Career QnA

Read about the career choices our mentors have made to become established biotech professionals. Each month, a new mentor will share their career journeys and advice for those wishing to follow in their footsteps.

Dr. Julian Davies

Jessica Zhang - Sunday, July 31, 2011

As a distinguished Professor Emeritus in the Microbiology and Immunology department at the University of British Columbia, Dr. Julian Davies has led an amazing career and shares his experiences in biotech with us.  We are led into the height of research in antibiotics and vaccines with regard to the growth in the biotechnology industry in the late 20th century through this month's Career Q&A

My life and good times in Biotech.

In 1956 I obtained my PhD in Organic Chemistry at Nottingham University, having worked on the chemical synthesis of two fungal products, flaviolin and sterigmatocystin. We had no idea that the latter molecule was the immediate precursor of the highly toxic aflatoxin! I produced many grams of sterigmatocystin by fermentation in large flasks and submitted the compound to various forms of chemical modification and degradation, such as hydrolysis, methylation with dimethyl sulfate and reduction using a variety of reactions. Everything was weighed in open balances with spatulas that were usually wiped out on one's tie (required dress in the lab; lab coats were non-existent). Precautions were few and far between, but apart from a few burned hands, we all survived. Postdoctoral positions followed, at Columbia University in New York and the University of Wisconsin Madison, to learn more about organic synthesis. No one thought about how and why the compounds were made.

In 1959 I returned to the UK for a lectureship in chemistry at the University of Manchester Institute of Technology. General dissatisfaction with what was being done in organic chemistry in Manchester led me to an interest in the biosynthesis of natural products.  A well-known microbiologist at Manchester University, Milton Salton, invited me to work in his lab in my spare time to learn about growing bacteria, isolating cell walls and organelles.  In a short time I was hooked, and Milton arranged for me to go to the lab of Bernie Davis in the Department of Bacteriology and Immunology at Harvard Medical School where I worked on the mode of action of the antibiotic streptomycin; this was really exciting stuff! After 3 years I moved on to the lab of François Jacob at the Pasteur Institute to learn some bacterial genetics.

I finally embarked on a serious career in 1967 when I accepted a position in the Biochemistry Department at the University of Wisconsin, arriving in Madison just as antiwar riots were beginning. Antibiotic resistance was becoming an increasingly serious problem in the late 1960s and I secured funding to work on the topic. This was an exciting time in science. Molecular biology was becoming the vogue (much to the chagrin of the fusty old biochemists) and in 1973 the work of Cohen and Boyer laid open the wonders of recombinant DNA. Our work on antibiotic resistance and transposons was of great interest with respect to horizontal gene transfer, and since I knew something about cloning, I participated in the 1975 Asilomar Conference, setting out the first recommendations (“restrictions”) for recombinant DNA research. We were already cloning antibiotic resistance markers into plasmids and were routinely using cloning for a variety of research topics in the lab. (A good friend of mine in Madison cloned turkey DNA into E.coli for US Thanksgiving in 1976!) Given the importance of specific DNA cutting to genetic manipulation, we came up with the idea that hospital isolates of bacteria would likely possess different kinds of restriction enzymes; having a good collection of strains and a simple way for identifying restriction patterns, one of my students quickly discovered PstI, KpnI, and MboI activities in 1976.

In the mid 1970s the biotech business began and companies were founded (mostly in California) to exploit recombinant technology; one of my best postdocs was hired away (abruptly) by Cetus and several students left to join Genentech and other start-ups. I kept up with what was going on and could not ignore the excitement over the potential of recombinant DNA technology; the beginning of nucleic acid sequencing introduced an additional dimension. My lab in Madison produced novel selective markers for cloning and we worked for a while with geneticin combined with an inactivating enzyme as a eukaryotic selection. I suggested that resistance genes could be patented for such purposes, but the University of Wisconsin was not interested, so I gave the recombinant plasmid to Paul Berg (Stanford) to try out in SV40 cloning experiments; it worked well. Geneticin is now widely used in recombinant DNA work with eukaryotes. All this added to my enthusiasm for the new field.

In 1980, Biogen, the newest of the biotech companies, advertised in Nature for a research director for their new lab in Geneva, Switzerland. I knew that they had won the race to clone alpha-interferon, a potential anticancer drug, and wrote to ask for more information about the position. To my surprise, Wally Gilbert, one of the founders, phoned me with an invitation to go to Geneva to take a look at the company. There were only 6 people in the lab at the time, but the prospects were exciting and when offered the job, I was happy to take on the challenge of building up the company and overseeing the development of the new boy on the block.

