Can Science be Stopped?

by William Wells

Today, GM foods; tomorrow, GM people. Does our attitude to every new technology follow an inevitable trajectory from fear to acceptance? Or can we affect how science unfolds?

Case study #1 — the past

For South Australia , my state of birth, the brave new world of genetic engineering began in a concrete box measuring approximately 10 feet x 10 feet x 20 feet.

This was no ordinary concrete box. The double, airlocked doors into the laboratory enclosed an area for changing into disposable gowns and shoe covers. The room itself operated under negative pressure so that any nasties would be sucked in, not let out. And an autoclave was built into the wall of the room, so that heat and steam could blast bacteria to death without the bugs ever having to be transferred outside of the secure box.

The laboratory was built in response to the invention of recombinant DNA technology in 1973 by Stanley Cohen of Stanford University and Herbert Boyer of the University of California, San Francisco— an invention that led to royalties of over $200 million. Cohen and Boyer came up with the idea of cutting and pasting DNA so that plant and animal genes could be grown up in large amounts (or cloned) in bacteria.

This was not Dolly - sized cloning, however. Cohen and Boyer were working not with a whole sheep but with one gene at a time. But they and others were sufficiently alarmed with the prospect of mixing genes from different organisms that an unprecedented international moratorium was declared, temporarily suspending any experiments involving recombinant DNA.

Recominant DNA

The issue was taken up in February 1975 at the Asilomar meeting in Pacific Grove, California. Guidelines for safe experimentation were proposed, and within a few years an Australian version of those guidelines gave birth to the airlocked laboratory; a laboratory that I used in 1988 as a student at the University of Adelaide, South Australia.

But when I entered the lab I didn’t don a gown or shoe covers. Instead I complained about tripping over the unused airlock as I wandered freely in and out. After all, I wasn’t working on Ebola virus or mad cow disease; I was doing the sorts of experiments that are routinely performed in high school science classes.

I was not the first to disregard the laboratory’s safety protocols.

Barry Egan, the Adelaide University researcher whose main laboratory is adjacent to the concrete box, says that he "would be totally surprised if there were any experiments done under [the fully restrictive] conditions." As recombinant DNA experiments started up after the moratorium, researchers realized that the dangers of genetic mixing and matching had been overestimated, and that the mixing happened all the time in nature in any case. Regulations were relaxed and, says Egan, "by the time [the laboratory] was available it was no longer needed. It was absolutely a white elephant." After gathering dust for 15 years, Egan says that "finally it was jackhammered out in 1994."

The history of that laboratory reflects how the attitude to recombinant DNA technology has progressed: from hysteria to blasé acceptance. But now there are new technologies thrusting their heads above the moral and ethical parapet. Will those technologies tramp an inevitable path towards acceptance, or will public opinion shape how, or whether, those technologies are adopted? These are not questions only for scientists. Society must get involved, and the first step in getting involved is getting informed.

Case study #2 — the future

In the science-fiction movie Gattaca, Ethan Hawke and Uma Thurman stumble around a world in which all but a few people have been genetically modified to society’s version of perfection. Gattaca’s script was more likely to induce sleep than paranoia, but in the real world the concept of widespread germline engineering (modifying the genes of eggs or sperm) is starting to look alarmingly possible.

"I certainly think it will happen," says Princeton geneticist Lee Silver. "The only question is when." Gregory Stock, director of the University of California, Los Angeles, Program on Medicine, Technology and Society, co-organized a 1998 symposium called "Engineering the Human Germline," the first major forum on human germline engineering. "The range of discussion," he says, "was whether it would happen in 20 years or 100 years, but not that it wouldn’t occur."

The general public remains, for the most part, blissfully unaware of this impending revolution. But discussion in academia has started because the technologies for achieving germline engineering are rapidly being assembled.

