A look back at the Canadian roots of the biotechology revolution.
By Tyler Irving
There are few better examples of Canadian chemical innovation than that of Kelvin Ogilvie. A Nova Scotian by birth, 69-year-old Ogilvie has been a chemistry professor at the University of Manitoba, McGill University and Acadia University, serving as president of the latter from 1993 to 2003. In 1981, Ogilvie was part of the team that created the Gene Machine, the first device to provide accurate, fast and inexpensive synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequences. He was appointed to the Canadian senate in 2009 and inducted into the Canadian Science and Technology Hall of Fame in late 2011. ACCN spoke to Ogilvie about how his innovation started the biotechnology revolution, and what today’s researchers can learn from his experience.
ACCN What was the field of DNA synthesis like when you got started?
KO By the 1970s, biologists had figured out how to use enzymatic tools in bacteria to cut open their DNA and to splice in genes from other organisms. The problem was that they couldn’t get their hands on synthetic genes. You had to somehow isolate a gene from a natural source, which was very complicated. It would be much easier if you could simply push a button and make the gene you wanted. But the methods we had were very inefficient. They were low-yield and time consuming, with some steps taking as long as 24 hours. To put it in perspective: putting together a 12-unit piece of DNA would have taken a team of highly trained post-docs roughly three to six months. Even the smallest genes have more than 100 units in them. Those methods would clearly not be the ones that would ultimately allow scientists to synthesize DNA and RNA sequences of any length.
(L to R) Kelvin Oglive, instrumentation specialist Peter Duck, and entrepreneur Robert Bender pose in front of the Gene Machine in 1980. The machine had just demonstrated the first fully automated synthesis of a 10-unit sequence of DNA.
ACCN How did you approach the problem?
KO I started by looking at RNA. Its monomer units are similar to those of DNA, but it has an extra hydroxyl group in the 2’ position of the ribose sugar. Because of that, RNA is harder to synthesize and less stable than DNA. I knew that if I found a highly efficient way of putting RNA units together, DNA would be a piece of cake.
The big issue was the problem of finding a protection system for the various functional groups of the RNA monomer units, for example, to keep that problematic 2’ hydroxyl group from reacting until it was the right time. I identified alkylsilyl protecting groups that were really efficient and stable and yet easily removed at the end without degrading the RNA chain. The group of choice for me was a tertiary butyldimethylsilyl protecting group. We attempted to use that with various coupling methods for the monomers that were being developed in different laboratories. Robert Letsinger from Northwestern University had come up with a phosphate coupling procedure for putting DNA units together and I instantly recognized that it would be compatible with my silyl protecting group system. We tried it with RNA and it was a beauty.
ACCN What happened next?
KO Once you are able to put those units together in very high yield and in the correct order, what you’re really doing is carrying out a lot of repetitive steps, so the idea of automation is always in the back of your mind. We got a team of people together, including a really exceptional entrepreneur named Robert Bender. He had the idea of trying to find a way to automate DNA synthesis and RNA synthesis independently, but he needed our methods, including these new protecting groups. So he put together the resources and developed instruments around this particular chemistry and the outcome was the Gene Machine, which we demonstrated live on TV in 1981.
ACCN Did you have trouble getting people to believe that you had accomplished what you said you had?
KO Absolutely. I remember that we went to the major biotechnology conference in San Francisco and set up a booth with the machine. We had cards that scientists could fill out with up to a 12-unit sequence that they would like to have. That was the length of segment that you could use to probe living systems for a particular gene, so a 12-unit piece was an extremely important scientific tool at the time.
We promised that the president of the conference would draw the winning sequence on a Thursday morning and we would deliver the completed sequence anywhere in North America the following Monday. I don’t think there was a single scientist who filled out one of those cards who believed there was any hope of it happening; they knew it was impossible to do that in a weekend. Nevertheless, hundreds of cards were filled out and on Thursday morning, the president drew the winning sequence from a laboratory in upstate New York. It was delivered to them on Monday morning, they used it and it appeared in a publication a number of months later. In one dramatic example, it transformed the thinking of scientists dealing with the manipulation of cellular organisms. To be frank, it launched the biotechnology revolution.
ACCN Can you give us one or two examples of products or techniques made possible by your innovation?
