In an exclusive interview_ controversial scientist and by dfsiopmhy6



Genome maverick
In an exclusive interview, controversial scientist and entrepreneur Craig Venter
tells Richard Corfield how he thinks synthetic genomics can save the planet

J Craig Venter is surprisingly quiet
and affable for a man who has
                                            ‘All of biology    as the scientists try to insert the
                                                               genome into a cell to create a living
                                                                                                        suicide by the horrors of Vietnam,
                                                                                                        he returned home safely, and
sparked such widespread praise and          is amenable        bacterium.                               determined to find the answer.
furore. Most famous for his role in
sequencing the human genome, the
                                            to this type of       Venter believes that these
                                                               powerful techniques could help
                                                                                                           That determination has propelled
                                                                                                        him through an eventful and high-
scientist has more recently hit the         manipulation,      to tackle some of the world’s most       profile career, notable for his refusal
headlines with his plans to create an
entire organism from scratch. He’s
                                            there’s no limit   pressing environmental problems,
                                                               by delivering tailored organisms
                                                                                                        to be cowed by orthodoxy and his
                                                                                                        unapologetic combination of science
often billed as a poster boy for the        to it’             that will eat CO2 or manipulate          with business. For example, his
burgeoning field of synthetic biology,                         hydrocarbons.                            success in sequencing the human
although he insists that his current                              ‘Whether we’re adding a gene at       genome – without public funding
work is specifically in synthetic                              a time, whole pathways or whole          – caused controversy partly because
genomics.                                                      chromosomes, there is basically no       of the clear commercial intent of his
   ‘There are hundreds of different                            limit to it. And we’re not just using    effort.
definitions of synthetic biology but                           bacteria, we’re also using yeast, so        Venter’s latest company is
synthetic genomics can be defined                              all of biology is now amenable to this   appropriately named Synthetic
very specifically because it is a field                        type of manipulation,’ he says.          Genomics. So where does he see
that we founded,’ he told Chemistry                                                                     its greatest and most immediate
World, speaking from his office at the                         Brutal inspiration                       potential?
J Craig Venter Institute (JCVI) in La                          By his own admission, Venter was            ‘Anything done right now in the
Jolla, California, US.                                         an undistinguished student – his         pharmaceutical, chemical or fuel
   ‘[It starts] with digitised biological                      own autobiography says that he           industry is amenable to this new
information in a computer and                                  was ‘rebellious and disobedient          field and these new technologies,’
we work back from that to design                               and constantly in trouble’. A life-      he says. ‘This has already started to
DNA macromolecules that can                                    changing experience during the           happen with a field called metabolic
change either the entire or partial                            Vietnam War, rather than academic        engineering which is the “harder-
physiology or biochemistry of a cell.                          success, ignited his scientific          work” version of synthetic genomics.
We then build the genetic code from                            ambition.                                A good example is what DuPont has
scratch based on the information we                               He was drafted and sent to what       done. It took them on the order of
get out of the digitised genetic code                          he refers to as the ‘University of       $100 million and 10 years to modify
in the computer.’                                              Death’ in Da Nang in 1967. Whilst        the bacterium E. coli to convert a
   In January this year, a JCVI                                there, he agonised over the paradox      six carbon sugar into a three carbon
research team announced in                                     of why a man with a tiny wound           propanediol. But now they can
Science1 that it had built an entire                           no larger than the diameter of a         do that with bacteria instead of
bacterial genome from laboratory                               pencil could suddenly die in the         chemists.’
chemicals. Stitching together the                              paddy fields of South-east Asia             He sees this as a major step
genome of Mycoplasma genitalium,                               while his compatriots – men of the       towards cutting the chemical
containing more than half a million                            same age and same supreme level          industry’s dependence on oil as
base pairs, was hailed as a key step                           of fitness – could lose entire limbs     its raw material. ‘Companies like
towards creating artificial life. The                          and still survive to be shipped home.    DuPont have started to make the
next stage is underway right now,                              Despite being pushed to the brink of     switch already, and we’re now
48 | Chemistry World | July 2008                                                                            
                                                            GETTY IMAGES   Chemistry World | July 2008 | 49
talking to the world’s leading
chemical companies, [which are]
                                         potential of. Early in his career,
                                         Venter left behind a securely
                                                                                  ‘Our ultimate               ‘Businessmen are more focused
                                                                                                           on the end result in many cases just
actively looking for applications        tenured job at the State University      goal is to be            being profit, whereas most scientists,
for the new science of synthetic
genomics to come up with
                                         of New York in Buffalo and joined
                                         the National Institutes of Health
                                                                                  faster, cheaper          like myself and my teams, try to do
                                                                                                           things primarily for the public good,’
innovative sources of the products       (NIH) in Bethesda, Maryland for the      and not using            he says.
