Two of the superstars of science at the helm of the effort to make a synthetic cell (a cell with a completely man-made set of genetic instructions) are Hamilton Smith and Clyde Hutchison, or Ham and Clyde as they are affectionately known to colleagues. Since 2003 when they started working together here at JCVI one rarely hears about one without the other – always together and cracking jokes amidst discussing the complexities that define their ultimate quest: To understand, “What is Life?” I like to think of them as the Abbott and Costello or Laurel and Hardy of science. A colleague said they reminded him of Statler and Waldorf – the muppet men on the balcony heckling the other characters –although Ham and Clyde are neither ornery nor disagreeable but their subtle banter with each other is hilarious. They play off each other perfectly and I had the pleasure of interviewing them for a more personal piece to coincide with the landmark announcement of their trailblazing work to make first living synthetic cell.
So I was to begin the interview diligently with a list of well thought out and leading questions that fed nicely into the next. Those quickly went out the window when Ham and Clyde walked into the room (them in San Diego and me in Rockville over a videoconference). “I cleaned the stain off my cuff!” declared Clyde holding up his sleeve, and “we wore our good suit jackets,” thinking I would be interviewing them in person. “Will this be recorded by video?” “No, no audio or video” I replied, “so you can say anything you’d like to and I’ll capture what I can with my pen.” They started talking before I could pose a question and I settled back for a hugely enlightening hour of landmark scientific achievements and hilarious stories. The Early Years Ham grew up primarily in New York and Illinois with a family who valued education and encouraged his interests in science and medicine. His father was a professor of education and his mother an aspiring writer. Ham was a mathematics major at the University of Illinois with an interest in neurophysiology, and attended medical school at Johns Hopkins University where he later would spend the majority of his career doing research. In 1978 he won the Nobel Prize in Physiology or Medicine for his work on restriction endonucleases (enzymes made by bacteria that cut DNA in specific places; the isolation of these enzymes provided a vital tool for molecular biology research). When asked how the Nobel had affected him Ham said modestly, “Getting the Nobel was a nice thing. I became nervous about how I should behave. I always looked up to Nobel Laureates but didn’t’ feel like I was one of them.” One of the perks he said was that he could “apply for any grant and get it!” Ham lamented that “Clyde should have gotten the prize in 1993 with Michael Smith” for their work on site directed mutagenesis. But Clyde is not the kinda guy who promotes himself like you need to for things like this,” said Ham. Clyde hastily added, almost interrupting him, “Ham isn’t the type either but he had good promoters.” But apparently his parents weren’t one of them! Clyde relayed a story about how Ham’s parents found out about the prize when they were listening to a radio show and heard the announcement that Hamilton Smith from Johns Hopkins received the Nobel Prize. His mother turned to his father and said, “I didn’t know there were two Hamilton Smiths at Johns Hopkins!” Ham slightly corrected Clyde’s story and said it was more like, Do you suppose there is another Hamilton Smith at JHU?” Modesty and humility are in his genes. Clyde also had a very supportive family who nurtured his interest in science at a young age. His father was a chemist and physicist. “A chemical physicist” said Clyde, “rather than a physical chemist.” Being a physical scientist his father looked down on biology as “messy business.” Although Clyde was a physics undergrad at Yale he eventually ended up in biology and joked that, “It allowed me to do science but rebel against my father.” Most kids rebel by getting tattoos or ditching school, but apparently Clyde wasn’t like most kids. Clyde’s entry into biology was serendipitous. He was on a scholarship at Yale and in order to maintain it he had to have a part time job. The first year everyone was put in the dining hall, but the 2nd year he lined up a job with an astrophysicist involved in radiotelescopes. By the time Clyde returned to school from summer break the professor gave the job to someone else. Clyde pleaded with school administrators for a science job and got into the Biophysics department working with then postdoc Carl Woese who discovered the 3rd branch of life- Archaea- and that piqued Clyde’s interest in biology. Clyde later moved to North Carolina and spent over 37 years at the University of North Carolina, Chapel Hill building an illustrious research career. How They Met In 1973 Ham and Clyde were both independently invited to a conference on restriction enzymes in Belgium and stayed in a