A huge advance in our understanding of the human genetic code has opened the way to potential cures for killer diseases. It has also set private drug companies against the public sector Human Genome Project over whether patenting is appropriate for human genes.by Tom Wilkie / July 20, 1998 / Leave a comment
Every night, as most of Britain sleeps, the computers at the Sanger research centre near Cambridge wake up and chatter briefly to the internet. Unreadable to all but the expert eye, their message consists of long strings of the four letters A, C, G, T repeated in different combinations.
These electronically published letters are spelling out the most important story ever written: the message of human heredity encoded in DNA. An international collaboration of scientific laboratories, of which the Sanger centre is part, is engaged in reading the entire human “genome”-every one of the 100,000 or so genes that makes a human being. By the year 2005, at a cost of $3 billion, the Human Genome Project-funded mainly by governments and public sector bodies-will be complete. The sequences of A’s, C’s, G’s, T’s which spell out the genetic code will have been teased out of human DNA and placed in the public domain for all to read.
But in May this year, the ordered progress of this project was rudely jolted. An American scientist, Craig Venter, broke ranks and announced a commercial deal with Perkin-Elmer, the company which makes the DNA analysing machines. Together they would use Perkin-Elmer’s latest analysis technology to sequence the human genome themselves, and they would do it in half the time for one tenth of the cost.
The reaction from the scientists of the human genome project was, well, human. They did not greet the news with enthusiasm. Others did: Perkin-Elmer’s share price leapt. For the stock market, DNA spells dollars. Annual sales of erythropoietin, which stimulates the production of red blood cells-just one of the new generation of drugs derived from genetic research-have already broken through the $1 billion mark, placing it alongside Glaxo’s legendary Zantac anti-ulcer drug.
Other drugs are more familiar. Diabetics once had to inject themselves with pig insulin; now they use the human version-produced by bacteria which have been genetically reprogrammed by the addition of the human gene for making insulin. Children whose growth is stunted through a hormone deficiency no longer have to be injected with hormone extracted from the glands of human corpses.
The pharmaceutical industry is pinning its hopes on the idea that many diseases will prove to be genetic even though they are not inherited. The payoff is expected in three big areas: cancer, heart disease and neurological disorders. Very few forms of cancer are inherited. Most cancers arise from environmental damage sustained long after birth. Smoking triggers lung cancer and there is a clear association between diet and bowel cancer. But precisely what happens to the cells lining the lungs or bowels so that they proliferate out of control to form life-threatening tumours? Somehow a few of them escape normal controls on growth. How?
There are thousands of different biochemicals within each cell and it is impossible to take a tumour cell and sift through all the biochemicals to find the one which has been damaged by smoking. But the revolution in genetics over the past 18 years means that it is easier to sort through a person’s genes than through the biochemicals which the genes produce. By looking at the genes of the few people who have inherited cancers, it might be possible to get a clue to what is going wrong not only in the inherited but also in the “sporadic” cancers.
In a recent article in the journal Science, Dr Eric Fearon from the University of Michigan, listed more than 30 different genes and genetic variants which have been implicated in cancer. Research over the past decade and a half has thrown up examples of “tumour suppressor genes” which act to control cell growth and which, if they are defective (either by heredity or environment) will allow a cancer cell to slip out of control. Normal cells receive signals from elsewhere in the body telling them to grow and multiply (growth hormone is one such messenger molecule) but aberrant cancer genes will equip a cell with too many receptors for these molecular messengers, so it gets an amplified signal and proliferates out of control. If a drug company can supply that tumour-suppressor protein or block the growth-signalling pathway then they will have an anti-cancer drug. Whereas once cancer was an intractable problem yielding no clues as to what was going wrong, now there are specific “targets”-proteins or the sites of their action-for drug companies to work on.
This is the theory of “molecular medicine.” It has not yet been realised in practice, although at least ten anti-cancer drugs based on this approach are already in clinical trials. One drug, made by the first biotechnology company, Genentech, blocks the signals which cancer cells receive to trigger their growth. In early clinical trials, out of 36 women with advanced breast cancer which had not responded to conventional treatments, nine showed tumour shrinkage of more than 50 per cent. The company is due to publish results of larger-scale trials within a couple of months.
With this sort of potential, the biotechnology industry has been plagued with hype. In the US and Canada alone, according to the investment newsletter BioTech Navigator, more than 1,400 biotechnology companies have been founded, yet fewer than 50 products have been successfully placed on the market to date. There have been some huge speculative bubbles and some spectacular recent falls from financial grace. But estimates suggest that products derived from genome research could account for drug sales of more than $60 billion by the year 2010-equal to about half the pharmaceutical industry’s current sales.
for such a mover of markets, DNA had an ignominious entry into scientific consciousness. In 1869, the Swiss biochemist Johann Miescher was the first to isolate DNA from pus-saturated bandages at the university hospital of T?bingen in Germany. But biochemists thought proteins looked far more interesting and so for the next 70 years, DNA was neglected. Then, over a period of 15 years, while most of the rest of the world was distracted by the second world war and the apparent triumph of physics as revealed in radar and the atomic bomb, molecular biologists laid the foundations for the science which now overshadows physics in both its social and financial impact.
