Scientist Spotlight: Hamilton O. Smith and Clyde A. Hutchison III

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.

Hamilton Smith and Clyde Hutchison III

Hamilton Smith and Clyde Hutchison III

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.

27 Responses to “Scientist Spotlight: Hamilton O. Smith and Clyde A. Hutchison III”

  • Congratulations on your widely publicized today success ! Hopefully, those fuel-producing algae are not far behind.

  • Loved the interview: very personable and informative. I am in awe with what has been achieved by Craig, Ham and Clyde and the JCVI. A million+ sequence that is self-replicating is an incredible and earth-changing event.

    I question, however, the wisdom of fuel-producing algae. Should we be looking for a fuel that produces less global warming? Freely available synthetic fuels are just going to exacerbate the carbon levels in our atmosphere. It will certainly help prevent disasters like the Gulf of Mexico BP issue where we’re trying to extract fuel from dangerous locations but I think we can do much better.

    I know to look for impressive results from JCVI from now on. Congratulations again.

  • Dear Sirs,
    From my childhood i was taught that there is only and only one God in this universe.Today i know that there are two Gods ….one is Ham and another is called Clyde.Although i am a Civil Engg from NIIT(Jaipur),Rajasthan,India i have spl interest for synthetic biology and….I do have some ideas rather peculiar dreams about like can we produce electricity generating bacteria which will cosume CO 2 or can we produce Petroleum …..can we have Illuminating bacteria which will only genrate Illumination and O2 as consume only CO2 and water.I think we can.If THOU have some spare time i can share.Regards

    subhendu sengupta

  • Very interesting, I hope Terry’s observation about fuel is valid and could it be that today the matter/atoms have ventured when it is possible for intelect/understanding to successfully cross from biological onto non-biological forms? Congratulations!

  • You people are amazing! This is a reality i still cannot believe it…. But yes the last question is what i ponder about…What is Life and can we ever understand it fully? Although i have no idea about synthetic biology and belong to a different field(herpetology)… I have a few simple questions for you “What impact will it put on evolutionary process if we start making synthetic organisms?? What about higher vertebrates???” Will it be a possibility in the near future?? if it can be we can save so much of flora and fauna that is getting extinct…. Simply amazing!

  • manas mukherjee

    loved the interview. Being a student of biochemistry these landmark achivements have always thrilled & inspired me.These are very exciting times with endless possibilities and we all are ready to embrace the future………

  • I want to automate their jobs.

  • Congrats, Clyde and Ham!

  • Congratulations on the achievements of Ham and Clyde. But a word of caution that it should be tested thoroughly and used ethically. Sufficient controls need to be built so that it does not land into the hands of unwanted

  • Could this be a step towards synthesis of specific cells to aid spinal cord regeneration. I hope so- I’m getting close to giving up.

  • Congratulations dear Sirs. Your work is bound to ignite an interest in science among the students; which has been declining in the recent years. The new technology developed has limitless applications. I can envision its practical use in medical biology soon apart from the commercial applications.
    Thank you.

  • Dr. Chetan C. Ambasana

    Its a nice work of preparing synthetic cell. Now the Question is how we can apply this method to modify multicellular form of life.

  • This is obviously a potentially earth-shattering and quantum leap biological development. Bravo!!!

    It’s only a nit, but could it possibly be that “Ham” and “Clyde” first met in 1973 in Bilbao, Spain and not Balboa, Spain?

    Fred III AB Johns Hopkins University 1964

    PS. The reason that I’m familiar with this is that there probably isn’t a finer or more romantic place to promenade on the boardwalk with your spouse or favorite “squeeze” during summer evenings than in San Sebastian just north of Bilbao on the northern Atlantic coast of Spain. [Just south of the French border]

  • This is obviously a potentially earth-shattering and
    quantum leap biological development. Bravo!!!

    It’s only a geographical nit, but could it possibly be that Dr. J. Craig Venter and Dr. Hamilton “Ham” Smith first met in 1993 in Bilbao, Spain and not
    in Balboa,(sic) Spain?
    > Fred III AB Johns Hopkins University 1964
    > PS. The reason that I’m familiar with this is that there
    > probably isn’t a finer or more romantic place to promenade
    > on the boardwalk with your spouse or favorite “squeeze”
    > during summer evenings than in San Sebastian just north of
    > Bilbao on the northern Atlantic coast of Spain. [Just south
    > of the French border]

  • vadivel prabahar

    Craig,Ham and Clyde- the most inspiring scientists on this earth…

  • Incredible!

    I think the real question is not what we are, for I think we are clearly seeing that we are chemestry bonded by physical laws, the real question we need to ask our selves is WHO created such a thing… Things to me look more like.. life and the universe itself is a huge laboratory where someone, ( an advanced civilization perhaps), has done what you guys just did, in greater detail, long long ago.

    What really intrigues me is how cells work. We know by you guys, that the software is read by cells in a systematic way, yet we do not know what tells that cell to do so, and how to read it, what is the processor for such a “computer” right? thats where we should get to. What tells cells to do what they do and how they do it, even before reading their our “software” DNA.

