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Unnatural Selection 

by Ralph Brave


On June 26, 2000, Celera Genomics Group and the National Institutes of Health announced that they have achieved a feat unique in all of history, one that will alter the destiny of all humanity for all time to come: the decoding of the entire human genome, the three billion or so units of DNA in every cell in the human body -- the code of human life in all its variety.


The effort of thousands of people and the expenditure of billions of dollars have gone into the making of this epochal moment, but perhaps it belongs above all others to James Watson -- first director of the federal government's Human Genome Project, the pioneering biochemist whose work uncovering the double-helix structure of DNA made the project possible. Thus it is only fitting that Watson provide the invocation for any effort to understand the meaning of this miracle. Here, then, is James Watson on the awesome responsibility of assuming stewardship over the sacred stuff of life itself:


"Evolution can be just damn cruel, and to say that 'we've got a perfect genome and there?' some sanctity. I'd like to know where that idea, 'perfect,' comes from, because it's utter silliness. We should treat other people in a way that maximizes the common good of the human species. That's about all we can do... To try and give it more meaning than it deserves in some quasi-mystical way is for Steven Spielberg or somebody like that... It's crap."


The "utter silliness" to which Watson referred during a 1998 panel discussion at University of California at Los Angeles (UCLA) is the concerns that have been raised about the prospects for genetically engineering what is called the "germline" of Homo sapiens -- the sex cells, our sperm and our eggs. The result of any engineering of these cells, of the human germline, will be that all future generations shall inherit the choices made by the engineers.


Some bioethicists, and more than a few of Watson's colleagues, have had the temerity to suggest that humankind might pause before embarking on such an irrevocable step -- before, in essence, "taking control of evolution," as Francis Collins, current director of the federal government's Human Genome Project, described it to a meeting of physicians. In May, Eric Lander, head of the Massachusetts Institute of Technology's Whitehead Institute for Biomedical Research and a close friend of Watson, called for "an absolute ban" on germline engineering.


With the announcement that the text of the human genome is in hand -- or, at least, in the data banks of a suburban Maryland corporation -- the genomic cognoscenti are engaged in what might be called germline warfare: the debate over whether we should directly alter and engineer the sperm and eggs of ourselves or our children. Some say never. Some say sometimes. And some say, in the spirit of James Watson, let's do it.


Assuredly, there remain dozens of other important concerns to be addressed as the genetic genie makes its way out of the bottle, following a race between the public and private sectors to pop the cork.





"I'm all for mapping the genome, whether it's the public or private sector doing it. It ought to get done, the faster the better," says Arthur Caplan of the Center for Bioethics at the University of Pennsylvania, perhaps the nation's preeminent bioethicist. "But there still is no guarantee that people can get genetic testing paid for if they want it in terms of insurance. There's still no national legislation protecting against genetic discrimination. There's still no guarantee that genetic testing will be affordable. There's still no guarantee that we won't test people without their consent, including children and embryos. There's no privacy statute.


"Want me to go on? There's nothing to prohibit testing of the dead. There's nothing to protect stored genetic information from being looked at by third parties. There's no guarantee that counseling will always accompany testing. There's not enough personnel to do it. There's no training in law and in ethics for people in medical and in nursing schools who will be asked to interpret genetic information. There's no standards for advertising and marketing so that there's no preying on others and companies don't exploit fear and even create panic.


"Other than that, we're all set."


Such issues may be difficult, yes, but not insuperable, in the view of Dr. Eric Wulfsberg, director of the clinical genetics and dysmorphology (birth defects) program at the University of Maryland Medical Center. Problems may arise in such areas as insurance or testing or counseling, but Wulfsberg maintains there are mechanisms in place to deal with them, whether it be Congress, the courts or government agencies and licensing boards.


What does concern Wulfsberg is the prospect that "the same technology that would allow us to alter a gene that causes disease would allow us to alter a gene important for intelligence or some other human trait."


This potential for "genetic enhancement," as it is known, raises problems that have increasingly gotten the attention of bioethicists. No one doubts that the mapping of the human genome will exponentially accelerate the arrival of this question on every human doorstep.


Most experts today put that timeframe at 10 to 20 years from now, but at the present pace of genetic breakthroughs, that estimate is far from certain.


