Masterminds: Genius, DNA, and the Quest to Rewrite Life

A greater source of discomfort surrounds the use of cloning to create embryonic stem cells. Scientists believe that stem cells made from cloned DNA will work best to reconstruct spinal cords and liver cells in a specific person because the cloned cells are an identical genetic match and won’t be rejected by the body’s immune system. Rejection is currently a major drawback in transplanting hearts, kidneys, and other organs. Cloning also allows researchers to study how diseased cells develop in specific patients. To clone stem cells from, say, Sam Melton, a researcher would take Sam’s own DNA and implant it into a denucleated egg, which would hopefully grow into an embryo that contains Sam-specific stem cells capable of developing into pancreatic cells. These stem cells would be harvested and the embryo destroyed, although the embryo up until then could be placed inside a womb and theoretically taken to term, creating a full-scale clone of Sam.

Melton and other stem cell scientists insist that they have no intention of creating cloned human beings. But mistrust and fear of scientists and their motives lingers in a society that wants treatments and gizmos from science but fears its potential dangers and excesses. “I’ve had to face up to the fact that most of our society thinks of scientists as people who are likely to do something bad,” sighs Melton. “Either bad to make money for themselves, or to cause trouble in the Frankensteinian sense. And the fact is, scientists that I know are trying to do good for people.”

Rogue scientists and quacks have fed into the fear. In early 2003, a company called Clonaid claimed to have created a cloned human on behalf of a New Age sect called the Raelians, founded by a former race car journalist named Claude Vorilhon, a.k.a. Rael, who says that humans were cloned and brought to Earth long ago by aliens. When the baby failed to show up, and Clonaid refused to allow independent verification, their announcement was declared a hoax. More legitimate is the Italian embryologist Severino Antinori, who has claimed to be working to create a human clone in an undisclosed location. In February 2004, the cloning issue heated up when a South Korean research team led by Hwang Woo Suk of Seoul National University cloned thirty embryos of about one hundred cells each—by far the largest number grown to date. They then successfully extracted embryonic stem cells from one of the embryos. Stem cell advocates were ecstatic, while their critics pointed out that the Koreans could have planted their cloned embryos into a womb and attempted to grow a Xeroxed person. Also in 2004, the British government for the first time issued a permit under the Human Fertilization Authority for a team of scientists at the Center for Life in Newcastle to clone embryos to create stem cells.

Geneticists insist that reproductive cloning does not work well for animals, and that clones are prone to illness and a short life span. The clones also don’t look like replicates of the parent. They are genetically identical, but environmental factors in the womb cause the clones to develop different features. For instance, a company in California recently cloned a calico cat that was born with a different calico pattern from its genetic “parent.” “So little Bobby’s clone won’t look like the original Bobby,” the pioneering molecular biologist Sydney Brenner told me. “Besides,” he said in his dry South African – British accent, “I can find much more pleasant ways of reproducing children that do not involve cloning.” Yet someone will one day most likely clone a human being, if no one has already. The scientists say that the technology is difficult, possibly impossible, though they used to say cloning a sheep would be impossible—and then came Dolly in 1997. “That will be a disaster,” says Melton, “first for the child, but also for science, if the child ends up getting sick and dying, or becomes an object of revulsion and ridicule.”

The controversy over embryonic stem cells being a force of good or evil is as old as fire. The Promethean myth is not just about a sympathetic god who gives mortals fire. A cautionary tale about the dangers of delving too much into the mysteries of the gods, it also underscores the dual nature of scientific discovery—that fire is a potent tool for improving life but can also be a force of destruction. Cro-Magnon scientists undoubtedly pointed to fire and realized the possibilities: Charbroiled mammoth steak! Torchlight to paint bison on cave walls! Cro-Magnon skeptics agreed that mammoth kabobs were better barbequed than raw, but what if the flames leapt up in a gust of wind and razed the village, burning people alive? For aeons, the profire and antifire forces have seesawed back and forth as the prevailing viewpoint when new technologies and discoveries appeared. Fire is still rightly feared in certain forms, and we have strict laws about arsonists and others who abuse it. Yet humans long ago decided the basics about what’s useful and dangerous about fire. We have imposed sensible regulations on its use, striking a balance that we can only hope will one day prevail for the work of Doug Melton and his fellow fire-bringers.

