LUNCHTIME  WITH  Mr  BIG
                                R Mann
                                        Auckland Jan 2001


       The big lecture theatre in the medical school was almost full by noon on Jan 26 when J Craig Venter, president of Celera Genomics, was to speak at 12.30.   A communist was giving out leaflets in the main foyer quoting Steve Jones on the failure of gene therapy and saying the human genome project is mostly a waste of money.  Extra 'security' was on.  
        I found myself sitting with a yacht broker who was here in NZ to help Venter buy a luxury yacht.  This engaging man was fulsome in praise of the NZ luxury yacht industry.  I felt ashamed that we aren't doing anything more useful with those skills, but I kept my peace.  Instead I advised him "sign him up quick on the way to the airport before the bubble bursts".
     The yacht dealer arrived with a charming woman, who had attended one of Venter's big announcements of "completion" and now gave the general impression of a devotee.   She spoke with warm evangelical vague enthusiasm of the many medical benefits to come from DNA sequencing of humans and animals.  I asked her *what* benefits she expected; as she recited again the vaguest fantasies, with no attempt to identify any reality, I felt I was observing a devotee  -  she held this faith with a blatant disregard for fact & reason that reminded me of totalitarian sects. 
    The reserved seats at the front were occupied at 12.25 by a phalanx of personages including the chief executive (vice-chancellor) Dr Hood who is also a director of numerous corporations [now V-C Oxon!!].  The chairman, Dr Peter Gluckman dean of the med school, then introduced Venter with fawning adulation  -  "one of the most distinguished scientists and entrepreneurs".

    J Craig began by simply saying he had followed for 5-6y 'basic science ideas'.  Early in his career he had sequenced an adrenalin-recognition protein, which took a decade by the then best methods.  (He also passed what was to me a welcome quip that biochemistry had at that time been fixated on a fad attributing almost everything to cyclic-AMP.  Now, if only he could see the current fad, rather than exacerbating it  ...) 
        Venter operates, in an area about the size of a football field, 300 x U$300,000 sequencing machines run by 9 staff.  A further 50 staff are employed in making each day 300,000 plasmid clones which are then sequenced.  These 'shotgun' sequences are far bigger than used in other approaches, necessitating huge computing to assemble them into the whole from one chromosome or one microbe, etc.   Venter's main impact on sequencing has been by computing.  He claimed he's doing one or two teraflops in 1500 "high-end" CPUs, with more than 100 terabytes of storage, collaborating with the hitherto kings of supercomputing, the modellers of nuclear explosions at Sandia Corp.  Thus, he said, the biggest computing effort is devoted entirely to what he is pleased to call "biology".
        Some couple dozen genomes have been caricatured into the 4-letter alphabet by this method at Celera and his wife's similar TIGR.  The first was _Haemophilus influenzae_ which took a year or two but today would take a day or two.  The 5-chromosome genome of a mustard-family plant, _Arabidopsis_,  120M base-pairs, about 4% the size of the human genome, is to be the basis of crop-GM; a sequence for it was announced Dec 2000.
       The number of genes in the human genome has been whittled back from about 100k just last year to 26k and falling (mainly by revising the definition of a CpG island).  I guess this may be intended to help relieve the log-jam at the Patent Offices  -  but patents were not mentioned. 
      The human genome has been classified 1.1% exons, 24% introns, and great grey lengths of non-coding DNA for which the term 'junk' was not used but which Venter stated to have "more forensic than biological function".

        J Craig's PR site www.celera.com features many claims of imminent medical product e.g.
>
>A Fatal Flaw in the Hearts of Children
> Scientists identify a gene involved in the sudden cardiac deaths of healthy children.

My favourite gleaning in a quick scan of Celera's website was
> Leverage the same infrastructure and workforce that sequenced and annotated the Human Genome!


    The popularity of these sequencing fads is, just lately, overwhelming.  Venter says he has spent U$250M without producing any sales.  Having got Blair & Clinton to hype his arbitrary 'draft' human DNA sequence, he now says Feb 15 is to be the real completion.  He still calls this future advanced draft "essentially complete"; nobody asked him what that key adjective 'essentially' means. 
   So far from claiming imminent benefit from any of this DNA sequencing, he now mocks genetic determinism.  The different genomes contributed by his "number of" volunteers allow us to "tell the males from the females", but "there will not be a genetic determination of African-American".  He announced, as if it were a great & recent discovery, that bowel cancer is caused by not only defective genes but also toxins from food, so that not only genetics but also environment contribute to the disease.  He mentioned biology with apparent respect, and used the term 'holistic' at least twice.  I wondered whether U of Ak honchos who had been purging biologists in favour of gene-tamperers felt any twinge at this stage.

    "Your stock rose from about $3 to $300, and now it's about $30.  How do you explain that?"  asked Mrs Dianne Yates MP (without identifying herself at all).  "Ah yes  -  there's always one in the audience  -  a stockholder!" replied Venter.  He ascribed the big rise to the hope of a new future; blamed Clinton for crashing the stock market; and added a few glib econobabblings which I couldn't understand let alone recall.
 