Drawing the line

"So often technologies are created for one purpose and used for another," says Silver. This is certainly the case with germline engineering. Genes suitable for transfer are coming from the Human Genome Project. Stem cells to receive the genes are being characterized by companies like Geron Corporation (Menlo Park, California) and Advanced Cell Technology (Worcester, Massachusetts), ostensibly to create transplantable cells and tissues. And artificial minichromosomes — the cassettes that would carry all the genes — are being created by two companies – Chromos Molecular Systems Inc. (Burnaby, British Columbia, Canada) and Athersys Inc. (Cleveland, Ohio). Both companies swear they have no interest or intent in the area of germline engineering.

But others are showing plenty of interest. "The only way [germline engineering] will ever be significant is through the use of synthetic minichromosomes," says Stock. "This is the only way you can produce a technology that is sufficiently reproducible, safe and reliable."

An artificial chromosome

Athersys, which appears to have the more advanced technology, is based on the research of Huntington Willard, now at Case Western Reserve University in Cleveland, Ohio. Willard is interested in the completely non-controversial area of how human chromosomes manage to distribute their copies evenly into newly born cells. To test his understanding of how chromosomes work, Willard decided to rebuild a human chromosome from known starting materials. This is what he has created for Athersys. Willard’s research contributes to fundamental biological knowledge, and it could help prevent genetic diseases like Down syndrome. Athersys, meanwhile, has a way to deliver large genes or groups of genes into human cells.

This idea is an advanced form of somatic gene therapy, and raises few hackles. (Somatic refers to any cells that are not eggs or sperm.) The controversial idea is the modification of entire organisms by inserting the artificial chromosomes into eggs, sperm, or embryos. A Chromos researchers says of such experiments: "We wouldn’t do it. It’s not in our code of ethics to make a better person." Athersys CEO Gil Van Bokkelen is no less emphatic. "It’s a no-no, an absolute mistake," he says.

They note that serious genetic diseases can increasingly be managed by physically selecting out embryos without genetic problems. And no one has a good idea of how a human with an extra chromosome could mate with an unaltered human without causing genetic complications.

But those protestations and more were faced down by participants at the UCLA symposium. Mario Capecchi (University of Utah, Salt Lake City) proposed a system that would destroy the chromosome in the recipient’s egg or sperm cells, yielding a temporary enhancement only for that person’s body rather than permanent germ cell therapy. "You wouldn’t want to keep [the chromosomes] anyway if the technology is advancing," noted Stock.

But what genes would we put in? "If you add in a new gene you don’t really know how it will work," says Silver. "So you add in a gene that already exists, like a gene that some people have that gives HIV resistance. It’s hard to imagine a government stopping parents giving their children something that other children already receive naturally."

These gene variants – including one that makes trained muscle more mechanically efficient (see Nature, February 10, 2000) – are a start. But the real impetus, Silver says, will come with genes that reduce susceptibility to major diseases. It will take many years to accumulate these genes, says Silver, but when enough can be piled onto a high capacity artificial chromosome, parents will demand it. "If there are meaningful enhancements they will almost certainly be adopted by some people," says Stock. "And then there will be intense competitive pressure for the rest of us to join in."

The gap widens

If blithe talk of GM people is alarming to most of us, what is the reaction of those whose job it is to think about how science and society co-exist? Thankfully, they are at least aware that there is a problem.

"Science is getting ahead of the public’s ability to absorb it," says Elizabeth Marincola, the executive director of the American Society for Cell Biology, based in Washington, D.C. "The only way to address this is to attempt to educate the non-scientific public to be better analysts."

Marincola is backed up by Keith Yamamoto, a researcher from the University of California, San Francisco, who is heavily involved in scientific policy initiatives. "I’ve long felt that as a society we are rushing headlong towards a future that is so technology-driven, with a citizenry that is not equipped to have an informed opinion about whether these things are good or bad," says Yamamoto. "I find that really troubling."

Unfortunately, any non-scientist who wants to become informed about topics such as stem cells, GM foods or cloning is dealing with a moving target. Stem cells are a case in point. They represent a potentially promising source of replacement cells for tissues damaged by disease. The ethical trouble is with their ultimate source: aborted embryos. But new methods hold the promise of yielding stem cells without a need for any embryonic material. Where does that leave the ethical debate?

