Make It Happen

 NIELS REIMERS

Niels Reimers was at his desk, paging through the mail. It was the summer of 1974, and his pilot experiment to encourage Stanford inventors to license their inventions was now a four-year-old official operation called the Office of Technology Licensing. Reimers’s office had moved from Stanford’s stately Encina Hall, once invaded by protesting students, to a small trailer behind the building. He and his assistant Sally Hines had hung ferns and covered the walls with memorabilia and a sign in all caps: MAKE IT HAPPEN.¹

The Office of Technology Licensing had moved from pilot to permanent in June 1970, after bringing in eighteen times as much revenue from licensing fees and royalties in a single year as Research Corporation had in all previous years combined ($55,000 versus less than $3,000).² In the ensuing four years, the office had brought in $461,000 and licensed twenty-two inventions,³ including a laser device licensed to a company interested in using it for eye surgery; a fluorescent activated cell sorter; and a sound-generating and -processing system, licensed to Yamaha, that would, in 1983, help launch a wave of synthesized music with the introduction of the Yamaha DX7.⁴

Reimers, determined to run “an entrepreneurial enterprise where the . . . yardstick of profit can be used to measure success,” faced the excitement and challenges familiar to leaders of any startup.⁵ His efforts to encourage inventors to license their ideas had been successful, but filing for patents was expensive. His office, which kept only 15 percent of the money that came to the university, was running an $11,000 annual deficit. So far, the office had filed for patents on only 5 percent of the 343 disclosures it had received.⁶

In the day’s mail one June afternoon, alongside letters from companies Reimers had approached about licensing and memos from government agencies that supported research at Stanford, was a photocopied news clipping, sent to him by the head of the Stanford News Service. Reimers, once characterized as “less patent officer and more talent scout,” always read the News Service clippings carefully.⁷ They often summarized or publicized university laboratory work that he otherwise might not know about.

This clipping was a five-column article from the New York Times. “Animal Gene Shifted to Bacteria,” the headline trumpeted. Two labs, one at Stanford and the other at the University of California, San Francisco (UCSF), had jointly developed a practical way to clone genetic material by transplanting foreign genes from a complex animal (in this case, a frog) into bacteria. Bacteria are cells that are very simple and multiply quickly. As the bacteria multiplied, they created exact copies of the frog genes and expressed them to make proteins. The bacteria, in other words, had served as tiny DNA-reproducing factories.

The implications were staggering. If bacteria could be engineered to replicate insulin-producing DNA and express genes coded for insulin, for example, it might be possible to make a limitless supply of the lifesaving hormone for diabetics. The same technique could be applied to make antibiotics to fight off infection or microorganisms that could reduce the need for fertilizers. The Times quoted Joshua Lederberg, the Nobel Prize–winning chair of Stanford’s Genetics Department, who called the breakthrough “a major crossroads.”⁸

Reimers did not know much about biology or genetics—“I’m just a mechanical engineer,” he often said—but Lederberg’s endorsement and the potential commercial applications impressed him. Moreover, Reimers knew and liked the Stanford scientist behind the breakthrough. Stanley N. Cohen, the head of the Clinical Pharmacology Division at the Medical School, had worked with Reimers to license a computer-based system to monitor potential drug interactions.

Reimers called Cohen. “Stan,” he said, “this looks like important and interesting work.” Had Cohen considered patenting the DNA technique?⁹

Cohen, thirty-nine and balding, with horn-rimmed glasses and a clipped beard, approached the world with deliberation and moral rectitude. When something bothered him, he was direct: “Listen, Chief,” he’d begin. His powers of concentration were so intense that once, deep in thought, he walked into a sliding glass door and shattered it with his forehead.

Cohen also had a gentler side. He was a careful listener and a musician who sometimes gave impromptu banjo performances during scientific conferences. He had paid his way through college, in part, with royalties from a song that had a brief appearance on the Hit Parade. Most Friday afternoons, he left campus for a run to Baskin-Robbins, where he would buy ice cream for the people in his lab.¹⁰

Cohen told Reimers that he had not considered patenting the breakthrough and was not sure he wanted to. But Reimers was welcome to come make his case.

