Rich Roberts's discovery of RNA splicing and his development of restriction enzymes as molecular biology tools caught our attention. Curious to know more, BioTechniques contacted him to find out about the ambition, character, and motivation that led to his success.
Understanding the code
How did you first become interested in studying restriction enzymes?
I always had a great interest in DNA sequencing because, ultimately, the DNA code is what leads to life. While I was a postdoctoral fellow at Harvard, there were no DNA sequencing methods available, mainly because there were no small DNA molecules to use for developing and validating an approach for sequencing. During my last year as a postdoc, I heard a talk by Dan Nathans from Johns Hopkins University on the first Type II restriction enzyme (RE), then called endonuclease R. He clearly showed that SV40 DNA could be cut with this enzyme, resulting in a lot of small fragments. It occurred to me that these small fragments, combined with the RE recognition sequence, might offer a path to developing a novel DNA sequencing methodology.
In 1972, I arrived at Cold Spring Harbor Laboratory (CSH) and began making known RE so I could work on sequencing. But we soon discovered many more enzymes, and of course each had uses other than for DNA sequencing. So we gave the RE we found to Fred Sanger and refocused our efforts towards characterizing the enzymes themselves.
What has been your biggest professional obstacle?
Many people were interested in RE for recombinant and genome mapping purposes and as we ended up spending a significant amount of time making enzymes to give away, I recognized that the coming recombinant DNA revolution would depend heavily on their availability. So I approached Jim Watson and suggested that we set up a company associated with CSH to make and sell these enzymes, using the profits to support research at CSH. Jim had no interest in the idea and declined.
Eventually, I found Don Comb, who also recognized the potential for RE and was planning to sell them through a distributor. I persuaded him to sell them directly, and he founded New England Biolabs (NEB). He offered me a partnership in the company, but since I was a young academic and not interested in giving that up to go into business, I took a position as the chief consultant and continued to work at CSH.
At the time, most academics in biology thought that getting involved in commercial ventures was inappropriate and somehow dirtied you as a scientist. I got into a lot of trouble as word spread that I had signed on with NEB. There was so much antagonism that I finally got called before the board of trustees to explain what I was doing. The chairman of the board of trustees, Walter Page, took me aside after the meeting and said I should ignore the negativity. He believed what I was doing was exactly right, which was nice to hear.
What has been your most significant scientific contribution?
While at CSH, we started using RE to look at problems of biological interest. In one of these projects, we cut adenovirus into pieces for transcriptional studies. I was particularly interested in finding adenovirus promoters and comparing them with those that had been discovered in bacteria.
During the course of those studies, we came across something quite unexpected; we found that the mRNAs of the late adenovirus messages all seemed to carry exactly the same sequence at the 5’ end. We soon ruled out the possibility that it was a repeated sequence in the genome, but it was not clear what was happening. My postdoctoral fellow, Richard Gelinas, and I worked to show that the 5’ end and the main body of the message were coded at different points in the genome. The biochemical data added up, but we didn't have proof until one day in March 1977 when I thought of an electron microscopy experiment that might show us exactly what was going on. We had the idea on a Saturday morning, approached electron microscopists Louise Chow and Thomas Broker for help that day, and by Tuesday we had results showing unequivocally that the RNAs did not correspond to contiguous segments of the genome. That was the discovery of introns, exons, and splicing.
This was the research for which you won the Nobel Prize. How did your work and life in general change after receiving the award?
My professional involvement with my company and the things I do each day did not change much. What did change was that now I receive a lot of invitations to do many interesting things and meet people I otherwise would never encounter. For example, I was inducted into the American Academy of Achievement the same year as Harrison Ford and Francis Ford Coppola. I receive far more invitations for meetings than I could actually attend, but it has been interesting and enjoyable to meet such a wide variety of people.