KO Prior to biotechnology, insulin was extracted from the pancreases of human cadavers. This was inefficient and you had the possibility of extracting toxic materials along with it. With the gene machine, it was possible to create a synthetic gene, put it in an E. coli cell and give it instructions to make lots of copies. You could then build up a huge fermentation tank of E. coli cells, all of which are now producing human insulin along with other protein molecules. The human insulin is then extracted from the final mixture. Not only does this produce human insulin free of any of the problems associated with extracting it from cadavers, but it also creates an unlimited supply. Within a few years, most countries in the industrialized world passed laws to ensure that the only human insulin that could be sold on the market was that produced from biotechnology. You can now do that for any protein molecule that you consider important, provided you know what the gene sequence is. Today, we can produce a myriad of proteins including human growth hormone to treat many different diseases.
Another example is the genetic engineering of plants and microorganisms to produce large quantities of isobutanol. This chemical can be dehydrated to form isobutylene, which is a major component of synthetic rubber. Creating these genes and putting them into organisms allows us to bypass the petrochemical route to produce a molecule that’s tremendously important in making polymers.
ACCN Who owns the Gene Machine now?
KO The company went through all of the stages from angel investing through venture capital, and ultimately a listing on the TSX and on NASDAQ. Unfortunately, it ran into serious management problems as it moved into large commercial stages and was purchased in a reverse takeover by another company. Its technology was eventually lost to Canadian commercial development. Other companies came along using similar technologies, patents expired and today companies providing DNA synthesis equipment are common.
The reality is that you rarely have one individual who can take a company from an embryonic concept into a major producing corporation. It takes different skills at different stages of corporate development and in those days Canada did not have a lot of that kind of experience.
ACCN When you look at the modernbiotech industry, what do you see?
KO Today, biotechnology is a huge, global industry with an enormous range of products that emerge from our knowledge and understanding of cellular systems and our ability to manipulate them. A lot of that knowledge came from being able to make any sequence of DNA or RNA in order to probe living systems and figure out how they worked. Anytime you are looking at studying life at the molecular level, you’re dealing with chemistry. So we chemists have made an important contribution and many of us in the 1960s and 1970s could imagine this kind of world. To see it coming to fruition is very satisfying.
Nurturing home-grown biotech innovation
Besides the Gene Machine, Senator Kelvin Ogilvie’s knowledge of RNA synthesis led to the development of Ganciclovir, an important antiviral drug used to treat numerous infections. For his success in translating scientific discoveries into the marketplace, Ogilvie received the prestigious Manning Principal Award from the Ernest C. Manning Awards Foundation in 1991. One year later, he was inducted into the Order of Canada. Ogilvie currently chairs the Senate Standing Committee on Social Affairs, Science and Technology.
Like many observers, Ogilvie is concerned about the so-called innovation gap in Canada. “We should be very proud of the tremendous strength we have in our research institutes, but we should be ashamed of how poorly we have done in translating technology into social and economic benefit,” he says.
Ogilvie believes that one of our biggest problems is geography: Canada is 35 million people spread over the second-largest landmass of any country. According to Ogilvie, innovation works best when there is critical mass in specific clusters, where people from related companies and organizations can meet and exchange ideas. He cites the development in the 1980s of the National Research Council’s Biotechnology Research Institute (NRC-BRI) in Montreal, where he played a key role. NRC-BRI provides laboratory space, access to fermenters and other research infrastructure to small technology companies, which in turn feed a community of spin-offs and secondary industries. Ogilvie would like to see other NRC institutes follow this model. “I would argue the NRC has gotten a long way from its original mandate and essentially attempted to become another academic research institute. The NRC should be a collaborator with university researchers, not a competitor.”
Much has been written in the past year about Canada’s Science and Technology strategy. A number of reports have advocated reform, such as streamlining the Scientific Research and Experimental Development (SR&ED) tax credit, or providing more direct funding for industrial research and development. Ogilvie believes these are important, but feels we also need to develop an innovation-oriented entrepreneurial class and receptor capacity for innovation in existing industries, along with critical infrastructure.
Meanwhile, many prominent scientists have argued against changes to government funding of basic research, as the next breakthrough cannot be predicted. Ogilvie sees the competition between fundamental and applied research as a false dichotomy. He cites the example of Louis Pasteur, who made many important discoveries, both fundamental and applied, with funding from private sources. “Every good scientist has an idea of why they’re trying to pursue their area of research and where it might ultimately have benefit in some way,” he says. “It’s critical for us to get over our parochialism, and invest in supports for technology development, regardless of who comes up with it.”
Photo Credit: Canada Science and Technology Museum
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