    Nevertheless, it is an amazing finding, and really makes me want to go back to school and retake biology!!!!

    Keep it up guys!!!

  • Dr Madhusudan Dabhole

    Dear Sir,

    Congrats, Fantastic work. Opened UP a new frontier for studies in rare genetic disorders and stem cells. HIV should be the first target.

    Dr Madhusudan Dabhole

  • Clyde and Ham,

    You are super stars. Wish you more success.

  • Ham and Clyde,
    You two gentlemen are truly remarkable and absolutely inspiring. The best for me was that the article captures a little about who you are as every day people.

    If you ever have a need for UV, VIS, NIR or scattered-light process photometers, my company would be proud to support your efforts and donate the needed equipment to JVCI.

    Thanks for your contribution to science and mankind, we all benefit from your work.

  • Dear Prof. Ham and Clyde,

    Great breakthrough, after human cloning efforts, though with lots of ethical issue surrounding the scientific development. The scientific understanding leading to development of self replicating cell probably will have far reaching implication to benefit the humankind ever in need of scinetific breakthorugh to solve the problems created by the very species. For instance, the greenhouse gases and climate change throught to be bigger threat with its ramification and threating habitability of earth, which may have doomsday effect on human kind. The scientific breakthorugh probably help tailor the microbial groups to eat/degrade and or resynthesize the greenhouse gases to nullify their effect. For instance, methane, a potent greenhouse gas of microbial origin and also oxidized by microbial groups. I strongly believe, such self replicating cell can be designed targetting the certain functions when it is released into natural systems. However, such an effort take a long-haul convinicing of very own humnakind about their adverse effects/mutants becoming probelmatic/alterations to living cells/The probable adverse effects they have on the system as a whole. Ironically, most often we raise ethical issue rather than looking at the long term benefits and solutions such a breakthrough science can provide and serve the humankind.

    Way to go! I am sure someday, sooner, I will read a breakthrough applications of breakthrough science of self replicating cell, keep self replicating the science for the benefit of humankind.

  • Mr. Chetan Kumar Jain

    Its realy great work. Please apply this science only for wellfare of the universe.

    Best wishes
    Chetan Kumar Jain
    SLS, JNU, New Delhi-110067

  • Sunandan Mukherjee

    First of all I want to congrats this duo for their achievement. No doubt, this will open a new era of Biotechnology.
    One more thing, I am personally very happy for this achievement of JCVI because I am a die heart fan of Craig Venter since my graduation.
    I have a request to all the scientist of JCVI and all other Biotechnology institute of the world as the consequences of this project as we can make a big difference on global warming by controlling the various means of pollutions as well as bio fuels.
    Once again, many many congratulations….

  • I am interested in doing research with your group. I have developed techniques using in situ PCR technologies which I can show you if you would be interested.


    Mark A. Meier

  • well done sir and mam,its makes me proud when it comes to congratulate scientists like you who are providing their service to science.. respected Hamilton Smith and Clyde Hutchison, or Ham and Clydei i congratulate you for this great achivement.i am a student of master of pharmacy , medicinal chemistry..sir and mam their are verious students are avilable in almost every corner of world who are lacking quality eduction nowdays ,i am one of them i want to learn almost everythig about genetics and gene science ,i have a great intrest in genetics.

  • No doubt, the hall mark of organic life and its origins will find its target by operating outside the box. Here, Professors Ham and Clyde have yet to adequately answer the question: What is Life?

    Their research to date has yet to reach the doorstep of life itself!

    Life’s protocol Form follows Function, Function follows form has never been addressed or considered.

    One wonders where science is going?

  • The annoucement of a replicating synethic cell by the Craig Venter Institute raises serious concerns about man and his understanding of organic life moving into dangerous frontiers.

    Today, we have scientists thinking they have a certain truths when they are no closer than the distant to and from the moon.

    Despite the three dimensional protein molecule being prep by the amino acids capturing them and promoting life’s ability to do! Thus, finds the intergity elasticity and plasticity of Form in terms non-plastic nature life’s functionality of fueling, metabolic processing, and wasting, afixing life’s protocol of Form (Plastic) follows Function(Non-plastic).

    Nowhere in Professors’s Ham and Clyde pronouncements can we begin to understand how life works in terms of reward and pleasure against life’s ability only to add (the nature chemical bonding)!

    In our quest to understand life, where life hides nothing, we go on shaking our head wondering how these two scientists can us any kind of understanding of: What life is?

    What makes Earth an ideal platform?

    Falling back on basics we continue to search for answers through the surface senstivity of our organic cell making everything possible. No doubt, the key is the protein molecule.

  • Hello,

    I hope you can answer my questions:

    1. How many decades or centuries have scientists tried to create life?

    2. Is there any organism anywhere on earth that can be seen coming to life on its own?

    3. What are the scientific odds that the perfect recipe of earth chemicals could mix together on their own and form a living organism organism?

    4. What are the scientific odds that an organism, which came to life on its own, could survive and reproduce to the quadrillions of life forms on earth?

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