they need. Ultimately, our goal is to
be faster, cheaper, and not use oil as
                                         tempting prospect of an intramural
                                         programme where he would not
                                                                                  oil as a raw                 Despite this, TIGR successfully
                                                                                                           revealed which genes carry the
the raw material.’                       – he thought – have to compete           material’                information used to build many
  Venter is interested in three major    externally for funding.                                           vital human organs including the
areas: designing bacteria for CO2           But within a few years he grew                                 heart, brain and lungs. But his next
remediation; designing bacteria to       tired of the limitations of a system                              step brought him scientific fame
produce the hydrogen needed by           that would not recognise the types of                             and notoriety: the sequencing of the
fuel cells; and the development of       research in which he was interested.                              whole human genome.
innovative medicines.                    So in 1993 he left the NIH to set up                                 His decision to carry this out in
  ‘We have a partnership with BP,        his own institute, The Institute for                              parallel with the Human Genome
using biology to convert [fossil         Genomic Research (TIGR).                                          Project (HGP) was very unpopular
fuels] into upgraded products.              Venter’s own eponymous research                                with the genetics community.
For example, we’re working on            institute was formed in October                                   The task had already been given
biological conversion of coal into       2006 through the merger of several                                to an international consortium
methane, as well as looking at           organisations including TIGR, The                                 of universities which collectively
upgrading oil sands into more            Center for the Advancement of                                     shared the biggest budget of any
volatile, lower viscosity, fuels using   Genomics (TCAG) and The J Craig                                   programme in the history of biology.
the natural biology in the organisms     Venter Science Foundation. These                                     Venter’s idea was to use
we find.                                 now all form one multidisciplinary                                a technique called shotgun
  ‘We are also working on                genomics-focused organisation with                                sequencing, which involves splitting
converting sugar and other               more than 400 scientists and staff in                             DNA into random fragments and
feedstocks, like CO2, into               multiple locations across the US.                                 then seeing how they can be fitted
new designer fuels. We have a               TIGR was initially funded by                                   back together by matching the
programme with a Malaysian group         the biotechnology venture capitalist                              overlaps. Many scientists at the time
looking at palm oil and jatropha as      Wallace Steinberg, who gave                                       claimed that sequencing the human
feedstocks.’ Venter is also looking      Venter $70 million (then around                                   genome in this way was impossible.
for ways to increase the scale of        £47 million) of start-up money. It                                   ‘Shotgun sequencing is shattering
combinatorial vaccine and chemical       was conceived and operated as a                                   a chromosome into millions to tens
production for the pharmaceutical        not-for-profit organisation. But it                               of millions of smaller pieces that are
industry.                                introduced Venter to a problem                                    amenable to DNA sequencing. The
                                         that would dog him for years – the                                DNA sequencing machines provide
The human genome race                    difficulties of doing basic scientific   The bank of computers    short “reads” of about around 900
When he first started work on            research funded by big business,         recording the DNA        base pairs a sequence, and because
DNA sequencing, it was a new field       with its eternal focus on the bottom     sequencing work of the   these are randomly shattered pieces
– but one that many saw the huge         line.                                    Human Genome Project     of DNA they (continued on p52)

                                                                                                                                                    JAMES KING-HOLMES / SCIENCE PHOTO LIBRARY

50 | Chemistry World | July 2008                                                                               
                                      overlap each other,’ he explains.                                                                         to address some of the world’s
                                         ‘If you have high enough                                                                               environmental problems.
