Nineties Retro: A Visit to the Human Genome Project (1998)

The receptionist is chatting to a friend on the phone. Should they meet for lunch? The canteen has savoury pancakes, and they're always nice. Oh yes, she's glad it's Friday too. On the counter in front of her is a book for signing visitors in and out, a little stand-up calendar, and a collecting box for a cancer charity. A couple walk past and one of them drops in a coin. The pair are both young, early twenties, dressed in casual slouching-around clothes. He has a pony tail and a teeshirt that says 'dazed and confused' in a fuzzy blurred-vision font. She has one of those tassled hippy skirts that comes from India by way of an outdoor craft market.

It must be coffee-break time. More kids file past, clutching styrofoam cups, apples, packets of crisps. One even has a skateboard tucked under his arm. 'Kids' feels like the right word. Some of them can't be older than seventeen. They are laughing, chatting each other up. Looks like this is a pretty relaxed place to work, a fun place.

I sit on a leatherette reception chair, and as the employees trail past I stare, mesmerised, at the box on the wall. I can't take my eyes off it. In itself the box is not particularly impressive, just one of those scrolling LED displays you see in shop windows, the kind that advertises cheap flights or deals on contact lenses. But it is the only hint in this identikit lobby of what this organisation is doing. A stream of green letters flows from right to left, nonsense letters with no spaces or punctuation.

GTTATACGTTAAGATGGATGAATGATCCTCGAATTAGATCCA...

Every so often the flow halts, to be replaced by an announcement.

138300449 bases sequenced

In the ten minutes I wait in the lobby this number rises rapidly. 138300937... 138301181... 138301913. The receptionist sees me watching and smiles. Amazing, isn't it, she says. I agree. I am watching, in real time, the latest results of the Human Genome Project. The little LED shop sign is reading out the book of life.


You know all about this. You saw it on TV. The evil scientist throws a switch and gradually the neatly laid-out Nazi uniform is filled with a body. The eyes flicker to life over the toothbrush moustache and - ta da! - Adolf Hitler, cloned from a fingernail clipping, comes goose-stepping back into the nineteen-seventies. Flick the remote and there are some more scientists screwing around with microscopes and babies. Flick. Doctor Moreau making hideous human-animal crosses. Flick. Cold War mutant superheroes (radiation accident, dummy) trading shapeshifting moves while battling the drug lords.

Even the news programmes use spooky music and uplighting when they run a genetics story. These are the items in which the presenter, always so gung-ho when taking apart a politician, listens to the talking head with unusual humility. Somewhere near the beginning Paxman-or-whoever will say something elaborate which means "we're scared" and the scientific expert will give an elaborate reply which translates as "don't worry, we know what we're doing." Then, as soon as the explanation starts getting technical, the producer sends kill messages through the earpiece, and the conversation is cut short. Science lessons make bad TV. On to developments in the Middle East.

Yeah, you know all about this.


The Human Genome project is the largest scientific data-gathering exercise ever conducted. It is also probably the most sophisticated, only rivalled by some esoteric things being done with billion-dollar particle accelerators and radio telescope arrays. It involves major teams in at least eighteen countries and associates in many more, all of whom upload their results to networked databases that are eagerly searched by thousands of researchers every day. The sense of global excitement is palpable and constant. The data I watch on the reception sign is a live stream from the main server, and it speeds past day and night. Any second the sequencing machines might hit an interesting gene, one that fits a profile, one that gives someone in a lab somewhere an idea. One that might make that someone, or their boss, a million dollars.

The building in whose lobby I am waiting is a low-profile glass and steel construction, screened from the main road by a line of trees. The Sanger Centre, named for a pioneer of gene sequencing techniques, is set in 55 acres of park land attached to an eighteenth-century country house a few miles outside Cambridge. The whole complex is owned by the Wellcome Trust, the world's largest charity, and they have just bumped up their funding to £205 million. This is a fraction of the money being spent on the Human Genome Project internationally, $3 billion so far from the US federal government alone. The Trust probably didn't want to sink in more cash - the centre is already cripplingly expensive, even for an organisation capitalised by shares in a vast multinational drug company. But its hand was forced.