Reimers grabbed his bike and clipped on his helmet. Five minutes later, he was weaving through a construction site around the medical school and hospital, speeding past heavy machinery, hard-hatted crew members, and the handful of striking workers from the hospital union who stood outside holding signs.¹¹

Once in Cohen’s office, Reimers reiterated that he thought the scientist should patent the process to make what would come to be known as recombinant DNA. Cohen explained why he thought he should not. First, the process depended, in part, on earlier discoveries by other scientists. What right did he have to patent just the latest breakthrough?¹² It felt unethical. Second, the process was important to scientific progress because it made it possible to “manufacture” large amounts of identical genetic material for experiments at a time when the scarcity of available natural DNA limited research; Cohen worried that a patent would restrict availability. Finally, the National Science Foundation, the Department of Health, Education, and Welfare, and the American Cancer Society had provided grants that had made some of the research possible. Was it right for Stanford to take public money but keep the spoils for itself?

Every one of the concerns that Cohen raised in this first conversation would become a significant issue that the men would have to confront in the years ahead. But Reimers, who had been talking to Stanford inventors about the benefits of patents and licenses for nearly five years, knew how to address Cohen’s points. “I had to work almost one-on-one with each scientist to explain the system to them,” he later recalled.¹³

“It’s not like an academic publication,” Reimers said in an effort to counter Cohen’s concerns about the breakthrough building on previous work. Academic papers include detailed references to prior work by other scientists, but a patent application refers to work by others only in certain cases. Reimers 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: there was an established process, called an institutional patent agreement, which allowed a university to petition for rights to an invention that had received public funding.¹⁴ Some people objected to those agreements—Ralph Nader’s Public Citizen organization filed unsuccessful civil actions against them in 1973 and 1974—but Reimers believed that the agreements were essential. Universities would be less inclined to pursue applied research, he said, “if the government would march in to take back any patent with significant commercial potential.”¹⁵ Reimers also explained that a patent application would cost Cohen no money and that Stanford had a good record of receiving the rights for which it petitioned.¹⁶

“Why don’t we proceed and let this all sort itself out?” he suggested.¹⁷ If the recombinant DNA process were not patentable, the application would be rejected.

Cohen, still hesitant, said, “There’s a co-inventor on this, Herb Boyer, and he will have to agree as well.”¹⁸ He would give Boyer a call, and if his coinventor agreed to patent, Cohen would, too.

Herb Boyer, a biochemist at the University of California, San Francisco, was a year younger than Cohen and as ebullient as Cohen was deliberate. “Stan doesn’t tell a lot of jokes,” Boyer once said of his coinventor. “On the other hand, I tell a lot of jokes, and some of them you don’t want to hear about.”¹⁹ Boyer had been a regular participant in the antiwar protests in the Haight-Ashbury district just a few blocks from his lab. When he first peered through his microscope and saw evidence that the recombinant DNA process was working, he started to cry.²⁰

Two years earlier, in 1972, Boyer’s lab had isolated an enzyme that could clip apart a strand of DNA.^II Once clipped, DNA from another source could be inserted.²¹ At the time, Boyer had not known if a molecule with its new “recombined” DNA was a lab curiosity, or if, inside a cell, the molecule (or gene(s) in the recombined DNA) would be reproduced intact as the cells divided.

Cohen, meanwhile, had developed a method that could help resolve Boyer’s uncertainty. He had figured out how to make bacterial cells take up and propagate foreign DNA, specifically a type of DNA called a plasmid. He had also isolated plasmids that could confer resistance to antibiotics. That trait made it possible to identify which bacteria carried the recombinant DNA.

