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What scientific question has most interested you over the course of your career?

I come to work even after retirement because I am deeply interested in biochemical processes that underlie normal and disease human physiology. The central theme of my interest follows from the discovery that DNA encodes the information for human physiology, and the challenge is to understand how this information is utilized. This led me to focus on the primary stage of access to this information – the regulation of its transcription into RNA.

I remain fascinated by the nature of the regulatory processes that specify what genes are expressed in particular cells, and what subset of each gene sequence is assembled by RNA splicing.

These questions are particularly challenging in understanding the malignant state of cancer cells, where cellular plasticity in terms of gene expression is high.

It’s been 50 years of discovery and advances, and there will be another 50 years before we’ll be satisfied, if we ever are, in understanding all the intricacies of these regulatory processes.

When you joined the MIT faculty in 1974, Kendall Square was largely vacant. Today, it is one of the nation's most economically vibrant sectors, thanks to the birth of biotech in the late '70s and '80s. What ingredients were necessary for this transformation to begin?

I think the documentary “Cracking the Code” illustrates the necessary ingredients quite well. First, the science at MIT and Harvard contributed enormously to the breakthrough of recombinant DNA technology in the mid-1970s, and our understanding of biological systems at that time.

Second, it was the engineering culture, particularly at MIT, of translating new advances to the benefit of society. Translating technology to society through investment and working with companies is part of the mind and hands of MIT. Daniel I.C. Wang, a professor of Biochemical Engineering at MIT, was a key figure in designing and engineering the critical processes for manufacturing the early recombinant DNA drugs.

Third, it was the vibrant venture capital community and financial community in Boston that was willing to take the risk of investment in the early biotechnology companies, such as Biogen and Genzyme.

Fourth, the empty lots in Kendall Square provided space near MIT and Harvard for research labs. You could build buildings right across the street from MIT, which made it easier to recruit students and fellows from across the country and around the world. It created a community that was very happy to have these investments and new people, and MIT was excited about the whole development, so there were opportunities for growth.

Finally, it was the willingness of Wall Street investors to finance certain new biotechnology companies that would not be profitable for 10 years in the future.

Your discovery of RNA splicing in 1977 rested on a key imaging technology: electron microscopy. What role did it play?

Historically, advances in technology have been critical for research in biology and molecular biology. The discovery of the structure of DNA by Watson, Crick and Franklin, for example, depended on the new technology of X-ray diffraction and computation programs to analyze helix structures.

Electron microscopy (EM) of DNA was originally not that informative. In the 1960s, methods were developed to coat DNA with protein and map genetic deletions by comparing regions of genomes using EM. Ron Davis and Norman Davidson at Caltech published the first example of mapping viral genomes physically using EM. I learned this technology from Ron Davis and extended it to mapping genes on a bacterial genome in 1969-1971.

In the discovery of RNA splicing in 1977, we used electron microscopy to compare the sequence structure of messenger RNA to the DNA genome from which it was transcribed. We could see these loops of DNA sequences, the beautiful loops that are now shown in most textbooks, that were no longer present in the messenger RNA. This revealed to us that genes were discontinuous and the process of RNA splicing.

Subsequentially, Wally Gilbert at Harvard coined the terms “intron” to refer to the non-coding regions of DNA and “exon,” the coding regions of DNA.

This relationship of new technology and advances in biological science will continue as we explore organisms at the level of a single cell and a single molecule within a cell.

If you could invite three people to dinner, living or deceased, who would they be, and what would you like to discuss?

This is a difficult question to answer because over the last century, we’ve seen an extraordinary transformation of biological thought and understanding.

But I’ll start with Thomas Hunt Morgan, the first scientist to relate genes to chromosomes. Morgan was a knowledgeable and impactful developmental biologist, but he was also a source of modern genetics. His studies in Drosophila, showing how chromosomes encoded genes, place his contributions about midpoint between Gregor Mendel and molecular biology. Morgan was a deep thinker and a broad thinker.

The next is Barbara McClintock, who discovered the importance of transposable elements in biology. I occasionally had the opportunity to talk with Barbara at Cold Spring Harbor when I was a fellow there. But I should have been more attentive to her deep thinking about evolution and how changes in DNA and these transposable elements were important. At the time, molecular biologists found it difficult to appreciate what Barbara was doing. But in hindsight, she had an understanding of life and biology that would be interesting to discuss at the table.

Third is Francis Crick, a physicist and co-discoverer of the structure of DNA, who then proceeded to become a leading spirit in understanding the nature of the genetic code. Francis later turned to one of the deepest questions in biology, which is how the brain works. I had several occasions to talk with Francis. He was a deep scholar and both critical and humorous.

I would like to sit down with those people and ask them what the last century in biological science has meant to our understanding of humanity, and how it has contributed to human culture. These are questions I think people have overlooked. Biology has changed how we think, because we now understand ourselves in a much more material way. And that shapes how we understand ourselves, the world around us, and what we do.

How did you end up starring in a documentary? Did you enjoy the experience?

Bill Haney, the producer and director, approached me about making the documentary. “Cracking the Code” is his 19^th documentary. He is a successful entrepreneur who, in addition, is committed to improving society by telling stories visually.

I would not say I enjoyed the process -- it is somewhat like undressing in public! --  but I learned a lot and found the final results meaningful. It tells a story of how education, discovery and entrepreneurship change society.