"That could be many years in the future," Hamilton Smith, a Nobel Prize-winning biochemist and director of DNA Resources at Celera, says of germline engineering. "Although it could come quickly."


Such momentous and even metaphysical meditations have little place in the offices of Dr. Jerry Winkelstein, director of the Pediatric Division of Allergy and Immunology at the Johns Hopkins Hospital. There, as in so many clinics around the country and the world, the face of human suffering is immediate and shattering.


Winkelstein has devoted a lifetime to helping those with some of the most ravaging genetically- based medical disorders, those of the immune system. On the doctor's bulletin board are pictures of and cards and artwork from dozens of his patients. Many are living bountiful lives due to the interventions of he and his coworkers. Many others are deceased, their lives cut terribly short by defective genes.


Winkelstein's experience leaves him with no doubts about the immediate benefits of decoding the human genome, and he can enumerate those benefits in detail.


"The reality is that the genome project is having a phenomenal immediate impact on families and on how identifying disease-causing genes translates so quickly into improved care for patients," he says. "Number one is, if you know exactly what's wrong, what gene's affected and what protein isn't being produced in the right fashion, it offers you a real chance to improve therapy very quickly. It doesn't always work, but when it works it's very exciting for the patient.


"The second thing it does is it allows you to define the disease based on molecular terms rather than clinical terms. So you can say, 'Look, there are milder forms of this disease. It's the same disease and maybe 20 years from now it may have the same outcome in this patient as in the other, but it's a milder form of the disease.' This allows us to be much more precise in our diagnosis.


"The third thing, which is of immediate benefit to patients, is it allows us to do carrier detection" -- people can be tested for gene mutations responsible for inheritable diseases and advised of the risk for passing that disease on to their children.


This, in a nutshell, is the case for genetic-based medicine -- the potential for breakthroughs in knowledge about diseases and possible interventions that promise to transform much patient care.


Winkelstein's patients are among the estimated one in 20 to 25 children born with a genetically-based disorder. Those genes come from us, their parents. But whether you or your children suffer from any such disorder, we are all "carriers" of mutated genes that can cause disease. Each one of us carries five to 10 single doses of recessive genes that would be lethal in a double dose. In that sense, we are all potential candidates for genetic rehab.


Genetic therapy has had limited success so far, and experiments in the field over the past decade have provided their share of frustrations -- including a recent spate of news of misconduct by experimenters, and the death of a teenager during a gene-therapy trial at the University of Pennsylvania. But efficiently and routinely altering human genes is feasible in principle. It's already been successfully done with plants, fruit flies and, most significantly, other mammals, including mice, goats, sheep, pigs and cows.


The work done on mice most vividly demonstrates what could be possible with humans. In the early-1990s, a method was invented for precisely targeting individual genes in mouse embryos so they could be inserted or deleted as desired. Last year scientists were able to determine that inserting certain genes made mice better at navigating mazes and performing other learning tasks.


Similarly, it is the human embryo that is expected to be the target for most germline engineering. Altering the genes in a single embryonic cell -- changing a disease gene, enhancing a growth gene -- will alter every cell of the person who develops from it, including the person's germline, or sex cells. That person will pass along the genetic alteration to any future progeny. There has been some research into how to modify the germline without that alteration being passed along, but the intent of most germline therapy will be to remove or insert genes in such a way as to make them permanent parts of the individual's heritable genome.


Many of the advocates of germline engineering tout it as more efficient and less costly in battling disease than "somatic gene therapy." In somatic gene therapy, the healthy gene has to be introduced to and taken up by enough of the millions of cells that make up the diseased organ or tissue to fix the problem. Germline therapy requires only that the corrected gene be implanted in one embryonic cell.


Some fertility clinics are already offering genetic screening of embryos for disease genes such as those that cause cystic fibrosis or contribute to breast cancer. And they would be the logical sites for embryonic genetic engineering. But such clinics are not currently subject to regulation, says Penn's Caplan.


Once the technology for germline engineering is in place, some advocates say it should go beyond repairing disease genes, or even enhancing healthy ones. "There is no limit to the kind of genes that can be added to the embryo," Lee Silver, a professor in the department of molecular biology at Princeton University, has written. "Genes from one species can be manipulated before they are placed in another to carry out their designated task."