                                      coverage, you can use a
                                      computer to reassemble the                                                                                  The farthest shore
                                      information. It’s easier to                                                                                  This project was a true
                                      understand by contrasting it                                                                                 adventure, a two-year mission
                                      with what was done before,                                                                                    to shotgun sequence the
                                      when people could only                                                                                        world’s oceans in search of
                                      sequence small pieces of                                                                                      new genes. And Venter says
                                      DNA, and then assemble the                                                                                     that the mission has already
                                      information largely by hand.                                                                                   had a huge impact. ‘The
                                      They had to work up in an                                                                                      first paper that came out of
                                      incremental fashion,’ explains                                                                                  the expedition more than
                                      Venter.                                                                                                         doubled the number of genes
                                         This is the key difference                                                                                    that were known to science
                                      between the ‘old’ DNA                                                                                            – in a single paper.’4
                                      sequencing technique and the                                                                                         As a hybrid businessman
                                      shotgun sequencing approach.                                                                                      and academic, Venter
                                      The former builds laboriously                                                                                     is tight-lipped about
                                      upward from individual bases                                                                                      commercially sensitive
                                      while the latter looks downward                                                                                   information. He only adds
                                      by matching the overlaps of large                                                                                  that ‘some of the ideas
                                      blocks of bases.                                                                                                   about what we’re doing
                                         ‘We can do in days to weeks                                                                                     with fuel and CO2 in the
                                      to months what used to take                                                                                         environment resulted from
                                      decades. The first genome we                                                                                        the Sorcerer expedition’.
                                      did in 1995 took four months to                                                                                         As well as planning his
                                      do – in contrast to 10 years and a                                                                                  own additions to scientific
                                      1000 people for the yeast                                                                                            history, he betrays a
                                      genome,’ he adds.                                                                                                    real appreciation of

                                         The HGP consortium was                                                                                            pioneering research. The
                                      outraged at the thought that                                                                                         genesis of the Sorcerer
                                      a company funded by venture                                                                                           II expedition is rooted
                                      capital was competing with them.                                                                                      in the Victorian voyages
                                      Venter himself was accused of                                                                                          of both HMS Beagle
                                      attempting to patent the human                                                                                         and HMS Challenger
                                      genome for his own financial gain                                                                                      (see Chemistry World,
                                      – an accusation he strenuously                                                                                        February, 2008, p56)
                                      denies.                                                                                              although with differing emphases.
                                         He says that the public versus                   But both Venter and his       Venter’s effort    ‘There are parallels with both,
                                      private dispute missed the central       technique were instrumental in           to sequence the    but much more directly with the
                                      point of the debate: the publicly        the ultimate success of the project,     human genome was   Challenger expedition – that was
                                      funded HGP proposed to use the old,      and he and the leader of the HGP         controversial      the first actual scientific expedition,’
                                      tried-and-tested cloning method.         – the director of the NIH, Francis                          he says. ‘There is the parallel with
                                      The fact that it was a heartbreakingly   Collins – made their triumphant                             taking samples every 200 miles
                                      slow process was part of the reason      joint announcement that the human                           around the globe trying to answer a
                                      for the billion-dollar budget.           genome had been sequenced, at a                             specific biological question. But also,
                                         Venter’s proposal was to use a        press conference held at the White                          it is a level of discovery – as was done
                                      huge array of the latest capillary-      House in 2000. (Celera and the                              by Darwin in the Beagle – that in the
                                      based DNA sequencers, that were          Human Genome Project scientists                             end moved science much further
                                      just rolling off the production line,    finally published their drafts of the                       ahead than perhaps the Challenger
                                      in conjunction with the shotgun          genome in February of the following                         expedition did.’
                                      sequencing approach to do in only        year, in special issues of Science and
                                      a couple of years what would take        Nature, respectively.2, 3) This was a                       Money talks
                                      the publicly-funded project almost       crowning moment in Venter’s career,                         His commercial connections are
                                      a decade. He did this with his           but soon after he was fired by Celera.                      almost as well-known as his science,
                                      company, Celera.                            Venter’s Kevlar self-confidence                          so does Venter entirely reject the
                                         And his technique did indeed          was dented by this, but he took                             mechanisms of public funding? ‘I
                                      allow the human genome to be             refuge in the one environment he has                        think that the processes in both [the
                                      sequenced much faster than using         always found the most sympathetic                           US and UK] are extremely limiting,’
                                      conventional methods. But the            on Earth – the ocean. Sailing aboard                        he says. ‘Governments are largely
                                      rivalry had become so bitter that        his sloop Sorcerer II on the North
                                                                                                                        ‘We more than      risk averse when it comes to handing
                                      in the end it was mediated by the        Atlantic Ocean he decided to move        doubled the        out funding – it’s not necessarily the
                                      most powerful man in the world           on to even more ambitious scientific                        best science and the best ideas that
                                      – President Bill Clinton. In March       goals. Venter planned to save the
                                                                                                                        number of          get funded.’