The first project was to hire more people, such as cloners, microbiologists, protein chemists, DNA sequencing experts, fermentation specialists and the like. A considerable amount of time was spent interviewing, listening to seminars, wining and dining. The positions we offered were attractive: all scientists were encouraged to spend 20% of their time on a project of their own; most did so and ended up publishing their findings. Two of my graduate students from Wisconsin finished up their PhD projects in Geneva.

Winding down the lab in Madison took a year and I had to go back now and then. Since the ice cream in Geneva paled in comparison with that made in Madison, we worked out a scheme to bring it on the plane without dry-ice: freeze the pots overnight at -80 and check them through on the plane in a polystyrene carton. By the time I arrived in Geneva the next day, it was perfect for eating!

Many new facilities were required for the production of eukaryotic proteins in bacterial hosts on a large scale and other projects concerning human insulin production and the cloning of antigens from foot-and-mouth disease and human hepatitis B viruses, all in E. coli or B. subtilis. As time went on, the company expanded in personnel and expertise and soon there were 100 employees and we had to find additional space. We needed room for clinical specialists who were running early stage clinical trials, more lawyers, business development experts and the like. Fortunately the labs maintained an academic-like atmosphere and we always attracted good visiting speakers.

Like the other early biotech companies Biogen had its own character and culture. For example, the company was set up initially with all research work being done in the university laboratories of the founding members of the Scientific Advisory Board. This was good in principle: things got going quickly. However, the development of the projects when they were transferred to the main lab in Geneva was not always effective. The SAB was largely a group of scientific prima donnas who wanted to maintain oversight of the work they had started, especially once we got things working properly. Biogen was the only biotechnology company that approached its science in this way.

In the company we were all good friends, enjoying ski days, picnics and excursions to the Rhone Valley to taste wine. Everyone was inspired to succeed for the company's sake. We did some terrific research. Alpha-, beta-, and gamma-interferon genes were cloned and expressed, all still employed for a variety of applications (more than we expected, in fact). We cloned and produced interleukin 1, 2, and 3, and tumor necrosis factor for which good applications are still being sought. We had trouble making a useful high-level insulin-secreting E. coli strain and were beaten to the goal by Zymogenetics in Seattle, who did the work in yeast. The search for a foot-and-mouth disease vaccine was discontinued after a couple of years, but we were successful with hepatitis-B vaccine. We travelled the world telling companies that they needed to switch to the use of recombinant DNA technology for success, and that Biogen was the group to do it! As a result the company had projects from companies in many countries: USA, Britain, Germany, Switzerland, Japan, Italy and Canada. Of course, Cetus, Genentech, Amgen and the others were all doing the same thing and we often crossed paths in airport lounges and shared experiences! We even worked for some time to improve microbiological processes for extracting nickel and to develop various ways of converting waste plant biomass with methanol for fuel. Biofuels were of some interest in the early 1980s and we had a well-funded project relationship on this, but the concept never caught on; progress was just too slow in a fast-moving business. Biogen also did a lot of work on using recombinant technology to make short bioactive peptides (hormones); one day in 1984 when we were low on cash (below $20 million?) and getting a bit desperate, we decided that vasoactive intestinal peptide (VIP) would be a great product for the treatment of erectile disfunction and produced the peptide in E. coli.  It never became a product because it was reported that the erections were apparently of such long duration that the subjects had a difficult time getting dressed the day after. 

One of the projects that gave me the most satisfaction was to improve the production of the antibiotic/herbicide bialafos by Streptomyces hygroscopicus. A Japanese company wanted us to try the recombinant approach and compare it with the traditional mutational method. Everyone came into the lab one Saturday morning for a mass colony-picking orgy to screen for mutants. The project had an unexpected benefit in the cloning of the endogenous resistance gene that could be used to confer resistance to the herbicide when cloned in plants. This latter project was in collaboration with a Belgian company PGS, who licensed out the gene and started to earn some money on it. Charles Thompson ran this project.

But all good things come to an end, and in 1985 Biogen was becoming too big, too clinical, and too US-based for me. A laboratory had been set up in Cambridge, Massachusetts in 1982 and I had to make frequent trips there. The Geneva lab was not given the good projects and I was getting frustrated, so I decided to leave at a time when the Pasteur Institute was looking for someone to form a unit in their new Batiment de Genie Microbiologique. I was asked to go there and that was that.

The early days of the biotech industry were exhilarating and rewarding. All the companies were doing things ahead of their time. It was somewhat of a roller coaster existence but we learned a lot quickly. Interestingly, of the "original" large biotechnology companies, only Amgen and Biogen remain independent – and are doing well. I would ride the roller coaster again if I had the chance. Come to think of it, I did when we started TerraGen in Vancouver in 1995 – however, that's another story.

Last but not least, I was partnered during these exciting times by my wife, Dottie. I don’t think they would have happened without her help and encouragement.

Julian Davies, Microbiology and Immunology, UBC

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