By Tim Harris, PhD, DSc
Being a child of the sixties in the United Kingdom, I am—to no one’s surprise—into cars, rock music, and all things DNA. In 1970, I travelled to Le Mans to watch the 12-cylinder “long tail” 917 Gulf Porsches and 512S Ferraris fight it out. This turned out to be one of the most iconic races of all time—the first outright win at Le Mans for Porsche (Figure 1) and the backdrop for Steve McQueen’s subsequent Le Mans film.
I’m still thrilled when I remember those cars roaring down the Mulsanne Straight (no chicanes in those days) at over 230 mph. And I still visit Le Mans from time to time. Every year, I listen to the race over Radio Le Mans, which reminds me of
almost-forgotten details—the café noir and baguettes that were served at 4 am, the pelting rain that fell during the afternoon and evening.
Back then, you would commit to memory important facts, such as the names of drivers and the makes of their cars. You couldn’t rely on Wikipedia to do your remembering for you—though of course, now you can. (Look up the Wikipedia article titled, “1970 24 Hours of Le Mans.”)
I could easily compile a soundtrack of the time—the Rolling Stones, Eric Clapton, and other heroes of blues and rock music. Others might like to consult, yes, Wikipedia. Besides reminding us of what was playing in 1970, Wikipedia can tell us all about the careers of the leading players. It has an article that tells us, for example, that Christine McVie was Christine Parfitt before she joined Fleetwood Mac and married John McVie. And the article on Eric Clapton informs us that he played for the Yardbirds, John Mayall’s Bluesbreakers, Cream, Blind Faith, and Derek and the Dominoes. It even tells us about his guitars (Figure 2).
By preserving so much detail, Wikipedia makes it easy to recreate the popular scene of the 1970s and how it evolved. If only Wikipedia did the same for the biotechnology scene! Granted, there are Wikipedia articles about some of the biotechnology-related events and figures from the late 1970s and early 1980s. For example, Wikipedia tells us that Genentech was founded by Robert Swanson, a venture capitalist, and Herbert Boyer, a professor of biochemistry at UCSF.
Such figures, however, are practically household names. Surely, Wikipedia could go a little deeper. It could tell us more about the people who frequented the early British biotechnology scene. They are less well known but still important to biotechnology in general and Britain’s biotechnology industry in particular. One day, these people may receive their due from Wikipedia, but until then, this article will have to suffice.
Starting out at Pirbright
I started in biotechnology back in 1978, cloning bits of FMDV RNA with a view to making a vaccine from VP1, one of the capsid proteins. I worked at the government establishment at Pirbright in Surrey called the Animal Virus Research Institute, now part of the Institute for Animal Diseases. As it turned out, our work wasn’t unique. A project like ours had been undertaken by Genentech, which was working with Plum Island—the U.S. equivalent of Pirbright.
I remember a visit to Pirbright by Dennis Kleid, who along with David Goeddel was one of the first employees at Genentech, eager to learn what we were doing. He and Goeddel were also responsible for the initial cloning of the insulin gene from synthetic DNA to develop one of the first products from recombinant DNA technology.1 Kleid later became the most senior patent attorney at Genentech. Goeddel, with Bob Tjian, went on to found Tularik, which was eventually sold to Amgen. (Kleid is now retired, and Goeddel is a managing partner at the Column group.)
The initial cDNA library we made at Pirbright was in a plasmid called pAT 153 (a U.K. derivative of pBR322 named after Francisco Bolivar Zapata and Raymond L. Rodriguez from Boyer’s lab). Our first library had (if I recall correctly) 257 clones and was made from pure FMDV RNA, a picornavirus—a positive-strand RNA virus. As it turned out, the library covered virtually the entire virus RNA including the piece coding for VP1. We did make VP1 in Escherichia coli and refolded it, but we never got any immunity that made any difference in animals, and neither did anybody else.
Despite the occasional setback, it was a very exciting time in the laboratory. Spurred on by initial interactions with Genentech and the prospect of being able to apply recombinant DNA to make therapeutic proteins like growth hormone and tissue plasminogen activator, I joined the fledgling British industry by moving to Celltech in April 1981.