On a break from an academic conference in Hawaii, the scientists had devised a way to help each other. Cohen’s lab would isolate the plasmids and get them to Boyer, who would clip them, insert new DNA, and send the now-recombinant plasmids back to Stanford, where Cohen would introduce them into bacterial cells and see if the recombinant structure reproduced as the cells divided.

Forty miles lay between the scientists’ labs at opposite ends of the San Francisco Bay. It was simple good fortune that Cohen’s research technician Annie Chang lived near Boyer’s UCSF lab and was willing to carry DNA between the labs. She would pack the test tubes in ice inside thermoses and then load them into her Volkswagen Beetle for the drive up the freeway and through the city’s famous hills; and she would do the reverse, as well, carrying materials from Boyer’s lab back down to Stanford. Chang was a key contributor in Cohen’s lab—she plated bacteria, analyzed DNA, offered suggestions, and, in Cohen’s words, “played a central role in the experiments”²²—and she, along with Cohen, watched the bacteria multiply under a microscope, waiting to see if any cells reproduced an exact copy of the hybrid DNA from Boyer’s lab.^I

“We worked literally almost day and night. Things were too exciting for us to get very much sleep,” Cohen recalls.²³ Even the hyperrational scientist wished that there were some way to get the bacteria to grow more quickly.²⁴

At the end of July 1974, Stan Cohen called Reimers. Herb Boyer at UCSF had agreed to apply for a patent.²⁵ Cohen would file an invention disclosure with the Office of Technology Licensing so that Reimers could move forward.

Cohen made one unusual request: he did not want to receive the 33 percent of royalties that would be due to him under the one-third each to the inventor, the department, and the school arrangement that Reimers had devised.²⁶ Cohen remained deeply ambivalent about patenting the recombinant DNA process and agreed to do so only after again reiterating to Reimers that the process he and Boyer had devised “has resulted from the efforts of many.” He would allow Reimers to move forward with the patent application only if it were “made perfectly clear to all concerned that the matter was pursued at the initiative of the University and that I would receive no personal gain from the patent.” Boyer likewise declined any “personal gain.”²⁷

The scientists’ reluctance is understandable. When Reimers asked Cohen and Boyer to pursue a patent, he asked them to break from their discipline’s cultural norms. Although physicists and engineers had long traditions of conducting research with an eye to practical ends, for biologists in the academy, basic research was the sine qua non. In the biological sciences, one scientist recalls, “an aspiration to do something applied . . . was a clear admission of intellectual weakness.”²⁸ Cohen worried that his scientific peers would interpret the patent application as an unseemly overreach, an attempt to claim credit for work that built on the breakthroughs of others. He told Reimers that he would donate his share of any royalties to Stanford.²⁹

At the same time that he agreed to file for a patent, Cohen shared another bit of news with Reimers: along with several colleagues, he and Boyer had published an academic paper on the recombinant DNA process.³⁰

The publication presented a challenge. Inventors have only a year from the first public disclosure of their innovation to file a patent. The paper, published in November 1973, meant that Reimers would have to file an application by November 1974. July was almost gone, and in four days, Reimers was leaving for a long-planned family vacation that would steal another two weeks.

Reimers wasted no time. As soon as he hung up with Cohen, he called the patent office at the University of California. He needed the university to agree to patent the recombinant DNA process, since Boyer, a UCSF professor, would be named as coinventor. Reimers introduced himself to the patent administrator, Josephine Opalka, and asked her to send a letter stating who had sponsored Boyer’s research. Two days later, he received a note naming the sponsors. Opalka would contact them and then “be in touch with you sometime next March.”

March? March was eight months away! Reimers had to file in four.³¹

He dictated a reply to the UC patent office, suggesting how to approach the sponsors. He also offered to have Stanford administer the patent, with any royalties split fifty-fifty after deducting a percentage to cover Stanford’s patent filing and licensing expenses.³²

He then left for vacation. But he did not leave the patent behind. Still unsure of the science behind the breakthrough, Reimers shoved into his suitcase a book Cohen had loaned to him: Molecular Biology of the Gene, a 662-page textbook written by James Watson, one of the discoverers of the structure of DNA.³³

Much like Bob Taylor pulling together computer scientists to develop the hardware and software that would eventually underpin the personal computer industry, Niels Reimers was beginning to knit together the legal, academic, and commercial connections that would underpin the biotech industry. Throughout Silicon Valley, the ground was being prepared for the birth of major industries that would shape the modern world.