        Dr Jorg Kistler, who recently earned a personal chair at Auckland in electron microscopy, asked  how realistic are hopes of gene therapy.  In a similar vein, but humorously, a local votary of the gene-tampering fad, director of biological sciences A R Bellamy, excelled himself by asking "what do you advise Dianne Yates to do about her insurance?".  The responses were a series of ill-connected sound-bites reminiscent of the style of our babbling minigorilla now 'heading' the WTO.  Venter downplayed the utility of DNA sequencing for predicting medical risks.  A dozen 'disease genes' have been announced in the past couple months, he said with implied disapproval.  Mutations in the CF gene cause not only cystic fibrosis but also 9 other diseases; and more importantly, many changes in that gene cause no ailment at all, he said.  Indeed, "variation does not come at a deterministic level."  We can crudely find predilections for some ailments, but at best estimate only a probability (said in such a way as to imply this is not enough for insurance companies).  Some of the predictions are unjustified, so laws are being misconceived on no better than novel prejudices.  If we can't tell a black from a white by their DNA, the insurance companies are likely to be disappointed by attempts to foretell illnesses.  Comparing individuals by 'vertical SNP analyses' i.e. single-base mutations has yield no clear conclusions.  For risk readings, we'll have to move on to 'proteomics', he averred.
       For this *really* up-to-the minute commerce, sequencing proteins, he showed a large box with few readouts or controls, a prototype sequencer.  A laser source feeds a time-of-flight mass spectrometer to sequence proteins even in mixtures.  (This claim is incompatible with his desire to ignore post-translation mods such as glycosylation, which certainly would be identified in such a sequencer  -  if it works at all.)
      The ultimate response to the misguided hopes for medical predictions from DNA sequencing would be to sequence everybody's genome; so many differences would be discovered that nobody would be able to get life insurance cover, joked J Celera.  I thought this was a serious contender for the title 'ultimate cynical nerdism'; although Venter insists Celera is a non-profit organisation, he made some smug vague complaint about high personal income taxes, and would not appear to be the sort of person who needs life insurance.

        In his regular glib flippant way, Venter seemed to affirm atheism.  A dating system for evolution over hundreds of millions of years is based on sets of at least 3 gene repeats, he seemed to suggest.  These data imply, he expounded, that it has taken 10^8 - 10^9y to create the human, rather than "somebody saying one day, 'let's do it' ".  In this flippancy J Celera was impliedly denying not only the 6-day creation but also the Creator; but he said nothing definite on these matters, so I hold out some hope that I misunderstood his vague theological quips.

        Gluckman was good enough to let me ask an early question:
                       "The leader of the Arabidopsis genome project which you mentioned  -  a graduate of this university [my first grad student, M W Bevan] -  passed thru here a couple years ago and gave a talk.  He said 'odd' bases do not occur in the copies which are sequenced.  But we have known for 4 decades that 'odd' bases exist in DNA.  Apart from the role of methylC in CpG islands silencing transgenes & so forth, he said 'we don't have a handle on them'.  So his sequences are not accurate but are simplified on the slogan 'The Big Four Rule OK'.  What is the role of odd bases in your work?"
Although so important as to show pictures of himself speaking at the podium with the crest 'The President of the United States', with Clinton looking up at him, Venter resorted to a personal wisecrack, quipping to Gluckman  "is this your local version of a minority?"  This childish behaviour may be a sign that he is not as confident as he seems in his ideas such as the slogan 'The Big Four Rule OK'.
                He proceeded to admit his output is indeed only in the 4-letter alphabet T, A, G, C.  This simplification he claimed to be minor, an attitude he mainly justified by pointing to the similar or worse backwardness in identifying 'odd' groups tacked on to some proteins.  "It's the same with proteomics  -  the glycosyl residues and so on can be pinned down later.  It'll take a century to get all these embellishments."
                Carrying on from this reply remarkable in part at least for its candour, he uttered what I thought was one of his more quotable conclusions:  "There's no single hi-thruput method to solve all biological problems." 
  The final questioner, quite possibly a devotee like my neighbour, cooed in Noo Eege style "how will folks be led to accept instead of fearing?".  Venter replied "it *is* fearsome  -  given genetic determinism", and warned that spurious detection of a fault in the CF gene in a foetal sample might provoke an unwarranted abortion.
        Gluckman asked for confirmation that the way going forward with the "Knowledge Economy" is for universities to transfer technology to biotech corporations.  Venter responded with some econobabble which I took to be affirmation of this strategy.  What is actually being done is that Bellamy is purging biologists to make room for gene-tamperers who are expected to bring in money from venture capitalists; this gives a somewhat different impression from Gluckman's sketch of the process.
        Gluckman appeared to be proximally concerned to use the occasion to persuade Hood & others that the University of Auckland should do as Venter said Australian universities had wisely done  -  pay to get connected to his database.  How easy this might be for students to use Venter perhaps hinted at in his advocating that advanced computer skills should be central in the med school.  Gluckman said a formal announcement should be out soon after negotiations on Feb 26.
   What good might come of all this was left completely unclear.  But the loud lengthy applause as the session ended left no doubt that the generally young audience agreed with Gluckman: J Craig is one of the great scientists and great entrepreneurs.

        Mrs Yates MP departed in the company of the devotee I had met earlier.  I accosted Yates with a brief attempt to disillusion her  -  should that be a step still open.  She identified her problem as inability to assess "the discrepancies"  -  I took her to mean the differences, which he had vaguely stated to be 5% and implied to be negligible, between Celera's sequences and those of the public team as he had called it.  I replied that almost everyone is similarly handicapped.  She moved on across the carpark, listening to the devotee.

        As J. Craig swept celerically out the med school front door I cheerfully called out exhorting him to keep after those 'odd' bases.  He smiled  -  but then he had done that most of the time.   I would be very surprised if he had learned anything from this event, so great is his cockiness.
        And yet the fact remains that he had not even claimed, let alone proven, any benefit from his sequencing.
        Truly, we live in the age of bullshit.  The biggest con, degrading science to junk and technology to disreputable dangerous furphies, is gene-tampering.


-- 
L. R. B. Mann  M.Sc  Ph.D
applied ecology
P O Box 28878  Remuera, Auckland 1541, New Zealand
(9) 524 2949
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