monastery. “We don’t really remember meeting each other,” said Ham but he distinctively remembers the communal bathroom (back then a novelty). It wasn’t until 20 years later that the two made a real connection. Craig Venter and Ham met in Bilbao, Spain in 1993 at a meeting. Craig gave a presentation on his Expressed Sequence Tag (EST) work at NIH. Ham said they met in the hotel bar and from that time on they liked each other as their science interests were similar. Craig soon afterward asked Ham to be on the Scientific Advisory Council for TIGR (The Institute for Genomic Research). “I saw the sequencing lab and that instantly convinced me” said Ham. “The biggest I’d ever seen! I was impressed by [the technology] he had.” Around 1994 Ham called Clyde to collaborate on a sequencing project. Craig, Ham and the team at TIGR had just sequenced the first bacterial genome, Haemophilus Influenzae. Ham noticed Clyde’s work on Mycoplasma genitalium and since it’s the smallest known bacterial genome he thought it would be a good candidate for their next sequencing project. That simple project would eventually turn into the quest to create a synthetic cell. Ham said that “synthetic genomes were discussed” by he, Clyde, and Craig starting around 1996. Then, with a wink, Ham said that he “made an offer Clyde couldn’t refuse” and they collaborated to sequence M. genitalium. Clyde split his time between TIGR and UNC, while Ham and Craig slowly wooed him into joining full time in 2003. After sequencing the M. genitalium genome (published in 1995), they began work on the “minimal genome project.” The goal of this project was to see how many genes are necessary to sustain life, and in this case they studied the genes essential for the growth of M. genitalium because it is a bacterium with the smallest genome known. This work was published in the journal Science in 1999. At the same time a group of bioethicists from the University of Pennsylvania published the results of their ethical review of this work. By July 1998 Ham retired from JHU to work full time at TIGR. He was there only a month before leaving for Celera, the biotech company Craig founded to sequence the first human genome. Ham and Craig were at Celera from 1998-2002 and had the idea to do the synthetic cell from Clyde’s work then but put it on hold for four years until after the draft human genome was finished. Early in 2002 Craig left Celera and founded two new institutes: the Institute for Biological Energy Alternatives (IBEA), and The Center for the Advancement of Genomics. Ham resigned from Celera to join IBEA (where he became scientific director) and “cashed in my stock” he laughed only half-joking. Ham and Clyde finally started working closely in 2003 when Clyde moved full time to work at IBEA, and since then have been inseparable. Clyde and Ham both did phage work in graduate school. Clyde worked primarily on phiX174, a phage virus that infects E. Coli. They thought this would be a good first target to test their new synthetic biology technology. They received a Department of Energy (DOE) grant to synthesize phiX in the lab and worked on it during the summer 2003. “Both of us moved into the Marriot Residents Inn and worked 12 hours a day on the synthesis of phiX” said Ham. He proudly added that Craig said, “We were the best postdocs he ever had!” Considering Ham was in his early seventies then and Clyde was not far behind, that was a pretty impressive claim! The synthesis of phiX was published in 2003 and laid the ground work for synthesis of a larger genome — that of a mycoplasma bacterial species. One of the keys to working together so well is how they complement each other both personally and professionally. When asked about how they would characterize the other, Ham divulged the important attributes first, “Clyde likes martinis and I like manhattans!“ he blurted out smiling. Ham continued, “I like his sense of humor very much. He’s very precise in his speech and thinking, whereas I get a little more disorderly. But our approach to science is very similar.” Clyde added that “Ham is great at coming up with things that should have been obvious to everyone but aren’t.” Key to Success I wanted to know what makes these two extraordinary men tick. What motivates and inspires their drive and successes — Good mentors? Good luck? Sacrifices? Hard work and determination? Or just a good time to be in biology? Clyde said simply, “You have to want to do good things, and have a motivation to do interesting science. We both have an aptitude for it, but need to just do things and see what happens.” So they appear to be open to risks and new adventures in their careers, maybe they could even be described as mavericks as Craig has been called. Ham said, “If I hadn’t met Craig I’d be retired and living on the farm (his wife of 53 years maintains the farm in rural Maryland). “Craig has given me the opportunity to continue [doing science]. Clyde added that “being at the JCVI (J. Craig Venter Institute) has