, an unemployed venture capitalist. Its name, a contraction of genetic engineering technology, captured its extraordinary agenda: to apply the radically new technology of recombinant DNA in engineering bacteria to make insulin, growth hormone, and other important pharmaceuticals. But no one had ever employed the technology as an industrial process, much

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health and safety. As if the deepening scientific, political, and cultural ferment were not enough, the infant company had to also navigate federal guidelines for recombinant DNA research, face the threat of restrictive legislation, and run the gauntlet of legal unknowns in patenting living things. Genentech’s future rested on technological innovation

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quantities of insulin, growth hormone, and other useful substances in bacteria. Despite their common starting point, Cohen and Boyer chose different avenues for industrializing recombinant DNA technology. Why they did so was a matter of personality and professional commitments. It was also a matter of the national environment in the U

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The message of commercial promise was hard to miss. A front-page article in the New York Times provoked the first concrete step toward commercializing recombinant DNA technology.64 Alerted to a breaking story, a Times science correspondent telephoned Cohen, who recounted the industrial applications he foresaw. The resulting article highlighted

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technology’s larger social and ethical implications. Striving to avoid government regulation, the scientists proposed to devise their own safety regulations with the idea that recombinant DNA research could then proceed. After contentious debate, the participants came up with a preliminary draft of recombinant research guidelines. Cohen, Joshua Lederberg, and James

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and Perkins sold the partnership’s shares in Cetus and abandoned the company. Cetus was not alone in its hesitation regarding the industrial application of recombinant DNA technology. Pharmaceutical and chemical corporations, conservative institutions at heart, also had reservations, anxious not to lose out if the radical approach proved competitive but

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also aware of the many unanswered questions concerning its industrial implementation and productivity. In the mid-1970s industry’s common watchword regarding recombinant DNA was “wait and see.” Only with evidence of commercial feasibility were established corporations willing to consider putting human and material resources into trying to transform

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the basic-science technique of recombinant DNA into a productive industrial technology. Cetus, despite its entrepreneurial traits, did not begin to build genetic engineering research facilities until December 1976, more than

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17 Not surprisingly, industry preferred voluntary regulatory compliance or, better yet, no regulation at all. Pharmaceutical companies, weighing the worrisome political issues on top of recombinant DNA’s uncertain industrial feasibility, largely decided not to initiate internal programs for the time being. Calamity meanwhile had befallen Bob Swanson. After the denouement over

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commercial promise. FOUNDING GENENTECH Sometime late in 1975, Swanson decided to act, driven by precarious circumstance and naive faith in the technology’s commercial prospects. Recombinant DNA felt to him “like important stuff,” important enough to build a company upon.21 His seven years in venture capital had provided valuable training in

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technology had never been tested as an industrial process. It did not mention the hostile national environment for a company premised on recombinant DNA technology nor the failure to license recombinant DNA technology under Stanford and UC’s hoped-for patent. Like most business plans, it was a thoroughly promotional creation, designed to

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“factories” efficiently spewing out quantities of insulin, growth hormone, and other pharmaceuticals.8 DNA synthesis, he was convinced, was the companion technology that would make recombinant DNA a feasible industrial technology, not sometime off in the future, as most imagined, but in the tantalizingly reachable near term.9 “I thought,” Boyer recalled

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from Genentech—the UCSF administration, ultra-cautious in light of the political fray, had decided that its new biosafety committee would review all experiments involving recombinant DNA, regardless of funding source. Although the biosafety committee determined the experiment low risk and performable under normal conditions, it stipulated higher physical and biological containment

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placed onerous restrictions on manufacturing recombinant products in quantity. As early as March 1977, before any company, aside from Genentech, had actually taken up recombinant DNA research, a federal committee had recommended legislation to extend the standards of the NIH guidelines to the private sector.57 In this climate of opinion

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produce. The joint City of Hope and UCSF news release put it concretely, claiming a genetic engineering feat representing “the first demonstrated practical benefit from recombinant DNA technology.” “Virtually identical techniques,” the release went on, “could be used safely in bacteria to produce complex biological substances ranging from insulin and other

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one might ask, was Boyer royally criticized and accused of conflict of interest? Most likely it was his central role in the efforts to commercialize recombinant DNA technology, first through the Stanford-UC patent application and then through Genentech. Detractors, already disapproving of his position as inventor on a disputed patent application