Becoming part of the Celltech team
Celltech, a brainchild of Sydney Brenner, had been formed in November 1980 with close ties to the Medical Research Council (MRC) and with Gerard Fairtlough, recruited from Shell, as the founding CEO. The company was located in Slough, near Heathrow Airport, made famous as the site of the fictional paper company in Ricky Gervais’ The Office. Unlike the paper company (where “life is stationery”), Celltech was always meant to go places.
Celltech was formed with what at that time was a very large Series A round of £12 million ($27.6 million), which was provided by blue-chip British investors who were persuaded by the vision of biotechnology changing the world. They included Prudential Assurance, British and Commonwealth Shipping, Midland Bank, and the National Enterprise Board, which was the precursor of the BTG and formed by the Labor government to stimulate innovation in industry. (I have no idea whether any of these investors made any money from their Celltech investments.)
You can access some of the history of Celltech from Wikipedia and learn how after a bunch of acquisitions, including that of Chiroscience, it became part of UCB. The founding head of R&D at Celltech was Norman Carey, who brought several people with him from a team at G.D. Searle (later Monsanto), including Mike Doel, Spencer Emtage, and Mike Eaton (a chemist), to form the nucleus of the first Celltech R&D team in November 1980.2
When I joined in early 1981, we started in an old Richardson Merrell (of Vicks’ fame) research building on Bath Road with wooden polished benches. Nothing like the startup space here now in Cambridge, MA. Richardson Merrell became part of Marion Merrell Dow, then Hoechst and Aventis, and now Sanofi-Genzyme.
Cloning everything that moved
At Celltech, I was responsible for running the cDNA cloning lab. Many people who have gone on to do great things in the industry (including Mark Bodmer and Simba Gill, both now at Evelo, and Tim Wilson, currently the CEO of Epsilogen) spent time in my laboratory. Our motto was: “If it moves, we clone it.” We cloned a lot of genes as cDNAs from both plasmid and lambda GT10 libraries: dog-eared copies of the Tom Maniatis cloning manual sat on almost every laboratory bench (Figure 3).
Our first project was to clone the enzyme calf chymosin, a major component of the “essence of rennet” solution that is used to clot milk in the first steps of cheese making. The first mRNA extraction at Celltech was from mucosa from the fourth stomach of the week-old sucking calf stomach (courtesy of a trip to the AFRC Institute for Animal Health at Compton, where calves were slaughtered every week). We used the old phenol/m.cresol methods (the Kirby procedure) that I’d first used to extract nucleic acid from rat liver at the Chester Beaty laboratory in Pollards Wood, when I was still at school and working in a laboratory with Roger Kirby (Ken Kirby’s son and now president of the Royal College of Medicine) when we were both 16.
We ended up cloning the enzyme successfully and were able to make the active enzyme from E. coli. It was a great occasion when we all got together for a wine and cheese party, not only to eat cheese that we had made with our recombinant enzyme at the Dairy Research Institute in Shinfield, but also to celebrate a paper that we had written and that was to appear in PNAS.3
Engaging in friendly competition
Prominent competitors based in the United States included Genentech and Genetics Institute—founded in 1980 by Maniatis and Mark Ptashne and later bought by Wyeth (now Pfizer) and Biogen (founded in 1982). Genentech won most of the races that we were all involved with. Biogen was a key player, but most of its early discoveries (such as interferon beta and hepatitis B surface antigen) came from the laboratories of their founders, who included Phil Sharp, Wally Gilbert, Charles Weissman, Ken Murray, and Heinz Schaller.
Coincidently, some of that cloning in the late 1970s and early 1980s was done at the Microbiological Research Establishment at Porton Down (now a Public Health England laboratory), where my father Bob Harris was the director. This site was used largely because it had a Containment Level 4 laboratory and was able to abide by the “GMAG” cloning rules, which reflected the guidelines that had been developed at the Asilomar conference organized by Paul Berg in 1975.