When Reimers returned from vacation, he wrote to Stanford’s staff counsel, asking for help in drafting an agreement with the University of California. “I am most anxious to have the arrangement with UC consummated soon and will appreciate your early attention to this,” he wrote.³⁴ He believed that recombinant DNA, like the transistor or silicon microchip, could serve as “the foundation of a major new industry in which the U.S. has the potential for being the leader.”³⁵

Reimers had never before coordinated a patent application with another university. At first glance, the patent office at the University of California shared several features with Reimers’s program at Stanford. Both organizations were small (three people at Stanford, four at UC); both worked with outside counsel, rather than keeping attorneys on their office staff; and both offered a generous share of royalties to inventors. The University of California shared net proceeds with the inventor fifty-fifty, a concession made, in part, because disclosure to the university patent office was mandatory.³⁶

The similarities ended there. Where Reimers asked companies about an invention’s commercial prospects, the University of California’s first step upon receiving an invention disclosure was to send a form letter to faculty experts in the field, asking for comments. The focus at UC thus was more on identifying a contribution to knowledge than on determining practical applications. When university technology licensing officers held their first conference in 1974, the head of the UC patent office warned that “you have to police your licensees” while Reimers urged an “entrepreneurial emphasis” and preached the importance of finding “the best way to market technology” because “inventions are very perishable.”³⁷ The UC office reported to an eleven-person Patent Board that sat inside the UC systemwide office, deep in the bureaucracy endemic to any large public university system. Reimers reported to the dean of research and was in regular contact with top Stanford administrators.

Stanford inventors could choose how or if to patent their inventions, but faculty and staff at all nine University of California campuses had to file invention disclosures with the patent office. That requirement meant each year, the UC staff of four received some three hundred disclosures—about five times what Reimers dealt with. The volume left the UC office so “overloaded with technology that they did not move,” Reimers recalled.³⁸

Administrator Josephine Opalka told Reimers that the UC office had no objection to filing for a patent for the recombinant DNA process, but it could offer only limited assistance. Stanford would have to shoulder the risk. UC would not cover any up-front costs.

Reimers pounced. He reiterated his offer that Stanford would pay all filing and related costs. In exchange, if fees or royalties ever did come from the patent, Stanford would deduct 15 percent off the top to cover the up-front expenses. The remaining 85 percent would be divided among the universities and inventors.³⁹ After a bit of back-and-forth, Opalka agreed.

Reimers was placing a large bet. If the patent was denied or did not yield licensing fees or royalties, Stanford would never recoup its costs, and the University of California would not have lost a penny chasing a failed idea. If, however, the patent proved valuable, Stanford would receive 15 percent of an unlimited upside on top of the 42.5 percent of royalties that would go to the university and its inventors. UC and its inventors would receive only 42.5 percent in all.

In the end, Reimers would win big. The patent ultimately yielded some $255 million in licensing fees and royalties, earning Stanford roughly $40 million from its 15 percent, even before receiving another $107 million from its share of the 85 percent.⁴⁰

Several years after their initial conversations, Reimers says, the University of California complained that Stanford’s 15 percent was “an over-recovery.” Stanford, it said, was getting too much money off the top before the balance was split fifty-fifty between the two schools. “You had your chance,” Reimers told them.⁴¹

As late as September, and with the November patent deadline looming, Reimers was still searching for a clear sense of the commercial viability of the recombinant DNA process, aside from the theoretical “it may one day be possible” list that he had first read in the New York Times article alerting him to the invention. He could not use the practice that had worked so well for the office since its beginning: asking a company in a relevant industry to offer an assessment of the invention. There was no biotech industry with members he could consult. The industry would be born of the patent.⁴² Instead, Reimers had a business school student whom he had hired for the summer talk to Cohen and Boyer about commercial possibilities. ⁴³

He had two months.