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of the industrial interests entering molecular biology. While Boyer experienced a roller-coaster ride of professional and personal highs and lows, the pharmaceutical industry monitored recombinant DNA science and politics with a combination of fascination and skepticism. That skepticism began to fade somewhat with Genentech’s making of somatostatin. Perhaps this radical

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. Human Insulin: Genentech Makes Its Mark Human insulin has been produced at last by genetically engineered bacteria in a California laboratory—an achievement that catapults recombinant DNA technology into the major leagues of the drug industry. Science News, September 16, 19781 Swanson had impatiently endured the somatostatin project, with its heart-

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insulin market, in forming a partnership on human insulin. Novo went so far as to send delegates to Genentech early in 1978 but, questioning whether recombinant DNA could work as an industrial technology, decided against an alliance. Swanson also approached Hoechst, the German pharmaceutical and chemicals manufacturer. For similar reasons, it

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business coups, validated the company as the proprietor of a promising new technology and showcased the fact that a corporation of Lilly’s stature considered recombinant DNA technology of sufficient industrial potential to warrant forming an R&D partnership with an insignificant start-up. Genentech’s alliance with the pharmaceutical giant enormously

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of a major drug and its pathbreaking partnership with Lilly riveted the pharmaceutical sector’s attention. As Science News asserted, achieving human insulin “catapults recombinant DNA technology into the major leagues of the drug industry.”95 With the investment window opening in the late 1970s after successive reductions in the capital

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to start immediately constructing the complementary DNA component. Instead, the project rapidly unraveled. What happened next speaks to the raw intensity and extraordinary competitiveness of recombinant DNA research of the late 1970s. A letter may have inadvertently set the ball rolling. In November 1978 Swanson and Kleid wrote to Goodman, requesting the

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research-based businesses as vehicles for helping to restore the nation to its rightful position as a world leader in high technology. National attitudes toward recombinant DNA research were likewise shifting. Earlier concerns about health and environmental safety, although not entirely absent from public debate, were giving way to expectations for

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not be available for clinical trials in humans until 1981 only whetted public expectation of an imminent cancer remedy. Mindful of that possibility, the NIH Recombinant DNA Advisory Committee (RAC), meeting a few days after the announcement in closed session (a concession to industry demands to protect corporate secrets), recommended approving

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nor inevitable, whether taken from the standpoint of technology, politics, cultural precedents, social norms, or the variable factors of human motivation and performance. Important as recombinant DNA techniques were, Genentech’s early evolution, social impact, and significance for a new industrial sector were emphatically not centered solely upon its technology.123 On

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history, 1994, 71. 90Boyer interview, 2000, 9. 91Boyer interview, 1975, 35. 92Ken Imatani to Reimers, memo, “Discussion with Dr. Boyer for Future Development Work for Recombinant DNA Process,” August 6, 1975, S74-43, patent correspondence 1974–1979, Office of Technology Licensing, Stanford. CHAPTER 2 1Boyer oral history, 1994, 72. 2Swanson oral history

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without success to interest Cetus in trying “to express genes for human hormones in bacteria.” Cohen oral history, 1995, 111. 16Cape interview, 1978, 30. 17“Recombinant DNA Research Guides Worry Drug, Chemical Industry,” Blue Sheet 19, no. 23 (June 1976). The pharmaceutical companies represented were Eli Lilly, Roche Institute of Molecular Biology

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89 per share. “Genentech, Inc., 1979 Corporate Plan,” Chief Financial Officer files, Genentech, Inc. 32Itakura oral history, 2005, 21–22. 33“Guidelines for Research Involving Recombinant DNA Molecules,” Federal Register 41 (July 7, 1976): 27911–43. 34“Expression of Synthetic DNA In Vivo,” Memorandum of Understanding and Agreement, February 9, 1977, AR86

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—the important Riggs-Itakura patents, which are legal mainstays of the biotechnology industry. 57Statement by Donald S. Fredrickson, MD, Director, National Institutes of Health on Recombinant DNA, before the Subcommittee on Science, Technology, and Space, Committee on Commerce, Science, and Transportation, United States Senate, November 8, 1977. 58U.S. Senate, Report

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& Co., 119 F. 3d 1559 (1997), Goodman cross-examination, August 29, 1995, 1235–36. 25For firsthand accounts of the moratorium and its effects, see the Recombinant DNA Controversy Oral History Collection, MIT Libraries, Cambridge, MA. Also see, Krimsky 1985. 26Walter Gilbert’s laboratory, Biological Laboratories, Harvard University, The Midnight Hustler (newsletter) 1