There is no current federal statutory law dealing with germline genetic engineering, and few laws or regulations governing any aspects of the emerging genetic technology. Bills banning genetic discrimination by health insurers and employers have stalled in Congress. There is still no federal law prohibiting someone from cloning a human being, though researchers using federal funds are barred from doing so.





The frustrations of some scientists and bioethicists trying to secure genetic safeguards before the technology is up and running surfaced as the genome project progressed, with scientists and public policy makers considering stopping the genome sequencing until Congress put genetic privacy and anti-discrimination laws in place.


But nothing happened, and now with the genome sequenced the time is likely past when bioethicists and their publicly minded and publicly funded scientific comrades can do anything about it.


Perhaps more significantly, the privatization of genes and genomics -- embodied most visibly by Celera -- dramatically shifts the ground from public policy to market forces.


"I think the genetic revolution is going to be privatized and going to be a business. It is simply inevitable," bioethicist Caplan says. "This is not an industry that's going to be run by universities -- they're not going to set up drug companies and testing companies and design drugs for people with different genes."


Caplan is so convinced that corporatization is the future of genetics that he signed on as a paid member of Celera's Scientific Advisory Commission and consults for the mega-pharmaceutical firm SmithKline Beecham. "I'm happy to be a handmaiden to industry as long as they don't mind my biting their hand," he says.


The corporatization of genetic technology has benefits, proponents argue, including more efficient results, as manifested by Celera's completing the human genome three years ahead of the federal project's schedule.


But as the technology advances into direct manipulation of human genes, questions arise as to how far to go in allowing the future evolution of the human species to be tied to profit margins.


In an interview at his Johns Hopkins Hospital office, Dr. Victor McCusick, who founded the field of medical genetics four decades ago, worries about a future of "Madison Avenue meeting up with genetics," bypassing the medical profession and marketing genetic therapies directly to consumers, as the pharmaceutical industry now markets drugs. Indeed, a Salt Lake City-based company called Myriad Genetics is already advertising on cable television, soliciting business for its breast cancer gene test.


Caplan views such developments as a rationale to create a stronger connection between the corporate and bioethics communities. "I want to get in there early and try to make them responsible," he says. "Staying away from them makes no sense. I think you've got to go in there and push them. Am I optimistic? No.


"But I've grown to believe that if you don't push the companies, if you don't move that industry, then you have a much tougher time moving Congress because they talk to Congress a lot."


But a colleague of Caplan's, Charles Bosk, a renowned medical sociologist at Penn, has publicly raised doubts about whether bioethicists can even do that pushing. In a recent article, Bosk questioned whether "bioethical analysis leads effectively to ethical practice" -- and cited among the reasons for his doubts bioethicists' unwillingness or inability to question "the replacement of professional [medical] values with corporate ones."





With the arrival of the decoded human genome, the debate over germline engineering is heating up.


"Already there are well-meaning discussions about improving the human DNA," observed Eric Lander, head of MIT's genomics center and a member of Millennium Pharmaceuticals' board of directors, at an MIT conference last month on "Genes and Society." "I find this somewhat hubristic myself. [The human genome has] been 3.5 billion years in the making. We've been able to read it for the last, oh, I don't know, year or so. And we suddenly think we could write the story better? It's very amusing."


Lander doesn't dismiss germline engineering altogether, however. "There is the prospect that by changing things we might put off aging, prevent cancer, improve memory," he said in his conference-opening address. "I find it a very difficult question, for my own part." But he ultimately called for putting "an absolute ban in place on human germline gene therapy. Not because I think for sure we should never cross that threshold. But because I think that is such a fateful threshold to cross that I'd like society to have to rebut that presumption someday, to have to repeal a ban when it thought it was time to ever try something like that."


Celera's Hamilton Smith agrees. "The only thing that I'm certain of is that we don't possess the knowledge to monkey with our germline," he said in an interview in his lab.


"If Congress wanted to pass a law in the near future, if they wanted to posture in such a way as to make it look like they were doing something, they could pass a law that we won't actually implement any modifications of our germline until such time as we know what we're doing," says Smith, a former Johns Hopkins faculty member.


As an example of the possible unintended consequences of germline engineering, Smith points to the gene responsible for sickle-cell disease as a prime candidate for deletion from the human genome. "But we better make sure we've wiped out malaria first," he says. (The gene responsible for sickle cell has also been shown to protect against malaria.)