"The Trust is concerned that commercial entities might file opportunistic patents on DNA sequence. The Trust is conducting an urgent review of the credibility and scope of patents based solely on DNA sequence. It is prepared to challenge such patents."

[Welcome Trust press release 13th May 1998]

For ‘commercial entities’, read ‘Celera Genomics’. Last May a private American company by that name announced that it possessed new technologies which would allow it to sequence the human genome by 2001, years earlier than the projected 2003 finish date for the international effort. By September it was offering stock for sale, its CEO commenting on his excitement at “entering the information side of the life science business” and reminding his backers that “this plan reaffirms [Celera’s] commitment to creating maximum value for our shareholders.” Celera promises it will share its information, eventually. But not before paying customers (which in practise means big drug companies) have checked out its database, and applied for patents on anything that looks useful.

To most people, the idea of patenting a gene is rather like patenting the speed of light, or the colour blue. It is information, a fact, just something that exists out there in the world to be discovered. But in the bright shiny future of corporate science the boundary between 'fact' and 'intellectual property' looks blurred. A decision has yet to be made on whether gene patenting is legal, but few scientists want to take the chance. So since last May the Human Genome Project, which is committed to public access to its data, has been in a race.


And the end of all our exploring

Will be to arrive where we started

And know the place for the first time

[TS Eliot 'Little Gidding']

The object of all the fuss was first seen by a Swiss biochemist called Friedrich Miescher in 1869. Every morning Miescher would call at his local clinic to pick up a bag of used bandages, choosing for preference the ones soaked in pus. This being the days before chemical antiseptics, supply was plentiful. Miescher was studying human cellular structure and in 1869 microscopes had quite low magnification. Pus contains a lot of white blood cells, and white blood cells have large nuclei, so unfortunately used bandages were where it was at, visibility-wise.

One day Miescher added an alkali to a sample, and noticed that the nuclei burst open to release an unknown substance, about which he could only discover that it was acidic and contained phosphorus. So he called it (with a certain logic) 'nuclein' and passed the baton. Ten years and a bigger microscope later someone else spotted that 'nuclein' was made up of little thread-like structures. These were christened chromosomes, which in scientist-Greek means 'coloured things', because they easily absorbed the dyes biologists used to stain samples. By the end of the nineteenth century it was becoming clear that the coloured things had something to do with inheritance, and since inheritance was a hot topic on account of one Charles Darwin, chromosomes became the object of obsessive global scrutiny.

It took fifty more years before someone could work out what they were all watching. In 1953 Francis Crick (maths, physics) and James Watson (molecular biology) skidded out of a prefab hut behind the Cavendish laboratory in Cambridge and into the pages of Nature with a structural model for the stuff that was now called DNA. They were just ahead of two rival groups, and their paper showed an extraordinarily long and thin molecule with twin coiled backbones of phosphates and sugars, like a ladder twisted round on itself. The rungs of the ladder were seen to be made from pairs of 'bases', substances that react with acids to neutralise them. DNA contains only four kinds of these bases - adenine (A), guanine (G), cytosine (C) and thymine (T). These are the letters scrolling past on the lobby LED screen, and the aim of the Human Genome Project is to read them all in the right order. All three billion pairs.

Another fifty years further on, we know something about what that string of letters means. DNA is data storage. Each triplet of bases, each string of three letters in the sequence, is an instruction. DNA instructions are read off by a molecule called RNA, which acts on them to build or link together one of twenty amino acids. Amino acids are the basis of proteins, and proteins are more or less what the human body is made of. An incredible variety of these complex molecules can be formed from folding together the twenty amino acid building blocks, and they do every kind of biological job from creating muscle tissue to regulating production of the white blood cells Herr Professor Miescher found in his bandages. Knowledge of proteins means control over the human body, and in 1999 control over the human body means happy stockholders. The Human Genome Project is, among other things, the twenty-first century version of an oil well.

