Morris Robins talks to Kathleen Too about turning crystalline sugars black, discovering Epivir and Cladribine and his new career in farming

 

Professor Morris J. Robins is a former professor at Brigham Young University, Utah, US. His main achievements have been in the areas of bioorganic, medicinal and organic chemistry and cancer research. He has pioneered several nucleosides as commercial drug candidates, for example Didanosine, Epivir and Cladribine.

 

Who or what inspired you to become a chemist?
I was inspired by a freshman chemistry professor, Lloyd Malm, at the University of Utah, US. He was very dynamic, fascinated by chemistry and he took an interest in me. That's why I really decided to pursue chemistry.

Which research are you most proud of in your career?
I had a research programme that was sort of focussed on two areas. One was the development of potential drugs, both antiviral and anticancer, and the other was the discovery of new reactions. So from a point of view of satisfaction, the development of a drug that would help people was a really major thing. But personally I also found it exciting to develop a new reaction so that you could do things that hadn't been performed before.

When I was a professor at the University of Alberta, in Edmonton, Canada, I met David Lorne John Tyrrell (he goes by Lorne Tyrrell). He was the head of the department of microbiology and infectious diseases in Alberta. We met for lunch and talked about the mode of replication of hepatitis B that had just been published. Since a reverse transcriptase activity was involved in the replication of the hepatitis B virus and we'd developed active compounds against AIDS, we talked about the possibility of working together on the hepatitis B virus. We discovered the first inhibition of hepatitis B by dideoxy nucleoside analogues, and then we partnered with Glaxo to develop Epivir (also known as Lamivudine), which could be applied to combat hepatitis B. A couple of months ago, my friend and colleague at the University of Alberta phoned me and said that now Epivir is the number one selling drug in China. There, hepatitis B is endemic and so it is quite pleasing that it is the number one drug. In 1998, Lorne Tyrrell and I were jointly awarded the Prix Galien Canada Research Award for this work.

I was also the first person to synthesise dideoxyadenosine. I then demonstrated that it was a good substrate for adenosine deaminase, which gives dideoxyinosine, the second compound approved for the treatment of AIDS patients. So those things have been very fulfilling.

Do you remember your first independent discovery?
When I was in graduate school, I actually developed the first synthesis of a compound, 2-chloro-2'-deoxyadenosine, which has the generic drug name of Cladribine. I got the idea from a group seminar in which we were talking about a fusion reaction developed in Japan where a purine and a sugar could be melted together to evolve acetic acid and form a glycosyl linkage. And so I thought, 'Ah, we could do that and make deoxynucleosides!' I took the deoxy sugar acetate from deoxyadenosine and fused it with different purines, but the deoxy sugar was much less stable and decomposed readily and I had multiple failures. I could turn beautiful white crystalline purines and colourless clear deoxy triacetate sugars into black mixtures very well. Eventually I got it right!

Dennis Carson at Scripps (La Jolla, US) discovered Cladribine's anticancer activity against B and T cell type malignancies, and so this drug is the current drug of choice for hairy-cell leukaemia. Hairy-cell leukaemia is a minor form of the disease in terms of the total number of people that have it, but the drug is curative or provides long-term remission for essentially 90% of patients, which is quite amazing! Over the years I've seen this drug developed as an anticancer agent.

More recently Merck Serano, a pharmaceutical company in Switzerland, has begun a large double blind clinical trial against multiple sclerosis using Cladribine. We recently developed a cooperation with them to use some of the new chemistry that I developed. 

What is your approach to success? 
Well, in my opinion, academic chemists should be involved with the discovery of new creative chemistry. I always focussed on the discovery of new reagents and new reactions. We were very fortunate in finding compounds with biological activity and we always had this application in the back of our minds. So my approach involved new creative discovery of new reactions, and then application to compounds that were previously difficult to access, rather than taking a compound and making multiple derivatives. Now that doesn't mean that I pass judgement on other academic chemists who use different approaches, but that is my approach.

What is your message to young people?
I would advise young people to find out what they are really interested in, what they can be patient about pursuing, and then become immersed in it. They should understand it and go beyond where most people are willing to go. I was able to make discoveries by understanding the fundamentals and going a step beyond on a more qualitative rather than quantitative basis.

Which scientist do you most admire and why?
I really admired Sir Derek Barton (Nobel Laureate). He had a broad understanding of chemistry and one of his main achievements was the invention of new chemical reactions. We were both working on the Barton reduction at the same time but he published first. This was fine as it was based on his work on thiocarbonyl photochemistry. I invited him to be our guest lecturer at Brigham Young University. We had a very infrequent but real friendship and respect for each other, which I admire because he was at the top of the world and I wasn't.

How do you plan to embrace retirement?
Enthusiastically! For me it's just a change of emphasis. I'm not retiring in any sense of the word but the time has come where it's right for me to not be teaching classes of 300 and to stop running a big group. So I bought a farm. I'm still interested in creative things and I get to figure out things like biofuels and green chemistry. I am as involved as ever and as busy now as I was before.

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