For other research areas the debate is not about the technique involved, but about whether we want the technology at all. Unfortunately these dilemmas are often debated only when the technology has already appeared (‘Here is a cloned sheep.’ ‘But did I want that?’). This is not a plot by scientists to cover things up. Often the only scientists who know that a breakthrough is imminent are those who are intimately involved with a tiny subspecialty. And even they may be skeptical about whether, or how, the breakthrough will be achieved.
Dolly the cloned sheep
Dolly was remarkable to scientists not just because of the implications of cloning, but because she contradicted the received wisdom of twenty years of embryology. According to the textbooks, Dolly should not have been possible.

Moral and ethical issues tend to be broad, sweeping concerns. But in science the devil is in the details. To prevent the generation of Dolly, activists would have had to wage a long and shifting war: first immersing themselves in embryology research, then protesting a whole slew of possibly promising experiments, many of which were designed only to answer fundamental questions about how animals grow from a single cell.

Even when research gets to the applied realm it can be hard to fight. During the 1980s the anti-biotechnology activist Jeremy Rifkin waged a guerrilla campaign of lawsuits and protests against the insertion of genes into plants. But the public couldn’t get very worked up about a tomato that resisted bruising, and that happened to have a single gene inserted into it. The tomato disappeared from markets for reasons other than protests (it didn’t taste very good). But meanwhile the public has woken up to GM foods, and decided that maybe they don’t like them after all. Too late folks. GM foods are now so pervasive that the prospect of banning all of them is vanishingly small. Don’t say that Jeremy didn’t warn you.

The power of Congress

Of course society is not powerless in the face of science — it can always pass laws to ban certain technologies. Marincola’s job is to inform the US Congress about advances in cell biology so that decisions can be made. And Marincola is impressed by that decision-making process. "Congress holds its authority pretty dearly," she says. "It is looking for the guidance of the regulatory agencies, but I’m surprised at the depths to which committees go to inform themselves. The Congress on these issues is not a rubber stamp."

Elizabeth Marincola

Congress gets advice from many quarters. "There’s a lot of money out there and people with money have influence," admits Marincola. "Biotech firms and their representatives are powerful voices on the Hill," she says. "But I don’t think they have disproportionate power. Congress is much more responsive to individual constituents and groups of constituents than is generally perceived to be the case. An individual voice carries disproportionate weight."

But even Congress cannot control everything. "One of the arguments in support of SB2015 [a bill that would allow the use and distribution of stem cells] is that, ‘Hey, it’s done anyway by non-federally-funded scientists and it’s done overseas’," says Marincola. "In the end science will be done and is done despite regulation because Congress’ reach goes only so far."
And Marincola thinks that Congress should leave the details of most research to the researchers. In the past, she says, Congress ‘earmarked’ certain funds for certain diseases or research projects. But science takes a twisted unpredictable path, and cures often come from projects that were initiated to solve basic not applied problems. Luckily, Marincola says, Congress trusted former National Institutes of Health (NIH) Director Harold Varmus, "and that trust earned a lack of earmarking."

Scientists take care of themselves

Where Congress is the generalist, the NIH is the specialist. At the NIH science policy is addressed full-time. Jargon and bureaucracy can make it hard for the public to find out what is going on at the NIH, and "former NIH administrations were rather isolationist," says Yamamoto. But, he says, "during the Varmus era there was a sea change in the outlook of the NIH in terms of inclusion of public representation in policy and decision making. I think the public representative groups were amazed by this."

Keith Yamamoto

NIH bureaucrats feared "that public representation would be disruptive and change the direction of research to immediate attacks on disease," says Yamamoto. "But instead [the public interest groups] became all the more supportive of basic science."

These groups also became involved in the process by which the NIH doles out huge amounts of money to researchers. Individual grants are approved (or not) in a two-level process: first the science is evaluated by peer review, then one of the Institutes evaluates whether the research is within the goals and mission of the Institute. Lay people and advocacy groups participate in the panels at the second level of research grant approval.