__

I walk along the corridors of the Sanger Centre, past cabinets of gleaming glassware and rows of hooks hung with starched white labcoats. People stroll by. A woman wearing plastic goggles trundles a hostess trolley of used test tubes. A bearded guy half-jogs his way to an appointment, his security pass whipping back and forth against his chest. Around four hundred people work here, but few of them are the high-powered research scientists you would expect. Some of the employees are sixteen year old school leavers, and many more are on day release from undergraduate university courses. Team leaders tend to be young graduates, and only those at the very top are veteran research biologists.

The hierarchy is telling. The Human Genome Project occupies a weird twilight zone between research and mass production. As I pass row on row of identical labs, each with the same layout, each performing the same repetitive tasks, the eureka clichés of heroic science fall away to be replaced by other images - car workers making model T Fords, nineteenth-century mill hands. This is knowledge gathering on an industrial scale. Only the upper levels of the organisation are engaged in what would popularly be recognised as scientific research. The lower levels are technicians, bio-hands servicing the sequencing machines.

Most of the Wellcome Trust’s funding goes on raw materials. Sequencing uses huge quantities of chemicals, and the Sanger Centre frequently puts in orders that exhaust the world supply of a particular biological agent. After materials, labour is the main cost, although month by month sequencing automation becomes more efficient. The Sanger Centre has an in-house robotics team, dedicated to shaving time off the process with new computer controlled machines. There is a quiet determination about the people moving around in the building. Every increase in productivity will give them a better chance of beating their rivals to the prize. Behind the casual exterior, there is an obsession with speed.


Darren is a sequencing star. In his mid-twenties, he has spiky toothbrush hair, a shy smile and a higher degree in one of the biological sciences. He looks like one of the lads who were always propping up the college bar, the ones I would meet in the very early morning when I was stumbling home from a bender and they were dragging their hangovers off to an 8am lab practical. Now I’ve given up wearing flourescents and Darren is in charge of a sequencing team at the Sanger Centre. He is, I am told, a man to watch. I like working here, he tells me, smiling and looking longingly at his computer. You go home and it’s over. At the end of the day you can see what you’ve achieved. You feel pleased with yourself. I ask if he thinks of his work as codebreaking. No, he says. It’s more like crossword puzzles. Then, as I process that information, he dives through his office door and is gone.

Darren, like most of the staff at the Sanger Centre, is working on sequencing the Human Genome. There are also teams working on pathogens, another area in which there is competition from private companies. Around the Sanger Centre are -70° freezers filled with bacterial cultures of malaria, tuberculosis, leprosy.... I peep into one of the TB labs, which looks just like all the other sequencing production lines. Perhaps it is the notice reminding staff not to touch the doorhandle with work gloves on, but I find myself trying not to breathe in until I leave the room.

Whether it’s TB, malaria, the C. Elegans nematode worm or human beings whose DNA is being sequenced, the process is the same. Tiny samples of DNA are induced to replicate themselves through the so-called Polymerase Chain Reaction, which causes the molecule to unravel and duplicate itself from a bath of raw materials. Each lab has a bank of PCR ovens, cycling samples through a precise sequence of temperatures, building microscopic fragments into gobbets of white gloop, visible chunks of pure DNA. The samples are then fixed into sheets of gel, a row of DNA dabs at one end, like contestants at the starting line of a race. And this is pretty much what they are.

When the gels are ready they are taken down to the main sequencing lab, a large white room containing regimental rows of identical computers. The loud hum of hard drive cooling fans forces you raise your voice to talk. The light is so bright and white that for a moment you think you might have wandered into some kind of Intel-sponsored afterworld. Here the gels are placed into racks, each one connected to a power source and a computer. A low voltage current is fed through them, and the DNA starts to split up and move. Effectively the gels are a filter. Bigger molecules travel further through it, and since each of the four bases is a different size, each one will end up in one of four positions. These positions can be read off by the computer, which brings the results up on screen as a coloured dot. The big white room is filled with monitors showing a patchwork of tiny red, green, blue and yellow smudges.