“Reimers called me and asked me if I knew what a plasmid is,” recalls Bertram Rowland, a San Francisco–based attorney whose firm had worked with Reimers on several earlier patent applications.⁴⁴ The lawyer had a PhD in organic chemistry and a good knowledge of biochemistry, but his degree was twenty years old, conferred before the discovery of plasmids or the popularization of the term “molecular biology.”⁴⁵ When Rowland admitted that he did not know what a plasmid was “but would find out,” Reimers said he would find another attorney. Rowland countered that because molecular biologists did not tend to take up patent law, his own scientific training was more than Reimers would likely find elsewhere. Reimers gave him the job.

“I had about three weeks to write the case,” Rowland recalled. Working from three academic papers and several conversations with Cohen—“he was teaching me about patents, and I was teaching him about biology,” Cohen recalls⁴⁶—Rowland drew up the application. He sent it, thirty-five pages long, with four carbon copies, to Cohen and Boyer for approval. ⁴⁷

Cohen soon called with a question: Why was Rowland limiting the claims only to recombinant DNA in bacteria? Plasmids occurred in complex organisms, as well. Why not make the patent as broad as possible?⁴⁸

This brilliant suggestion presented a pedestrian problem. Had Rowland been at Xerox PARC, he could have changed the application with a few keystrokes on his Alto. But the personal computer had not made its way down from PARC’s empyrean perch, which meant that making Cohen’s suggested changes would require retyping the entire application. That was “not an alternative in view of the time pressure,” according to Rowland.

His solution was to add a new claim to cover “a cell.” He was confident that this generic term, along with earlier language in the application, “could be interpreted to support [claims] other than bacteria.” He added 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 Cancer Society to waive their interest in the invention to a third sponsor of the recombinant DNA research: the Department of Health, Education, and Welfare. After a single agency had the rights to the invention, it would be much easier for Reimers to petition for the rights to revert to the universities. Without those rights, even if a patent were granted, Stanford and the University of California would receive no royalties.⁴⁹

On November 11, 1974—one week before the deadline—Stanford filed a patent application for “Process and Composition 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.”⁵⁰

Cohen, the Stanford inventor, calls the patent application “truly remarkable,” given the lack of precedent and the need to prepare the application with little time and assistance from only Cohen, who, in his own words, “had little or no understanding of patent law at the time” and wanted nothing more than to “get the application out of the way, and go back to my research.”⁵¹ At the time of the application, Cohen told Reimers that he did not want to be kept informed about Stanford’s licensing efforts and left for a sabbatical in England, staying in touch with his lab via a teletype machine and an Arpanet connection.⁵²

While Reimers, Cohen, and Boyer saw the promise in recombinant DNA, many others saw only danger. The science was new and opened a field that would potentially give humans godlike powers to create never-before-seen hybrid life-forms. Cohen and Boyer’s patent uses one common term for recombined DNA cells: “chimeras,” a reference to the mythical monster with the head of a lion, the body of a goat, and the tail of a serpent.

Months before Reimers heard about Cohen and Boyer’s breakthrough, Boyer had 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 hazardous to both laboratory 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 attorneys, convened at the Asilomar Conference Grounds near Monterey, California. The conferencegoers wrestled with a monumental question: how to proceed safely in the hitherto unimaginable world in which genes could be swapped between species and easily reproduced. The terrifying implications included the possibility of pathogens or drug-resistant genes infecting large segments of the human population. With some scientists urging caution and others eager to press on with research, harsh rhetoric and accusations punctuated many sessions. (“You fucked the plasmid group!” was one comment offered on the floor.)⁵⁵ Both Cohen and Boyer attended the Asilomar conference, and both deplored its unprofessional fractiousness.