Around this time, several lines of inquiry were pursued by several scientific teams simultaneously. For example, hepatitis B surface antigen for use as a vaccine against hepatitis B infection was investigated by multiple companies, including Genentech (where Art Levinson and Kleid were working) and Chiron (which was collaborating with Bill Rutter’s UCSF laboratory), as well as by Ken and Noreen Murray in Edinburgh.
At Celltech, we cloned cDNAs coding for several important proteins including tissue plasminogen activator (as did everyone else, including Joe Sambrook and Ashley Dunn), various metalloproteinases, Factor I and Factor H, and glutamine synthetase. The last was a good example of a project that turned out to be quite important commercially but was an unsanctioned skunkworks project.
Peter Rigby (who was on the Celltech SAB with Sydney Brenner), Spencer Emtage, and I were having a conversation over coffee about amplifiable systems that might compete with the methotrexate/DHFR system used by many to amplify plasmid-derived sequences in CHO cells. We came upon glutamine synthetase. This glutamine synthetase gene could be amplified like the DHFR gene using a transition state analog methionine sulphoximine.
A group in Scotland (Richard Wilson’s laboratory) was cloning the glutamine synthetase gene found in CHO cells that overproduced glutamine synthetase, and we ended up cloning the cDNA (rather easily) from a large lambda gt10 library.4 Chris Bebbington and Spencer Emtage then made an amplifiable gene from the cDNA and a segment of genomic DNA (using a shared Kpn1 site) and showed that this construct amplified genes as well if not better than the DHFR/CHO system and was at the same time proprietary to Celltech. The technology was ultimately licensed to Lonza and is still available today (the GS Xceed® Expression System).
Working on humanization
Celltech used it for many of the recombinant antibody projects that were started in the mid-1980s by Mark Bodmer and members of his team, who were some of the first (other than Greg Winter at the MRC) to use CDR grafting and other humanization techniques on cloned cDNAs coding for mouse monoclonal heavy and light chains. The antibody projects originated at Celltech largely because we were working with the MRC Laboratory of Molecular Biology to grow Campath1 (an anti-CD52 antibody derived from a rat antibody raised against human lymphocyte proteins by Herman Waldmann at Cambridge) and other antibodies. This work began in 25-L stirred vessels and eventually moved to airlift fermenters in our manufacturing suite.
Some of these recombinant antibody humanization studies continued at the MRC technology site in Mill Hill (by Chris Hentschel and his team). This resulted in considerable royalties accruing to that organization from the humanization of pembroluzimab, which in turn led to the creation of Life Arc, a prominent British venture investor.
Parting ways with Celltech
In 1987, Celltech moved to the new building at 216 Bath Road. One year later, I moved to Glaxo Group Research. In those early years, several British biotechnology companies were created including British Biotechnology (which was formed in 1986 by G.D. Searle alumnus Brian Richards) and Cambridge Antibody Technology (which was formed in 1989). British Biotechnology folded into Vernalis without ever achieving much. In contrast, Cambridge Antibody Technology was very successful. It became part of MedImmune and was involved in the creation of both Humira and Benlysta.
References
1. Riggs AD. Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin. Endocr. Rev. 2021; 42(3): 374–380.
2. Biotechnology: Celltech set up. Nature 1980; 288, 110–111.
3. Emtage JS, Angal S, Doel MT, et al. Synthesis of calf prochymosin (prorennin) in Escherichia coli. Proc. Natl. Acad. Sci. USA 1983; 80(12): 3671–3675.
4. Hayward BE, Hussain A, Wilson RH, et al. The cloning and nucleotide sequence of cDNA for an amplified glutamine synthetase gene from the Chinese hamster. Nucleic Acids Res. 1986(2); 14: 999–1008.
Tim Harris, PhD, DSc, is executive vice president at Repertoire Immune Medicines, Cambridge, MA. He has held leadership roles at many biotechology companies, including Biogen, Structural GenomiX, Sequana, and Celltech. Email: [email protected].