This period of scientific creativity culminated in 1953, when James Watson and Francis Crick announced that the molecule of DNA-deoxyribonucleic acid-had the structure of a double helix. But although the double helix has become an icon of our times, the two winding strands which make up the backbones of the helix are actually rather boring. The real interest lies in the cross-links-the steps of the spiral staircase which wind up the inside of the helix keeping the two strands together. These links are formed from four chemicals: adenine (A); guanine (G); cytosine (C); thymine (T). A, C, G, T form the letters of the genetic alphabet; it is the particular sequence of these letters which determines everyone’s genetic inheritance. Hence genetic analysis is known as DNA sequencing.
Human DNA, like that of animals and plants, does not come in one continuous strand, but broken up into single molecules called chromosomes contained within the nucleus of every cell. In total, the chromosomes represent some 3 billion letters of human DNA; the 100,000 individual genes are those stretches of DNA which carry meaningful genetic information. The genes are separated from each other by stretches of “junk” DNA which seem to have no function.
Genes are active all the time; they do not come into play just during reproduction. As I write this essay, my nails and hair are growing and my cells are reading the genes-the recipes-for collagen and keratin, two of the constituent proteins of hair and nail. I am digesting breakfast, so my system is secreting enzymes-proteins designed to absorb food-and the production of each protein requires the cells to “read” the gene recipe written in DNA. Red blood cells last only 120 days and have to be made afresh all the time: the cells in my bone marrow are actively reading the genes for haemoglobin and all the other constituents of red blood cells. Each day, I am attacked by bacteria and viruses desperate to hijack my body for their own ends and my immune system makes antibodies-reading the genetic recipes-to fight them off. Mostly, the process is so successful that I never notice.
With a few exceptions, each cell in the human body carries all our DNA and all our genes. The genes in my body will stop when I die. But my genes will not stop altogether as I have children who have acquired half my genetic complement. The differences in genetic structure between people are, of course, significant-they account for many of the differences in appearance and, at least in part, in behaviour-but most of us are genetically very similar. Indeed, the differences in DNA between humans and chimpanzees is less than 1 per cent.
It is the elegance of form and function which gives the double helix of DNA its particular appeal, both in science and popular culture. James Watson chose the form as the title for his controversial autobiography, The Double Helix. In a speech given in 1990, he extended the metaphor: “I have come to see DNA as the common thread that runs through all of us on this planet Earth. The Human Genome Project is not about one gene or another, or one disease or another. It is about the thread that binds us all.” Scientifically, DNA has given to biology the sense of a unity underlying the immense diversity of the living world which the theory of the atom earlier gave to fundamental physics and to chemistry.
Popular culture has reflected this fascination with DNA. Renault and BMW have used genetic metaphors in recent advertising campaigns in Britain, and the science-fiction film Gattaca used the letters of the genetic code for its title. The most compelling scene in the film is where one of the characters, crippled in a road accident, struggles to climb the stairs in his house. The staircase is, of course, helical.
the discovery of the double helix structure of DNA marked a turning point. But a further 30 years would pass before researchers could begin to see that the genome project itself might be possible and worthwhile. For most of that period, human genetics was regarded as a medical sideline. For some years after Crick and Watson’s discovery, researchers could not even count the correct number of human chromosomes in each cell, believing there were 48. Only in 1956 did Jo Hin Tjio and Albert Levan realise that each adult human cell had 46 chromosomes. They are arranged in 23 pairs: one of each pair is inherited from the father, and one from the mother. The number matters: Down’s syndrome is caused by having 47 rather than 46 chromosomes, by having three rather than two copies of chromosome 21.
But the modern revolution in genetics-post Watson and Crick-started not with human DNA but in the human gut. The best keys to unlock the secrets of the human genome were discovered in the enteric bacterium, E. coli. This bacterium has recently earned an undeserved reputation for harming humans following the outbreak of food poisoning in Scotland. But most of the time, E. coli resides harmlessly in the lower gastrointestinal tract and we would be unable to digest our food fully without the help of these micro-organisms. Bacteria are about the simplest forms of life and, at first sight, appear to have little to do with human DNA. But because they are small and simple, bacteria are easy to study. (Science answers big questions but it does so by way of small steps. Those disciplines which insist on tackling “big” questions head-on, like philosophy, seem condemned never to make progress. All philosophy, as the tag has it, is a series of footnotes to Plato.)