This process is 95% accurate. The raw sequence data is then ‘hand-finished’ by human beings like Darren, who look for ambiguities and resequence doubtful areas to double-check. The Sanger Centre is proud of its quality standard. They reckon on making only one mistake in 10,000 base pairs. The finishers spend long caffeinated hours in front of their screens, trying to make things fit. All this technology can only deal with relatively small bits of the molecule at a time. The sequencers have to use enzymes to chop it up into manageable segments. Most of the work lies in fitting the sequenced bits back together in the right order, finding the order of the letters in the newly-read code.

The job is enormously complex. Not all DNA codes for proteins. There are spaces, stop and start signals, stretches which instruct protein production to be switched on and off in particular circumstances. This being life, the result of millions of years of suck-it-and-see evolutionary strategies, DNA is also far from efficient. Protein-building instructions are duplicated, sometimes hundreds of times on a chromosome, and there are huge stretches of DNA which seem to do nothing useful at all, evolutionary remnants, nonsense repetitions and garbled messages. Junk DNA.

Even when the job of sequencing is done, whether by Celera or the international project, it will only be a beginning. At the moment around 7000 of the possible 100,000 genes have been identified, along with fragments of perhaps another 10,000 more. The map of the Human Genome is still mostly blank areas and signs saying “here be dragons”. Geneticists have a lot of tantalising hints, clues, strange phenomena. On chromosome four there is a gene which has led to babies being born with extra fingers and toes in inbred Amish communities. On chromosome seven there is a mutation which makes modified lab mice grow enormously fat. On chromosome eight another mutation causes accelerated premature ageing. This is the sort of thing geneticists know in 1999. It is going to take years, but the results of sequencing the human genome will turn this fragmentary information into something systematic, into knowledge which will allow prediction and, eventually, control.

__

“When a low race is preserved under conditions of life that exact a high level of efficiency, it must be subjected to rigorous selection. The few best specimens of that race can alone be allowed to become parents, and not many of their descendants can be allowed to live. On the other hand, if a higher race be substituted for the low one, all this terrible misery disappears. The most merciful form of what I call ‘eugenics’, would consist in watching for the indications of superior strains or races and in so favouring them that their progeny shall outnumber and gradually replace that of the old one.”

[Francis Galton Inquiries into Human Faculty 1883]

The word ‘gene’ just means a stretch of DNA which codes for a particular protein. No more, no less. Keep that in mind the next time you hear someone talking about how homosexuality is ‘genetic’, or women are ‘genetically’ less intelligent than men. Single genes do not specify complicated human qualities like who you fancy or how good you are at playing the violin. They make molecules.

The dream of eugenics, Francis Galton’s science of selective breeding for human betterment, came to a terrible end in Auschwitz, or at least with the Unesco (United Nations Educational Scientific and Cultural Organisation) “Statement on Race” in 1950. This declared that World War 2 had been made possible by “the doctrine of the inequality of men and races”, and enshrined global scientific opposition to it. At least that’s the official story.

In practice, eugenics has not so much died as retreated into a dark corner. Eugenic ideas still circulate widely in Eastern Europe, their targets usually socially-disadvantaged Romany communities. In America the publication of ‘The Bell Curve’, a book which claimed that white Americans have higher average IQs than black ones (and implied a set of right-wing social policies based on this finding), became a major media event. The advent of the Human Genome Project has led more than one newspaper commentator to look forward to a future where prenatal screening for ‘genetic defects’, and perhaps active manipulation of foetal genomes, can be performed for the good of society. Knowledge of genetics has immense potential for misuse.