made it possible to do things we couldn’t do otherwise in an academic setting.” For example, Ham said, “When sequencing first took off in the late 80s a lot of good scientists didn’t see value [with pure data collection]. I’ve always said “sequence, sequence, sequence” then later we can figure out what to do. “It’s the code of life!” Ham performed his first sequencing experiment in 1976 using the Maxim-Gilbert method and realized its potential back then. “But I was sequencing before Ham,” said Clyde who trumped him in that area by doing a sabbatical in Fred Sanger’s lab in 1975. Speaking of aptitude, science isn’t the only activity at which Ham and Clyde excel. Ham played classical piano starting age 7 or 8. He never practiced and said he was a lousy pupil. Every 6 months or so his mother said he could quit. At age 12 a friend took him to a music store where he heard the Pathetique Sonata by Rubenstein that he had struggled to play and when he heard it for the first time he felt an instant change – he started practicing 3-4 hours a day up to 8 hours a day during the summer. It’s not a surprise that this type of diligence contributed to his later successes in life. Presumably complimenting Ham’s ability to tickle the ivories, Clyde said, “He’s remarkably fast with his hands and can shuck edamame faster than anyone.” Ham added that “I was the fastest newspaper shuffler and hand-bill stuffer in high school.” He would race his friends to finish the chores. Clyde also took classical piano lessons as a kid but quit after a few years to take up the saxaphone and clarinet. He listened to jazz alot and learned how to play in his forties, going on to perform regularly in clubs in North Carolina. Although he stopped taking formal piano lessons as a youth he has kept up with it to this day. He is now playing solo piano accompanied by computerized bass and drum every Thursday in a restaurant in La Jolla called Bernini’s Bistro. What is Life? To finish up the interview I wanted them to leave us parting words of wisdom and so asked, “When you look back on your illustrious careers do you think about how far science has come or how far we have to go to understanding “What is life?” Ham: “It’s hard for me to believe how far we’ve come. If you think about how far things have come since sequencing the first mycoplasma genome (15 years ago) it’s hard to conceptualize what it will be like in 15 years.” Clyde: ”We grew up reading Dick Tracy with his wrist radio, and the iPhone makes the wrist radio look like trash.” When I asked what he meant by a wrist radio, he explained that the comic book character, Dick Tracy, used it to communicate. Ham added that if you sent in cereal box tops they would send you a wrist radio. “It didn’t work of course but you pretend,” he smiled. Ham and Clyde then started to banter about the fantasy uses of wrist watch radios. I threw out an analogy I was familiar with – the legendary 80s show, “Knight Rider” and the “Kit” car that David Hasselholf could summon on his wrist watch. They nodded in familiarity and added that some cars today can parallel park themselves. Getting back to the question of “What is life” I asked them if synthetic biology will provide more for us initially as a research tool in molecular biology or as a chassis for production of bioproducts. “Both” they chimed together. Clyde remarked, “It will have a lot of basic science value that will allow us to get at questions that motivated us in the beginning such as, what are the minimal number of genes essential for life?” “It will promote a better understanding of cells” added Ham. There will be practical applications too, Clyde continued, but “this synthetic cell [M. mycoides ] is not a good production host to make useful bioproducts since it’s expensive to grow and fastidious (requires special nutrients).” “But it provides the proof of principle that it can be done,” Ham exclaimed. We’ve developed a bunch of methods that we can build whatever chromosome we want as long as we know the DNA sequence, said Clyde. Using synthetic genomics “we can take apart a cell and figure out what every gene does in that cell. There is currently no cell we can fully understand,” said Ham. We can reduce the number of genes we don’t know down to a dozen or so and once we’ve done this “then I retire” Ham grinned. I ended the interview asking which comedian duo they thought they most resembled- Abbott and Costello or Laurel and Hardy. They both kind of shook their head not thinking that was a good analogy. But that same moment (just before the videoconference equipment unexpectedly cut off our connection), Clyde said with a laugh, “Neither, but maybe the Keystone Cops!” There they ended the interview as they began – being unduly modest, charmingly funny and easy. And to think these two individuals have been key figures in science, whose work has spanned both the dawn of molecular biology continuing through to the dawn of a new frontier in science- writing the code of life.