The analysis of single-base-pair variations dubbed "SNPs" in our genetic code is exploding inside academic, government and biotechnology laboratories. SNPs stand to help simplify and automate myriad steps in disease management, from targeting individuals for specific therapies to creating a smart card profile that includes suggestions for optimized health maintenance. But there is no easy way to sever the exciting medical potential of these research tools, from the exotic, provocative, and sometimes controversial legal and ethical concerns they also conjure.
By Bruce Goldman
Special to Signals
DNA base-pair is effectively the genome's smallest possible accounting unit--the penny, as it were, of genetic variation. Think of your genetic inheritance as two stacks of 3 billion pennies that are indistinguishable except for the fact that each bears one of four mint marks: A, T, C, and G. Line up your stack from mom and your stack from dad side by side, and compare mint marks. At least once every thousand pennies or so, those mint marks differ. If your parents are radically diverse, for example an Aborigine from Australia and an Icelander, the differences may crop up as frequently as once every hundred pennies.
Such pinpoint DNA differences (a G and a T instead of two Gs, say) are called single-nucleotide polymorphisms, or SNPs (pronounced "snips"). If one variation every 100 base pairs doesn't sound like much, realize that a 1 percent variation has long been an estimate of the degree to which we humans genetically differ from chimps.
The consequences of these variations could be staggering. As tools, SNPs are more precise and automatable than the much bigger chunks of suspicious or unusual looking DNA that scientists have traditionally used as genetic markers. Vast technological strides over the past year or two have so speeded the rate at which SNPs can be found that, in the words of Glenn Miller, head of Genzyme's Molecular Profiling Laboratory, "It's like drinking out of a fire hose." Miller was one of several hundred attendees who packed a recent pharmacogenomics conference in San Francisco to discuss everything from the technical hurdles scientists are confronting to such issues as race and behavioral traits that could be lurking in SNPs.
As they struggle to swallow all this newfound SNP data in addition to all the sequencing info coming from the public and private sector, it's becoming painfully obvious to scientists and companies alike that the "human genome" isn't. Rather, it's the comparison and analysis of billions of genomes that will yield the answers to understanding and fighting disease. The reduction to the smallest accounting unit simplifies some things, but speeds up our confrontation with other, much more complex aspects of genomics, including ones far afield of medical treatments per se.
One is patent rights: The May issue of Science, for example, includes several interesting articles sparked by SNPs. One is by a member of the U.S. Patent Office arguing in support of patents on SNPs that meet novelty, utility, unobviousness, and other standard patent criteria; another argues that SNPs patenting conjures the "Tragedy of the Anticommons," or threatens to create the underuse of vital resources. Other simmering issues include race and inherited behavioral characteristics such as I.Q. or violence -- the perennial bogeymen of genetics which are unlikely to stay under the bed despite the wish of academics and companies that they remain separate and distinct from today's scientific activities.
Cranking up the SNPs-works
Genes play a role in every illness we get, but it's rare that disease follows a Mendelian, you-have-it-or-you-don't script. Rather than stem from a single gene defect, predispositions to most major diseases result from the subtle interplay of several genes acting in concert. Unfortunately, finding the genes involved in a multigenic trait is akin to teasing out several dull, straw-colored needles from the genomic haystack. This can sometimes be accomplished by means of so-called association studies, in which DNA from two groups, one with a common pathology and the other without, is compared. Suppose those who share a given trait -- high blood pressure, for example, or high serum cholesterol or multiple sclerosis -- are found to be more likely than others to harbor even one SNP or a small group of them in a particular region of the genome. Subsequent inspection of stretches of DNA in the vicinity may reveal relevant genes, as has been done with Alzheimer's and the infamous apoE4 allele.
SNPs' utility goes beyond the identification of important genes, however. Within or near a single gene already known to be involved in a disease process, it's hypothesized that SNPs will serve as markers distinguishing those who are likely to succumb from those who aren't. Nor does the value of finely dividing populations into SNP- labeled genetic clusters stop with diagnosis. Allelic variations--from SNPs to deletions to repeat sequences--may also spell differences in drug absorption, transport, and clearance. With this in mind, drug companies are pouring money into genomics skunkworks. The hope is that SNP profiles can be used to separate would-be trial subjects into subgroups of likely responders and nonresponders, speeding those trials up, cutting their costs, and upping the odds of approval in one fell swoop. Doctors, using diagnostic SNP-scopes marketed by pharmas along with their drugs, could prescribe them with more comfort to their carefully selected patients, who in turn would get more benefit and suffer fewer side effects.
Because SNPs are densely distributed throughout the genome and are relatively stable genetically, they are also ideal elements for constructing a high-resolution, global genomic map for gene discovery, and industry wants in. In mid-1997, Abbott Laboratories announced it was seeding Genset, a French genomics company, to the tune of $42.5 million in an effort to construct a map of some 60,000 SNP markers that would effectively resolve the human genome into 50-kilobase sections. A five-year, $40 million collaboration is also underway among Bristol-Myers Squibb, Millennium Pharmaceuticals, genetic researchers at MIT's Whitehead Institute, and Affymetrix, maker of a high-throughput SNP-snooping device.