                                      2000, Clinton announced that the         planet from human exploitation           genes known           ‘I think that represents a big
                                      human genome sequence could not          by sequencing the genome of the                             challenge as society is so dependent
                                      be patented, and this sent Celera’s      oceans, to catalogue the genes of
                                                                                                                        the science in a   on science for our future survival.
                                      stock plummeting.                        microorganisms that could be used        single paper’      We can’t continue to take this
                                      52 | Chemistry World | July 2008                                                                           
                                                                                                                                                               GETTY IMAGES
average, mediocre approach. There                                    medicines and new fuels for the            [development]. We’re working
has to be a much greater element of      Venter has set out with     environment, where the public good         with another group, designing new
risk funding – to fund new ideas.        his vessel Sorcerer II to   is only reached through a business         approaches to chemotherapeutics.
   ‘All the breakthroughs that my        sequence the genome of      being involved. Governments don’t          I think a new set of rules will enter
teams have come up with – which          the oceans                  produce drugs, they don’t produce          the biological repertoire and, if
certainly for a small institution                                    fuels, certainly not alternative ones      scientists use their imaginations and
have been worthy in many people’s                                    to try to stave off environmental          break out of their current moulds,
eyes – none of them originated with                                  damage.’                                   they’ll find an immense number
government funding of a project                                         It seems that philanthropy might        of applications for these new
based on submitted ideas.’                                           tick all of the necessary boxes: ‘We       technologies.’
   ‘In fact the idea for shotgun                                     have a unique phenomenon in the               The immediate priority for this
sequencing of genomes was soundly                                    US of funding by people who have           technology is in facilitating the
rejected by the NIH, but, because                                    made their fortunes in business            move away from a hydrocarbon
we generated some independent                                        giving back to society. I don’t see that   economy. ‘I think the future of
funding, once we proved the idea                                     happening substantially anywhere           humanity is absolutely dependent
worked we were able to get very                                      else in the world, including in the        on new science and I think that
substantial government backing,’ he                                  UK.’                                       creating artificial life forms that
recalls.                                                                                                        produce new sources of energy
   ‘So it makes you wonder how                                       Future drug design                         will be part of that repertoire,’ says
many equally powerful ideas never                                    Although his present concerns              Venter.
see the light of day because people                                  are largely focused on the                    ‘Our goal is not to put chemists
don’t have alternatives when                                         environmental benefits of synthetic        out of business, but rather to expand
they’re rejected by the conservative
                                         ‘None of the                genomics, Venter has not forgotten         the repertoire and the scale of what
establishment.’                          breakthroughs               his roots in medicine amid the             can be done.’
   Bruising encounters with                                          jungles of Vietnam. He thinks that
venture capitalists have coloured
                                         that my teams               synthetic genomics will soon have          Richard Corfield is a freelance science
his views of business-funded             have come                   major health implications for drug         writer based in Oxford, UK
science, but he still feels there is a                               design.
need for the momentum generated
                                         up with have                   ‘I have had discussions over the        Reference
by commercial interest in new            originated from             last few weeks on that topic, and          1 D G Gibson et al, Science, 2008, 319, 1215
                                                                                                                2 J C Venter et al, Science, 2001, 291, 1304
research.                                                            I have for a couple of years been
   ‘There are many things, for
                                         government                  talking about how it could affect
                                                                                                                3 International Human Genome Sequencing Con-
                                                                                                                sortium, Nature, 2001, 409, 880
example the development of               funding’                    antibiotic, antiviral and new vaccine      4 J C Venter et al, Science, 2004, 2, 66                                                                                                   Chemistry World | July 2008 | 53

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