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of Lilly’s human insulin trials, see Hall 1987, 299–301. 68Genentech, Inc., Business Plan, December 1976, Chief Financial Officer files, Genentech, Inc. 69“First Recombinant DNA Product Approved by the Food and Drug Administration,” for release October 29, 1982, Corporate Communications, Genentech, Inc. According to one source, the first marketed recombinant

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State Assembly,” April 25, 1977, Cohen correspondence, Department of Genetics, Stanford University. For a contemporary account of government regulation, risk assessment, and public perception of recombinant DNA research at the outset of the 1980s, see Weiner 1982. 12See Wright 1994, 395–400, for RAC’s concessions to industry. But Wright also maintained

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Jasanoff, Sheila. 1995. Science at the Bar: Law, Science, and Technology in America. Cambridge, MA: Harvard University Press. Johnson, Irving S. 1983. “Human Insulin from Recombinant DNA Technology.” Science 219 (February 11): 632–37. ———. 2003. “The Trials and Tribulations of Producing the First Genetically Engineered Drug.” Nature Reviews 2 (September): 747–81

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The Golden Helix: Inside Biotech Ventures. Sausalito, CA: University Science Books. Krimsky, Sheldon. 1985. Genetic Alchemy: The Social History of the Recombinant DNA Controversy. Cambridge, MA: MIT Press. Lear, John. 1978. Recombinant DNA: The Untold Story. New York: Crown. Lécuyer, Christophe. 2006. Making Silicon Valley: Innovation and the Growth of High Tech, 1930–1970

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Role for Professional Scientists in Industry: Industrial Research at General Electric, 1900–1916.” Technology and Culture 21, no. 3 (July): 408–29. Wright, Susan. 1986. “Recombinant DNA Technology and Its Social Transformation, 1972–1982.” Osiris 2, 2nd series, 303–60. ———. 1994. Molecular Politics: Developing American and British Regulatory Policy for Genetic Engineering

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://bancroft.berkeley.edu/ROHO/projects/biosci/. Berg, Paul. 1978. Interview by Rae Goodell. Massachusetts Institute of Technology, Oral History Program, Oral History Collection on the Recombinant DNA Controversy, MC 100, box X. Massachusetts Institute of Technology, Institute Archives and Special Collections, Cambridge, Massachusetts. ———. 1997. A Stanford Professor’s Career in Biochemistry,

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Science Genetics 5(9): e1000653. Cape, Ronald E. 1978. Interview by Charles Weiner. Massachusetts Institute of Technology, Oral History Program, Oral History Collection on the Recombinant DNA Controversy, MC 100, box X. Massachusetts Institute of Technology, Institute Archives and Special Collections, Cambridge, Massachusetts. ———. 2003. Biotech Pioneer and Co-Founder of Cetus.

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oral history conducted by Sally Smith Hughes, Regional Oral History Office, Bancroft Library, University of California, Berkeley, 2006. Cohen, Stanley N. 1995. Science, Biotechnology, and Recombinant DNA: A Personal History. An oral history conducted by Sally Smith Hughes, Regional Oral History Office, Bancroft Library, University of California, 2009. Crea, Roberto. 2002. DNA

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Leo Slater, Chemical Heritage Foundation, Philadelphia. Falkow, Stanley. 1976. Interview by Charles Weiner. Massachusetts Institute of Technology, Oral History Program, Oral History Collection on the Recombinant DNA Controversy, MC 100, box X. Massachusetts Institute of Technology, Institute Archives and Special Collections, Cambridge, Massachusetts. Gelfand, David. 1978. Interview by Charles Weiner. Massachusetts

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Institute of Technology, Oral History Program, Oral History Collection on the Recombinant DNA Controversy, MC 100, box X. Massachusetts Institute of Technology, Institute Archives and Special Collections, Cambridge, Massachusetts. Glaser, Donald. 2003–4. The Bubble Chamber, Bioengineering,

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biotechnology it became possible not only to identify a desirable phenotypic trait but also to identify the precise genetic material responsible for that genetic trait. Recombinant DNA and plant transformation techniques have made it possible to alter the composition of individual plant components (lipids, carbohydrates, proteins) beyond what is easily possible through

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risk can be minimized by the judicious use of antibiotics and observance of washout periods [164]. Genetically engineered neo-antigens Food biotechnology, the use of recombinant-DNA and cellfusion techniques to confer selected characteristics on plants and animals used for food, can be used to increase agricultural productivity. The transfer of genes

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