In the biggest SNP-related deal to date , the Icelandic company deCode signed a reported $200 million deal with Hoffmann-LaRoche that includes an equity investment, research funding and milestone payments: It focuses on the discovery of genes with alleles or mutations that predispose people to the development of up to twelve common diseases including four cardiovascular diseases, four psychiatric/neurologic diseases, and four metabolic diseases. The company hopes to take advantage of its connection to the genetically isolated Icelanders and special software algorithm to zero in on key genomic areas.
Prospecting unexplored genomic terrain is one strategy; boring ever more deeply into genes of obvious pharmacological relevance is another. New Haven-based Genaissance Pharmaceuticals, for example, is examining allelic variations (the company calls them "isogenes") among large populations in two receptor genes, one for estrogen and one for endothelin A, in an effort to develop "personalized pharmaceuticals" for cancer and hypertension, respectively. Spectra Pharmaceuticals, a Palo Alto company bought by Glaxo Wellcome last year, is looking at a dopamine receptor allele shown to be over-represented among migraine sufferers--a finding that could shift attention from serotonin-related to dopamine-related research. This in turn could conceivably give new life to old dopaminergic drugs that have already been through the costly developmental mill.
Patent Nonsense?
Dr. Francis Collins, Head of NHGRI |
Last autumn all this activity set off alarm bells among nonprofit researchers including National Human Genome Research Institute (NHGRI) chief Francis Collins, who worried that private companies might hobble research by sopping up every SNP in sight, patenting them, and either declaring them off-limits to less-profit-oriented researchers or pricing them out of easy reach. Were SNPs to become ensnared in a "tangled mesh of patents and licenses," he worried aloud at the time, "then we are really in a mess." So Collins set into motion a federal effort to identify 100,000-plus SNPs quickly in a race to place them in the public domain and thereby prevent privateers from cornering the marker market.
In a Nov. 28, 1997, article in the journal Science, Collins and two colleagues, Mark Guyer and Aravinda Chakravarti, proposed a torqued-up non-profit SNP-discovery plan. The federal initiative, with a three-year budget of $30 million provided mainly by an unprecedented consortium of 18 separate NIH agencies, should start cranking out SNP IDs late this year. Subsequently, support for a public database has also emerged from industry: Alan Williamson, the respected former vice president of research strategy at Merck, called a meeting in April, asking pharmaceutical companies to fall in and support the establishment of a public SNPs database. Williamson is optimistic: "The next meeting will take place before the end of May, and I anticipate a good attendance based upon the response so far. Some companies have a very a positive attitude towards the idea of supporting a public database, either financial or one in kind."
Dr. Gualberto Ruano, CEO Genaissance |
Williamson's position is consistent with Merck's position to date that genomic data should not be tightly locked up, but rather broadly available to researchers. Many biotechnology companies (and some academic groups) have taken the opposite tack, arguing that identifying and isolating certain discrete chunks of DNA such as ESTs, or even these single base-pair mutations, represents novel invention and should be patentable. However, the latter camp seems to be responding to Collins' concerns with more of a shrug than a shudder. "Talk about a 'race' is a good way to get funding," says Lewis Gruber CEO of Hyseq, a genomics company based in Sunnyvale, California. Like Genset, Hyseq is aiming to put together a pharmacologically useful SNP map. There are already plenty of SNPs in the public domain right now, notes Gualberto Ruano, CEO of Genaissance. If the NHGRI wants to chip in, he says, the more the merrier. "My only problem with that is that the Human Genome Project is less than 10 percent complete. They should get that job done first."
More significantly, he notes: "I don't think a SNP patent per se is going to be worth much. It's the clinical significance that really counts. Each SNP has to be evaluated epidemiologically or pharmacologically." Adds Williamson: "Patents are being filed but I suspect that they will cover only a small fraction of the SNPs. Remember that a large collection of SNPs will be much more valuable than any individual SNP. Therefore I hope that people will see the value of extensive cross-licensing of any issued SNP patents." Patents fuel investment and excitement and lead to a faster, not a slower, rate of advancement, insists Genaissance CFO Kevin Rakin. The idea that somebody will stifle research by incurring the expense of finding and patenting SNPs en masse and then sitting on them is irrational, he says. Of course, the fact is that despite their casual protests that individual SNPs have trivial value, many private companies are busily applying for patents on SNP after SNP.
Coming to terms
No biotech executive is going to admit to trying to lock up research in such a fundamental area, of course. But Collins explained to Signals that the issues he raised are far more complex than whether to allow patents or not. "I'm not making a stand that SNPs should never be patented. I am making a stand that if patenting is to be contemplated, it had better be done in a way that still guarantees accessibility to a broad range of investigators without inhibiting their interest in using these tools.