It was bacteria which led to the next step in the revolution. In 1970 Hamilton Smith in the US discovered an enzyme in the bacterium Haemophilus influenzae which could “cut” the strands of DNA. These molecular scissors could recognise a specific sequence of DNA and then cut always in the same place in that strand. Even though bacteria separated out from the line of evolution which led to humans billions of years ago, the enzymes that cut bacterial DNA operate just as well on human DNA. The way was open to take samples of blood or tissue from thousands of individuals-as the Human Genome Project does-and to “Xerox” them biologically many billions of times so that a large enough quantity of one well-defined stretch of human DNA was available for analysis. Equally, human genes could be stitched into bacteria or yeast or mice or sheep, so that the recipe for human protein would be read by the other organism’s cells. In this way, previously scarce human proteins suddenly became widely available: insulin; growth hormone; interferons. The era of biotechnology had begun.
The ability to chop up DNA at precisely specified points also opened the way to reading the sequence of A’s, G’s, C’s and T’s. It may not seem obvious how this follows, but then those who worked it out won the Nobel prize for their efforts. One of them was the British scientist Fred Sanger. His low public profile says something about the British attitude to science; Sanger ranks with Marie Curie as one of the few scientists this century to have won the Nobel prize twice. He was awarded it in 1958 for his work on insulin and shared the 1980 prize for work on the sequencing of DNA. The leading method for DNA sequencing today, embodied in the machines that the US company Perkin-Elmer builds, is derived from his work. And the Sanger centre, at Hinxton south of Cambridge where Sanger did his work-as earlier Watson and Crick had done theirs-takes its name from this modest but creative scientist.
In 1980, the last piece of the jigsaw was put in place. Molecular biologists realised that the natural genetic variation between people would mean that the point where the enzyme cuts would be different in each person. Here at last was a technique by which researchers could look at the differences between individuals at the genetic level. They no longer had to probe some physical or biochemical trait, nor even to look for the proteins expressed by the genes; now they could sort through personal differences in DNA directly. All the tools were in place for the Human Genome Project.
The first successes came rapidly. In 1983, a group led by the charismatic American Nancy Wexler showed that Huntington’s disease, a fatal brain disorder, was due to an inherited defect on chromosome four. This was a personal triumph for Wexler, who herself was at 50 per cent risk of the disease. The discovery offered predictive testing for those at risk. But it took a further ten years before the gene itself was identified, isolated from human DNA, and cloned for analysis and study. A huge effort is now underway to work out the function in the brain of the protein which the gene produces.
The gene which, when damaged, is responsible for Duchenne Muscular Dystrophy was identified in 1986; the one for cystic fibrosis in 1989. With these diseases, it was impossible to identify what had gone wrong by using the traditional medical route of starting with the clinical symptoms, narrowing the search for a cause down to the muscles or lungs, and then sorting through the aberrant cells to look for the cause. Instead, molecular medicine works in the opposite direction: pinpointing genetic differences between affected and unaffected individuals, identifying the gene or genes that are affected and working out the particular protein which must be going wrong. Nowadays, scarcely a week goes by without the announcement that a new human gene has been identified, cloned, sequenced. And patented.
over the past quarter century, western governments have been reducing their financial support for basic science and encouraging industry to step in to finance scientific research and, equally, encouraging basic scientists to forge links with industry. In Britain, this process was exemplified by the last government’s science White Paper “Realising Our Potential” which put wealth creation as one of the main goals of scientific research. But science traditionally has produced “public goods”-knowledge about the natural world which is available to everyone. Commercial companies, on the other hand, have a duty to their shareholders to capture the results of research upon which shareholders’ money has been expended and to exercise ownership over the fruits of research as the company’s private intellectual property.
Nowhere is that more important than in chemistry and molecular biology. With bacteria acting as factories for pharmaceutically valuable human proteins (such as erthyropoetin), drug companies cannot rely, as, say, motor manufacturers can, on competitors being dissuaded by the huge start-up costs. Over the past 15 years, commercial companies have been engaging in gene-discovery which might once have been the business of not-for-profit researchers working in universities or state-funded laboratories. Many university scientists, in Britain and the US, have been encouraged to set up their own biotechnology companies and many of these have no assets other than the intellectual property represented by data about a particular gene sequence. The inevitable (but unforeseen) result has been inexorable pressure to claim patent protection over stretches of human DNA.
According to the Science Policy Research Unit at Sussex University, between 1981 and 1995 a total of 1,175 patents for human gene sequences were awarded around the world. (Not all of these patents cover entire genes; some concern stretches of sequence information only.) Among the genes which have been patented are ones concerned with cystic fibrosis, breast cancer and the “relaxin” gene. The latter is present in every woman and is expressed in the final stages of pregnancy to soften the birth canal. Those who hold the patent on the gene hope to be able to make the relevant human protein and market it for use in difficult labours.
