A Noble Pursuit: Biotech Pioneers Remembered

The death of William (Bill) Rutter at the grand old age of 97 in July reminded me to remember not only him, but several of the other pioneers of our industry—lest we should forget them.

In the late seventies, Bill was an important player in the cloning of the insulin gene. His group at UCSF, with Howard Goodman, was determined not to be left behind in the exploitation of the new recombinant DNA techniques. They actively competed with the Biogen group led by Wally Gilbert (now 93 years old) and with other people in the Biochemistry department at UCSF to clone the cDNA for rat pre-proinsulin, as a route to the human version. They lost the race to a product from Genentech, who made a chemically synthesized DNA copy of the A and B chain coding sequences, which was subsequently expressed in E. coli and refolded into insulin.^1,2

The Rutter UCSF group were successful in cloning the hepatitis B surface antigen and its expression in yeast at the same time in the late seventies as Ken Murray’s (died in 2013) group and Biogen in Edinburgh, and the Pierre Tiollais (died in 2024) team at the Pasteur Institute in Paris. This was the second recombinant DNA product to be approved after human growth hormone.^3-6 Bill was also involved in cloning growth hormone and forming relationships with Lilly while at UCSF.

In 1981, Bill set up Chiron with Ed Penhoet and Pablo Valenzuela (both now 84 years old). Chiron was very active in the infectious disease space and was responsible for both the cloning of the hepatitis C virus and for helping to sequence the HIV genome. They acquired Cetus, which was founded by Ron Cape (died in 2015) in 1971 B.C. (before cloning). Cetus was the company that did the second and largest (over $100 million) biotech IPO at that time in 1981, orchestrated by the infamous Lehman banker Fred Frank (died in 2021) after Genentech went public in late 1980. By acquiring Cetus, Chiron acquired the PCR patents, based on the work of Kary Mullis (died in 2019), which were subsequently licensed to Roche. Chiron also obtained recombinant IL2 (Proleukin) as part of the deal.

As chairman of the Chiron board and still active at UCSF, Bill was a prime mover in all these activities. I met him when Structural Genomics acquired Prospect Genomics, a computational protein structure design company (it would be called an “AI company” these days). Among other things, Bill taught me to be wary of liquidation preferences, which are not just about liquidation. According to Google Gemini, which summarizes liquidation preferences better than I can: “Liquidation preferences determine the order in which investors are paid out when a company is sold or undergoes a liquidity event. They prioritize preferred shareholders, like venture capitalists, over common shareholders (including founders). This means preferred shareholders receive their initial investment (or a multiple of it) back, plus any accrued dividends, before common shareholders get any proceeds.” As a common shareholder or founder, it is important to realize what your investors might get in returns before you do!

David Baltimore, another biotech pioneer, died just last month. He was there at biotech’s beginning, being the discoverer of reverse transcriptase with Howard Temin and the recipient (with Dulbecco and Temin) of the 1975 Nobel Prize in Physiology or Medicine. Discovered in retroviruses, this enzyme was fundamental to recombinant DNA research by providing a way to synthesize DNA from a mRNA. The resulting DNA could be made double stranded using DNA polymerase and subsequently cloned. David was a prime mover at the 1975 Asilomar conference on the safety of recombinant DNA technology with Paul Berg (died 2023).² He had an outstanding research career at the Rockefeller, MIT, The Whitehead Institute, (founding director), and at Caltech, where he was President until 2005. David was involved in the seventies with the company Collaborative Research and he co-founded CalImmune (HIV gene therapy), s2a Molecular, and Immune Design, a precursor to most of the immunotherapy (CAR T) companies. Many obituaries are and will be written about his importance to advances in molecular biology. I last met him in Greece in 2024, when he told me he was writing a book about his life. I hope he had time to do that, given his many achievements.

Biotech Blues

This is not about the state of the industry under the present U.S. administration, but it is related to the above in remembering people who were important to our Industry. Although the birth of Rock and Roll and Blues music predates biotechnology, some of the artists who were important, and who we listened to while cloning genes in the lab or doing biotech deals in the office, are also aging and dying. It is quite interesting to do a Wikipedia search of some of the musicians and see who played for what bands and how different bands emerged after success or failure. Not dissimilar to the biotech industry, where some companies were founded by successful entrepreneurs who brought their co-conspirators into their new “band.” If you read the Wikipedia entry for Eric Clapton for example (who is still going strong at 80), you will see that he played for the Yardbirds and the late (died in 2024 at age 90) John Mayall’s Bluesbreakers (see the famous Beano album) before forming Cream.

Please forgive the somewhat U.K.-biased version of events. I grew up there, and Clapton and Dire Straits were what I listened to, although I was aware of U.S. bands such as Love, Steppenwolf, Canned Heat, Santana, and The Eagles, along with Canadian bands like Foreigner and Bryan Adams. I remember listening to the track Telegraph Road in 1985 while at Celltech. I reflect now on the story told in the song and think that the biotech road is similar, with companies being built on both sides of the road as time goes by—not driven by the telegraph or telephone but by biotechnology. Maybe there should be a song called Kendall Square or South San Francisco Blues, evocative of the parts of the biotech industry that have been built there and 50 years later are still going strong.

I don’t know what you emerging biotech pioneers listen to these days while doing your work, but I hope you and your music will be remembered, too.

References

1. Hall S. Invisible Frontiers: The race to synthesize a human gene. New York:Atlantic Monthly Press;1987.
2. Harris T. In pursuit of Unicorns: A journey through 50 years of Biotechnology. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2024.
3. Burrell CJ et al. Expression in Escherichia coli of hepatitis B virus DNA sequences cloned in plasmid pBR322. Nature. 1979; 279:43-47.
4. Charney P et al. Cloning in Escherichia coli and physical structure of hepatitis B virion DNA. Proc Natl Acad Sci USA. 1979;76: 2222-2226.
5. Valenzuela P, et al. Nucleotide sequence of the gene coding for the major protein of hepatitis B virus surface antigen. Nature. 1979;280:815-819.(Rutter)
6. Pasek M et al. Hepatitis B virus genes and their expression in E. coli. Nature. 1979;282:575-579.

Tim Harris, PhD, is a British biotech veteran entrepreneur and author of “In Pursuit of Unicorns” (Cold Spring Harbor Lab Press, 2024).