Eugenics 2000 will not be conducted through a coercive Nazi-style programme. It will probably not be associated with any kind of government-run project of social engineering. Like everything else in our hypermarket culture, it will come about through the magic of consumer choice. We ‘freely’ undergo cosmetic surgery procedures to conform to a current norm of beauty. Why should we not be free to screen our unborn children, simply to ensure they are what we want them to be? When a competitive market for prenatal screening procedures comes about - as it certainly will - the commercial pressure will always be in the direction of more testing, not less. A market for products and procedures which allow rich parents to design babies, or at least to believe that they are doing so, looks likely to boom. Will such consumer decisions be taken from a position of full knowledge, dispassionately applied? Or will mummy want a perfect little Mozart, and no chances taken? The market looks likely to dictate free will, despite the best efforts of scrupulous geneticists to point out the flaws in the ad copy. Doctor Michael Morgan, CEO of the Wellcome Trust’s Genome Campus, shrugs. “At every stage of medical advance, there has always been quackery. What can we do?”

Without the spectacle of uniforms, flags and white supremacist rhetoric, the idea of being free to choose to terminate a foetus carrying, say, the Cystic Fibrosis gene (as do 1 in 25 Northern Europeans) seems only a good thing. Genetic screening for disease will prevent much human misery. Gene therapies promise improved lives for sufferers of many common diseases. However, who lives and who dies has always been the fundamental political question facing any society. Who is born must now be added to that equation. Prenatal screening, a patriarchal culture and the government one-child policy have led to mass terminations of female foetuses in China. For every 100 girls born, there are now 118 boys. The Chinese government has jumped at the opportunity to institute mandatory genetic testing, and is reportedly pressing ahead despite a howl of protest from the international scientific community. What kind of effect will advances in genetics have in that society?

As soon as opportunities are given or denied to someone because they carry a particular gene, a eugenic society will be in place. Insurance companies are already clamouring for the right to screen clients. Perhaps in ten years time you find yourself paying a higher health premium than your neighbour. At your insurance screening they discovered an AD4 mutation and hence you are considered at greater risk of contracting Alzheimer’s disease. Perhaps ten years later still this finding prevents you from working as, say, an air traffic controller. Then another ten years further down the line it becomes mandatory to declare your screening results on an employment form, just like a criminal record today. Perhaps your prospective boss at the widget company reckons that this Alzheimers thing means your brain must be like Swiss cheese and you won’t be able to answer the phone properly. So he doesn’t hire you. Perhaps. Perhaps. Perhaps...

It’s a slippery issue. The boundary lines between disease prevention and paranoia are fuzzy, and it is not in the interest of the emerging gene-market to clarify such issues. Michael Morgan advocates legislation to allow individuals to keep genetic information private, and points the finger at the motivations of employers and insurance companies. “It is when genetic testing becomes an instrument of public policy that we really have to worry,” he tells me. As we sit in his fifth floor office at the Wellcome HQ in London, I feel worried enough anyway. It is important to point out that the villains of the piece are not, for the most part, the scientists. Geneticists know the public perceives them as power-crazed Frankensteins, hell-bent on turning middle-England into a B-movie horror set. A few are undoubtedly complacent about the effects of their research. Most are just frustrated at the level of popular ignorance. It is when science gets mixed up with the market that things get really sticky.


GenBase is a trademark of The Perkin-Elmer Corporation.

GeneAmp is a registered trademark of Roche Molecular Systems,Inc., licensed to The Perkin-Elmer Corporation.

GeneAmplimer is a registered trademark of Roche Molecular

Systems, Inc.

GeneAssist is a registered trademark of The Perkin-Elmer

Corporation.

GenePure is a trademark of The Perkin-Elmer Corporation.

GeneScan is a registered trademark of The Perkin-Elmer

Corporation.

GenoPedigree is a trademark of The Perkin-Elmer Corporation.

GenoTyper is a registered trademark of The Perkin-Elmer Corporation....