James Watson has little use for hand-wringing about the unknown. "Some people are going to have to have some guts and try germline therapy without completely knowing that it's going to work," he said at the 1998 UCLA conference. And when it comes to consulting any extra-scientific body for permission to proceed, he's even more adamant: "I'm afraid of asking people what they think. Don't ask Congress to approve it. Just ask them for money to help their constituents. That's what they want -- money to help their constituents... And if we can help them not be sick, they'll be on our side."


Watson is equally set against seeking cooperation with the rest of the world. "I think it would be a complete disaster to try and get an international agreement" on a germline-engineering protocol, he said in 1998. "I just can't imagine anything more stifling. You end up with the lowest possible common denominator. Agreement among all the different religious groups would be impossible. About all they'd agree upon is that they should allow us to breathe air... I think our hope is to stay away from regulations and laws whenever possible."


There are those who not only agree with Watson's approach, but advocate the improvement and extension of the species through technology. Last year, an organization calling itself Extropy hosted respected academics and scientists from all over the country to promote the use of computers and biotechnology to "challenge the inevitability of aging and death," enhancing all human capacities to create a "post-human condition."


One of the most respected physicists of the 20th century, Freeman Dyson of the Institute for Advanced Study at Princeton, has suggested that the development of genetic engineering of humans to reduce suffering and enhance capacities will inevitably lead to the creation of a variety of competing human species. As Dyson sees it, this will provide the final catalyst for colonization of other planets. "To allow the diversification of human genomes and lifestyles on this planet to continue without restraint is a recipe for disaster," he wrote in his 1999 book The Sun, the Genome, and the Internet (Oxford University Press). "To give us room to explore the varieties of mind and body into which our genome can evolve, one planet is not enough."


Incredible? Ask Hamilton Smith. "Dyson's a very smart guy, and he's given a lot of thought to this," the Nobel laureate says. "I think there's a lot to what he says for the future. It's hard to tell where mankind is going here."


"There will be some who will be arguing that it is time for us to take charge of our own evolution... and see if we can improve ourselves into some higher state," Collins says, "a concept which I must say gives me chills up and down my spine."





So where are we going in the post-genome landscape to which the Watsons and Collinses and Smiths have delivered us? From all indicators, the next decade should see some blockbuster breakthroughs in medical diagnostics and treatments. At the same time, there will almost certainly be a raft of problem cases that begin to define the outer limits of Americans' tolerance for the market determining their genetic futures. Will people continue to allow corporations to own patents on gene therapies, as is happening today with companies filing patents as fast as they can to be ready to profit from the coming genetic revolution? Akin to patenting the molecular formula of, say, water, can something so central to all of humanity as genes be considered the property of a corporation?


Within the next 10 years, it will also become increasingly apparent that the technology that cures long-feared diseases can also alter our genetic inheritance in as-yet-unseen ways, as a matter of design -- someone else's design. As philosopher Philip Kitcher wrote a few years ago in a book about the implications of the genome project, once we lose our genetic innocence, we are committed to some form of eugenics. Then, the question becomes the one posed by Johns Hopkins' Victor McCusick at a gathering last summer in honor of his pioneering genetics work: "Who will decide what is desirable?"


Perhaps the gut-wrenching concerns of a generation of people that came of age before the advent of biotechnology will simply be deemed irrelevant by those who never knew the pre-genomic world. Sitting on the patio of a Starbucks earlier this month, a college student working behind the espresso machine joined me outside to have a smoke. She's pre-med, thinking about going into obstetrics. "I have a friend doing genetics now at a college in Massachusetts," she tells me, "and my friend told me that in her lab she had created an eight-legged fruit fly" -- as opposed to the normal six-legged kind. "And she says that after we graduate we should go into business together: She'll design the babies and I'll deliver them." The student laughs and ponders the possibilities.


Perhaps with each biotechnological advance, the values that seemed so threatened will simply vanish. That's what happens to the beautiful replicant Rachel in the film Blade Runner, which depicts a world where factory-made humans live alongside real ones. Employed by the very corporation that genetically engineered her, Rachel is forced to ruefully acknowledge, "I'm not in the business. I am the business." With the human genome sequence now completed, so are we all.

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