The Story of Biotechnology

Although the story of biotechnology began much earlier, it was Jim Watson and Francis Crick's 1953 announcement of the structure of DNA that made the new biology a public issue.^[1] The double-helix model they described was simple and eloquent. It provided an explanation for the replication of life at the molecular level.

An avalanche of research followed, but it was not until 1972 that Paul Berg and colleagues at Stanford University developed techniques to "cut and paste" DNA, creating the first recombinant DNA molecule containing DNA from two different species.^[2] As an analogy, think of editing an audiotape. Suppose you cut the tape with a pair of scissors at a point between two songs, insert a new piece of tape with a new song at the cut, and use an adhesive to join the ends together. If you insert the spliced tape into a tape recorder, you'll hear a different sequence of songs.

Even at this early stage, Berg postulated that recombinant DNA technology could provide a pathway to gene therapy. Berg shared the 1980 Nobel Prize in chemistry for this pioneering work. In 1973, Herbert Boyer (of the University of California, San Francisco) and Stanley Cohen (of Stanford University) were credited with being the first "genetic engineers"; they used restriction enzymes to selectively cut and paste DNA and then inserted the new DNA into bacteria, which, by reproducing, made millions of copies of the new DNA. In effect, this was the creation of a DNA factory.^[3]

The news spread. Advances in recombinant DNA were exciting and yet frightening. Scientists, then the news media, and finally Congress became concerned about the implications of gene manipulation. Would it create a modern Frankenstein's monster? What controls should be imposed? In early 1975, more than 100 interested parties from around the world, guided by the leadership of Paul Berg, met at the Asilomar Conference Center in California to debate the promise and pitfalls of recombinant DNA.^[4] The recommendations of the meeting were sent to the National Institutes of Health (NIH) and served as the basis for the official guidelines for the technology, published in 1976.^[5]

Boyer and Cohen's success in inserting a gene into bacteria aroused the interest of a young venture capitalist, Robert Swanson, from San Francisco.^[6] In 1976, Swanson's question was, how could the Boyer-Cohen technology be used to produce a marketable protein product, perhaps a therapeutic product such as human insulin? In April of that year, Swanson and Boyer each invested $500 to create Genentech, the world's first biotechnology company. Competition quickly followed, with the formation of Biogen. The flag of the biotech industry had been planted, and the first goal was to create human insulin.

Genentech and Biogen chose different technical paths to this common goal. Genentech focused on chemically synthesizing the human insulin gene, whereas Biogen relied on cloning techniques. The chemically synthesized gene would escape the NIH safety regulations, but the cloning of the human gene would be subject to the NIH controls.

At the time, Genentech was a company in name only. It had no staff, no facilities, and no money. Boyer turned to Arthur Riggs and Keiichi Itakuratwo colleagues at the City of Hope National Medical Centerand asked whether they would accept a contract to synthesize the human insulin gene. Riggs and Itakura were in the process of writing a grant proposal to the NIH for the synthesis of the human hormone somatostatina simpler task, but one that would demonstrate the pathway to the synthesis of insulin.

Riggs answered Boyer's question with a question: Would Genentech be willing to sponsor the somatostatin project first? The answer was yes, and the Genentech and City of Hope teams joined forces. Soon thereafter, Riggs and Itakura inserted a 21-nucleotide-long strand of DNA into E. coli bacteria, and with the collaboration of Herb Heyneker, a young chemist from Boyer's lab, they demonstrated for the first time that man-made DNA would function in a living cell.

Sixteen months later, the combined team successfully synthesized a gene for somatostatin, cloned it, and expressed the somatostatin protein hormone in bacteria.^[7] This was the first time anyone had successfully expressed a protein of any kind in genetically engineered bacteria. The race for human insulin accelerated.

The Riggs-Itakura technology was remarkable because it was a general technique, one that could be used to manufacture most proteins in a bacterial host. It resulted in numerous U.S. and foreign patents, from which billions of dollars' worth of pharmaceutical products have been developed. In the meantime, the NIH turned down Riggs and Itakura's grant proposal on the grounds that it was too ambitious and without practical purpose!

With the somatostatin success, Swanson began to raise funds in earnest, holding out the real promise of human insulin to investors. By June 1978, Genentech was hiring scientists and had built a laboratory facility near the San Francisco airport. Three months later, near the end of August, the combined City of Hope and Genentech team had produced human insulin from a synthesized gene. The improbable had become reality.

The story of Genentech and the launch of the biotech industry is well told in histories by Hall and by Evans.^[8], ^[9] It is the story of basic science from an academic environment turned into a phenomenal business success. It is the story of an industry starting from scratch, not a spin-off from a mature business sector, as with pharmaceuticals.

Today, nearly thirty years later, biotechnology is on its way to being a trillion-dollar industry producing hundreds of therapeutic and biological products.^[10] As we anticipate the future development of nanotechnology, lessons from the biotechnology revolution can offer a useful perspective, particularly with respect to two concepts fundamental to an understanding of technology innovation and commercialization.