Perkin Elmer is the parent company of Celera Genomics. In February 1999 Celera got its first customer, the US biotech giant Amgen. Founded in 1980, Amgen has just three products, including a red blood cell regulator which in 1997 netted it a cool 1.2 billion dollars. If Celera manages to sequence the human genome, Amgen will get first look at the data. In their press information the two companies look forward to a “whole new world of individualised medicine.” This is how advances in genetics translate into marketing speak. You’ve got couture clothes, a custom-designed home interior, personalised number plates on your car. Of course you want drugs tailored for your individual personality and requirements. Rich people shouldn’t have to suffer off the peg healthcare.

If the biotech companies have their way, they will be allowed to patent bits of the human genome, allowing them to exploit their own little tracts of DNA much in the way that 49’ers staked claims during the Californian goldrush. A company called Incyte has already had a US patent accepted for an Expressed Sequence Tag, a kind of marker showing a gene of potential interest. Encouraged by this Incyte has patent applications outstanding for another 1.2 million EST’s. Meanwhile in Europe a precedent has been set by the acceptance of patents on three simple organisms with industrial and medical applications. Since these living things can be patented, how the principle might extend to human-derived material is unclear. In Iceland a company called DeCode has made a deal with the government for the right to take samples from its citizens. Iceland has a relatively isolated (and hence genetically interesting) population. It also has a long history of keeping excellent health records. Cross-referencing the two will yield much marketable information. DeCode has just sold database access rights to multinational pharmaceutical company Hoffman-LaRoche. Many Icelanders feel this is happening without their consent.

The gene market is moving fast, too fast to be monitored by a public still watching late night TV movies about cloning Hitler. If patents are accepted on areas of the human genome, the vaunted idea of science as the disinterested collective pursuit of knowledge looks likely to collapse. Sharing data will be a thing of the past, and what is perhaps the final religious belief of the cynical Western World (the belief in knowledge as an absolute good) will be washed away. Patent law works on a single basic principle - you can patent something that is an invention, but not a thing that is merely a discovery. In the brave biotech future, the very act of understanding DNA may well come to be seen as one of invention. Looking and making collapsing into one. What happens to science then?

The young technicians working at the Sanger Centre seem largely untouched by such big questions. The parkland they work in is beautiful. Their prospects, as junior employees in a booming industry, look bright. As I walk round the building, photographing the brushed steel and plate glass exterior, I find a barbecue. It has obviously seen a lot of action. It is such a domestic object, such evidence of carefree times, that I have to laugh. Over by the lake there is a football match going on. One lab is taking on another. I stand by a little pile of ash and watch.


*Certain statements in this press release are forward-looking. These may be identified by the use of forward-looking words or phrases such as "believe," "expect," "anticipate," "should," "planned," "estimated," and "potential," among others. These forward-looking statements are based on the Company's current expectations. The Private Securities Litigation Reform Act of 1995 provides a "safe harbor" for such forward-looking statements. In order to comply with the terms of the safe harbor, the Company notes that a variety of factors could cause actual results and experience to differ materially from the anticipated results or other expectations expressed in such forward-looking statements. The risks and uncertainties that may affect the operations, performance, development, and results of the Company's businesses include but are not limited to (1) complexity and uncertainty regarding the development of new high-technology products; (2) loss of market share through competition; (3) introduction of competing products or technologies by other companies; (4) pricing pressures from competitors and/or customers; (5) changes in the life science or analytical instrument industries; (6) changes in the pharmaceutical, environmental, research, or chemical markets; (7) variable government funding in key geographical regions; (8) the Company's ability to protect proprietary information and technology or to obtain necessary licenses on commercially reasonable terms; (9) the loss of key employees; (10) fluctuations in foreign currency exchange rates; (11) the development of new sequencing strategies and the commercialization of information derived from sequencing operations; and (12) other factors that might be described from time to time in Perkin-Elmer's filings with the Securities and Exchange Commission.

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