On the final day, a majority of the assembled 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 had proposed self-regulation since early in the Second World War, when some physicists had agreed to keep nuclear data from German scientists.⁵⁶ One biologist was so alarmed by the risks that he wrote in Science that the world was now facing “a pre-Hiroshima situation.”⁵⁷ The Stanford biochemist Paul Berg, one of the conference organizers, recalls, “It was the period just after the Vietnam War. People were concerned about doing things that would come back to haunt us.”⁵⁸

The safety concerns presented a special challenge for Reimers. Paul Berg, the leading voice of the scientists urging self-regulation for recombinant DNA research, was also an esteemed member of the Stanford faculty. Berg was not concerned that recombinant DNA research posed dangers to the general public, but he feared that if the scientists did not regulate the research themselves, the science-unfriendly Nixon administration would do it for them.⁵⁹ To anyone looking at the situation from outside, however, it appeared that Stanford, led by Reimers, was attempting to garner profits from a breakthrough that deeply concerned one of the university’s own top research scientists.

When Reimers joined several contentious meetings in Berg’s office, the subject was not safety or self-regulation but patent law and claiming credit. Berg, along with two Nobel laureates on the Stanford faculty, Joshua Lederberg and Arthur Kornberg, had shared Cohen’s concern from the beginning—that the process, a basic building block of science, never should have been patented in the first place. The mission of a university is to increase 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.”)⁶⁰ This objection echoed an anonymous reviewer of the patent application at the University of California who wrote, “I am concerned that given the fundamental nature of the work and the number of scientists involved, either directly or indirectly, that this patent will not reflect favorably on the public service ideals of the University.”⁶¹

These issues were of such importance to Stanford that the university provost attended at least one of the meetings in Berg’s office. In February 1975, Reimers agreed to discuss with the vice provost for research whether the patent application should be turned over to Research Corporation or even abandoned.⁶²

It was a delicate balancing act for Reimers. He wanted to patent the process. He needed to do so without undermining the protocols of open science, skewing incentives for Stanford research, alienating top faculty, or undermining the very premise of the university.

Reimers, who had built an innovative, entrepreneurial office that embraced the get-it-done spirit of the nearby startup companies, now juggled two inventors, two universities, three sponsoring agencies, a legal team, the U.S. Patent and Trademark Office, objecting scientists, advocates convinced that Stanford had no right to patent an invention supported by public money, and a global research community with some members concerned that the invention could irrevocably alter life as we know it.

At the same time, he was running an office, sifting through roughly six patent disclosures each month, helping to launch the Association of University Technology Managers, and trying to convince companies around the world to license other Stanford-patented inventions.⁶³

Reimers was certain that the DNA patent was worth the extra demands, even as he claimed to be working on another 130 projects.⁶⁴ He told one Stanford administrator, “This is an invention of the sort that, if it pays off, will pay off big.”⁶⁵ He told another that “the recombinant DNA invention has the potential for being Stanford’s most important-ever invention in terms of income potential [. . . and] the most important in terms of potential public impact.”⁶⁶

The desire for “public impact” motivated Reimers in everything he did at the Office of Technology Licensing. In general, he believed that corporations were the best vector for transferring academic ideas to the broader public, and he was willing to fight anyone—the university, the patent office, government officials—who disagreed with him. The patent counsel for the Department of Health, Education, and Welfare, who called Reimers “the number one 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 of incentive in developing them.”⁶⁸ He wanted the Office of Technology Licensing to provide the necessary incentive by connecting interested companies to important ideas that could improve people’s lives. Mindful of the sign on the wall of his trailer office, he was determined to MAKE IT HAPPEN.

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I. Cohen later promoted Chang to the position of assistant.

II. The restriction enzyme, called EcoR1, cuts DNA at a specific place in the molecule. Janet Mertz in Paul Berg’s lab at Stanford used EcoR1 to develop a highly efficient genetic “cutting and pasting” technique.