At the second stage, says Yamamoto, "in general there are several thousands of applications that flow through and in general there is a blanket recommendation and the council rubber stamps that recommendation. But increasingly individual applications get pulled out to be looked at."

Advocacy groups have more recently been seeking participation in the first stage of peer review. Yamamoto oversees this whole system as the chair of the Center for Scientific Review (CSR) Advisory Committee. He opposes further participation by non-scientists.

"It comes down to what a peer really is," he says. "It’s my view that the peer really needs to be an expert in that area who is currently active in that research endeavor. The [advocacy groups] believe that they do have an expertise that would contribute to making a better decision about grants. I guess we just differ there."

Yamamoto does not fear that public participation would cause the process to grind to a halt. "If people are willing to sit on the panels they are unlikely to be disruptive," he says. "But those members are almost certain to vote along the party line. There’s very little more that they can do. If they don’t they are just flattening the scoring."

Dilution, he says, is a real concern. "Scientists are already concerned that their applications will be evaluated by scientists who are not up to speed. If you layer onto that having people who don’t have the scientific expertise you increase the danger."

Participation can educate people about how well the system works, he says, but that comes with the risk of breaking that very system.

"I haven’t seen a problem that is calling out for a solution here," he says. "I think the scientific community has been very responsible in developing its own oversights."

What concerns can be heard?

The original anti-technology protestors were the Luddites, who rioted in 1811 to destroy labor-saving textile machines. Some arguments for banning specific research areas sound a lot like the protestations of a latter-day Luddite — a person who opposes all technical changes. This is a valid position, but not one that fits well with modern science. "Without a clear rationale, without an opinion based on a clear set of arguments, I hope that the scientific community won’t give credence to these arguments," says Yamamoto. "Reflexive conservatism does not serve us well."

Fred Gould of North Carolina State University heard such arguments as a member of the National Academy of Sciences (NAS) panel that reported on regulation of GM foods. He agrees with Yamamoto that "we should not take into account theological type issues." But, he says, the NAS panel "realized that we must take into account non-scientific issues." Gould points out, for example, that GM crops that resist salinity and water shortage may not be an automatic boon: planting in marginal areas could damage and ultimately destroy farmland. And Nobel-Prize-winning economist Amartya Sen has observed that the headiest promise of GM crops may be misplaced. Poverty arises from failures in food distribution, he says, not the low crop yields that GM technology promises to improve.

One of the NAS panel’s more controversial conclusions was that regulation of GM crops is reasonable, even if there is no regulation of crops that appear biologically identical but that have been produced by regular breeding.

The panel attracted criticism from scientists for such pronouncements. And with science and commerce becoming ever more tightly entwined, such allowances for public qualms may become harder to extract. But, says Gould, "this is not about science. The public really is concerned. Not being arrogant is an important goal."

Gould says that the public can still affect outcomes by direct protest, citing the demise of the first herbicide-tolerant plant, which was designed to resist atrazine. Environmentalists complained that atrazine was one of the more toxic herbicides, and researchers dropped the atrazine project in favor of the far more challenging task of making a glyphosate (RoundUp)-tolerant plant. "If you are a big company you have to worry about public opinion," says Gould, "and I think public opinion stopped the atrazine-tolerant project."

Yamamoto says that other decisions on technology may come down to what we choose to buy, eat or do. "Science will keep changing and technology will keep coming at us," he says. "You and I might not like being surrounded by cell phones but they are there. It comes down to the personal decision level."

He doubts, however, that drastic measures like Asilomar-type moratoriums will be implemented in a newly emerging research area. "If anything the people involved in the Asilomar debate are the staunchest opponents of a repeat performance," he says. "Time was wasted. In hindsight it proved to be a lot of ado about nothing."

Marincola also relies on the lessons from that era. "Time and again we’ve seen that an opportunity that looked very scary settled down," she says. If that comforts her, it doesn’t lessen her resolve to keep everybody thinking and contributing to various ongoing debates about biological research. "It doesn’t mean," she says, "that people shouldn’t be vigilant."

Originally published in the web magazine Access Excellence.