Patenting genes, plants and animals, has provoked concern and opposition, particularly in Europe. Critics argue that it is not right to put living creatures and entities, such as DNA, which are capable of self-replication, in the same legal category as mechanical inventions. There is a sort of “genetic essentialism” discernible in some of the objections-the idea that while proteins might be patentable, there is something about genes which deserves special protection. This belief has been encouraged by some scientists who speak of the human genome as “the holy grail” of biology, or “the book of man.”
For many, the real objection is that human gene sequences are objects in nature and writing out the genetic sequence is a discovery, not a patentable invention. Genes are not products and are not given as drugs. Gene therapy has not yet been successful (and is in any case more akin to organ transplantation than to prescribing a medicine). In some cases, the real products may be the proteins for which the genes represent the recipe. In others, the real products may be small molecule drugs which block the action of a protein whose gene sequence is known. In this view, there are many more “inventive steps” before something useful can result from a gene sequence, so patents should not cut in too early.
Some of the early genome patents were very broad. They embraced anything resembling the gene sequence, the protein produced by the gene, tests for the presence or absence of the gene and a whole host of downstream applications. There was no requirement to demonstrate that any of these things had actually been made or that the applicant for the patent really knew how to construct them.
The aim of a patent system is to create proper financial incentives for creative work and to promote innovation-by publishing the design of one mouse-trap it is hoped to inspire someone to devise an even better one. The worry in genetics is that if someone holds a broad gene-patent, they have rights over everything that can be done with that gene. So if someone invents a better genetic test, because it uses knowledge of the gene sequence, it will infringe on the earlier patent. In this way, there is a risk that patents on gene sequences could act to inhibit rather than enhance innovation. The cystic fibrosis gene, for example, is patented and anyone who makes or uses a CF diagnostic kit which employs knowledge of the gene sequence should pay a royalty to the patent-holders. Demands have already been served on the NHS Regional Genetics Service to pay royalties for cystic fibrosis testing. As that patent is valid, so far, only in the US, the first demand for money was legally ignored; patents only cover one country, although European filings often follow the grant of a patent in the US. (The European parliament has just voted for an EU directive which will make patenting human genes, already easy in the US, much easier across the EU.)
Nearly 1,500 patents now exist claiming rights over human gene sequences. This is, inevitably, a matter of tension between the Human Genome Project-funded by governments, public sector bodies and charities such as the Wellcome Trust (for which I work)-and parts of the private sector. But neither defenders nor opponents of current patenting practice actually know whether the current arrangements are damaging to innovation. And some “public” bodies are beginning to adopt “private” practices, such as the Cancer Research Campaign which has patented one of the two breast cancer genes. Patenting genes is probably here to stay; the real anxiety about the Perkin-Elmer deal is over “cherry-picking.” The Human Genome Project laboratories are committed to the immediate open publication of every bit of sequence data they produce. Once in the public domain the gene sequences cannot, of course, be patented. But Venter and Perkin-Elmer will place their work in the public domain only every three months, and will reserve 300 genes for patenting.
Also, the Human Genome Project is committed to sequencing to an accuracy of about one part in 10,000 but it is not clear how precise the commercial sequencing will be. This matters: the human disease sickle-cell anaemia arises as the result of just one mutation in the genes for haemoglobin. Just one letter out of the 3 billion that make up the human genome can go wrong and a disabling, painful and sometimes fatal condition results. Venter has acknowledged that his method will leave up to 5,000 gaps in the sequence of human DNA. These will be disproportionately expensive to close and it is clear that the commercial company will just leave these difficult bits to the public sector.
In the week of the Perkin-Elmer announcement, the Wellcome Trust announced that it was more than doubling its investment in the Sanger centre’s human genome sequencing work. An extra ?110m is being made available over the next seven years to bring the investment up to ?205m. This will allow the Sanger centre-already the world’s biggest single provider of public domain sequence information-to move from sequencing a sixth of the human genome to sequencing a third. The Trust also said that it would consider a challenge to patents which it thought were too broad in their claims and thus obstructed innovation.
The outcome of the race between the private and public gene sequencers will determine whether knowledge of the human genome becomes the intellectual property of private individuals and companies or is part of the common heritage of mankind. But the political economy of gene research is, of course, only one part of the story. Many people fear that the more we know about the genetic code the more we will be able to play God-the easier it will be to interfere with an embryo to determine eye colour, or perhaps sex, or even eventually IQ. We are still at least a decade away from dealing with inherited diseases which require adjustment to a single defective gene; and IQ involves dozens of different genes (not to mention the environment). So this Brave New World may be several decades away. It is, in any case, the subject of another essay.