"It all depends on the terms: What kind of licensing is being contemplated? Exclusive? Nonexclusive? What are the royalties? What kind of reach-through obligation is attached to the opportunity to use these things? The worst outcome would be a SNP approach that basically put them all away in a private database that no one would see unless they paid up front some large fee, which is the strategy currently being pursued by Genset with funding from Abbott. If you agree that these are general research tools--useful not just for an occasional project here and there but for virtually every study that is trying to uncover the heritable component of illness--then any arrangement that limits the benefits to one or two parties is unfortunate. For many academic investigators, steep licensing fees or reach-throughs are going to chase them away in a hurry."
There's no way anyone will get a lock on enough SNPs to shut down other groups' mapping research, contends Hyseq's Gruber, himself a patent attorney. "By the time the final SNP is found, the first ones will already be off-patent." Thus, he argues, the vaunted private-vs.-public SNP slugfest will probably turn out to be something less than a blood-feud.
[For its part, the NIH is so concerned about the whole topic of patenting research tools, including SNPs, that it's sponsoring a director's policy forum to sort through the implications. Also, stay tuned for an upcoming Signals cover on this topic.]
Dividing lines
Patent issues aside, the bevy of freshly identified SNPs and what they tell us has potentially far-reaching implications outside of medicine. Clearly, one of the great tools heralded by SNP technology is the advent of high-resolution maps for pinpointing multigene traits. Among such traits, it should be noted, are not only cancer and diabetes, but height, attractiveness, intelligence, and gregariousness. It's just a matter of time before medicine goes from a detailed understanding of individual variation to the ability to predict an embryo's developmental path on many fronts. Add to this the even more politically charged issue of inherited racial characteristics.
Ethical concerns about the practical and general significance of SNPs in particular are not unlike those raised about genetic analysis in general. But the speed with which SNPs are providing sufficient information seems to make these concerns more imminent. Genetic diagnostics, already wrinkling ethicists' brows, are currently confined to testing for single-gene variants that confer a high likelihood, environmental factors be damned, of developing somewhat rare syndromes such as Huntington's disease or cystic fibrosis. But what does a doctor, or an insurance company, do when a sophisticated test for a multigene disease reveals a 10 percent increase, subject to a huge environmental fudge factor, in the probability of contracting a relatively common case of cardiovascular disease or prostate cancer? Do you yourself want to know your genotype when its relationship to your phenotype is that slippery?
If that question seems too mundane, flip forward to this scare scenario: It's the year 17 A.G. (After Genome) and you're sitting in the storefront of some molecular biologist in Russia or Colombia (we'll assume that what we're about to suggest is illegal in the U.S.). After a quick, cheap genetic test the biologist tells you you've got a bright little male embryo in there--with an ominous emphasis on the word "little." But not to worry, there's a way to change a base pair or three and give your baby a few additional inches of height; it'll cost only 3 IQ points, tops--not a bad trade-off. What's more, you can get those points back by sacrificing a bit of altruism. What would you pay for aggressiveness, height, and intelligence--in this competitive age?
The Race Is On
That scenario may be farfetched. But what one can say with more certainty and immediacy is that the SNP-discovery race resurrects the troubling question of race. There is no question that intermarriage, immigration, assimilation have blurred what may once have been more well-defined racial and ethnic boundaries. Yet, genetically, these terms appear to still be valid. In studies of Jews, for example (among all ethnic groups Jewish genes are among the world’s most studied), despite the nearly 2,000 years during which that originally Semitic people has been mixing with European stock, Jews of diverse European backgrounds are still genetically identifiable. Modern genetic techniques have already demonstrated terrific similarities in the Y-chromosomes of most Jewish men whose last name is Cohn or Cohen or Kahn, for example, presumably owing to their shared ancestry. And for its SNPs-identification project, the NHGRI has set out to collect DNA samples from significant numbers of Asians, Europeans, Africans, and Native Americans, thus implicitly endorsing the concept of race.
At the San Francisco pharmacogenetics conference sponsored by Global Business Research, Jeff Hall, senior director of genetics at AxyS Pharmaceuticals, drew a few hushed whispers when he cited major black-white differences in frequencies of alleles at numerous gene sites. Some of these differences are associated with differential drug responsiveness, conjuring potentially sticky consequences for drug labeling: Would a company that, in the interest of better efficacy, submits data showing racial response differences be branded racist by some activist group after the FDA decreed that the drug be used only by those of particular racial stocks? In any study of individual differences at the genetic level, the revelation of group differences is a corollary.
SNP technologies aren't qualitatively unique, but their increasingly high-throughput aspect is bringing the future--and all the ethical complexity that comes with it--closer and faster. And while some of these controversies may seem quite distinct from the central mission of basic research, they can come together quite quickly and unexpectedly. "One worry," notes Williamson, is that "private databases could be used to generate controversial genetic observations that could not then be checked because the database used was not publicly accessible."
You can reduce genetics to technical penny-pitching, it seems, but the prickly $64,000 questions that plague this field continue to defy easy answers.