3

Doug Melton grew up on the South Side of Chicago in a working-class home. His father managed a grocery store and his mother was a court reporter. He says he spent most of his time playing tennis and basketball and trying to avoid the violence and tensions in his racially charged public high school. “I went to a rather difficult high school,” he says. “It was right after Martin Luther King had been killed. There was that period of race riots. It wasn’t exactly what I would call a college preparatory school. It was a huge school on the South Side of Chicago—I think there were nine hundred students in my class, bigger than some colleges.”

Leaving Chicago for the University of Illinois, Melton discovered the world of the mind as a biology major. “For the first time in my life, I felt myself part of an intellectual world,” he says, and he loved it. Melton excelled at Illinois and won a Marshall Scholarship to study at Cambridge University in England, where he earned a second undergraduate degree in history and philosophy of science at Trinity College. He stayed on at Cambridge to earn his Ph.D. in molecular biology, working at the famed Laboratory of Molecular Biology (LMB) and training under the legendary geneticist John Gurdon. Gurdon’s breakthroughs in the fifties and sixties were key to the experiments performed by Ian Wilmut, the former Gurdon student who went on to clone Dolly the sheep. In the early sixties, Gurdon showed that by inserting a mature, differentiated frog cell into a frog egg stripped of its nucleus you could create an embryo that would grow into a clone of the original frog. Melton was also mentored by Sydney Brenner, then the head of the LMB.

In 1980, Melton left England for Harvard. There he launched his research on developmental biology, working to catalogue growth-factor proteins called morphogens that control the development of organs, including the nervous system. In one experiment, one of Melton’s postdocs, Hemmati Brivanlou, an Iranian raised in France, knocked out the action of the growth factor activin just after a frog egg was fertilized. The result surprised Melton and Brivanlou by shutting down the usual formation of the embryo, causing it to stall out. On closer inspection, Brivanlou realized that the lack of activin had stopped the development of a mesoderm, the layer of tissue that forms in an embryo that eventually develops into muscle, bone, and connective tissue. More astonishing was that nearly all of the cells in the failed embryo had turned into brain cells, simply by shutting down this single protein.

“For some years I studied what happens right after fertilization,” says Melton; “that is important for telling cells what to become, the problem of developmental biology. And among the areas we worked in were studies on a process called localized messenger RNA. So if you think about the egg as sort of a uniform ball, you put a messenger RNA on one end of the egg and when you cut up the ball, then only the cells at that end get that information. It’s a way of making one end of the egg different from the other.” That is, one end of the egg develops differently than the other end.

“Through studies like that, we’ve been able to show how the main so-called germ layers for the embryo are formed—ectoderm, mesoderm, and endoderm. And many people found interesting the hypothesis we put forth, which now seems to have even more experimental support: that the nervous system forms by a kind of default mechanism. It’s the easiest thing for the embryo to form. That was sort of surprising, because neurobiologists wanted to believe that neurons were the highest, most complicated types of cells.”

Melton also made his name with Hal Weintraub of the Fred Hutchinson Cancer Center in Seattle as the first to report on antisense techniques. This process uses artificial nucleotides—bases that are created by scientists beyond nature’s A, C, T, and G—to shut down genes that cause disease by attaching synthetic “antisense” sequences to messenger RNA. These delivery vans of the cell can’t make their scheduled delivery to the ribosomes, which then don’t translate the melodious gene into the protein or reaction that causes the disease. During the late eighties and early nineties, the potential offered by antisense generated intense interest in biotech companies, and Melton cofounded Gilead, a biotech start-up launched to investigate whether compounds developed using antisense techniques would work as drugs. Unfortunately, antisense turned out to cause side effects—and Gilead went on to develop other drugs. “Antisense has never been used as a drug,” says Melton, “even though the idea’s an intriguing one.”

In 1991, Melton was happily working on basic developmental biology with his frogs when one November night Sam, then six months old, started vomiting. What at first looked like a virus grew worse. When Sam went limp, Melton and his wife, Gail, rushed their baby to the emergency room at Children’s Hospital in Boston. Sam was near death when doctors realized that he has diabetes, the youngest person ever diagnosed with diabetes at Children’s. Sam recovered, and his condition launched the Meltons on the regimen of keeping an infant diabetic alive—frequent blood tests, a closely monitored diet, and up to five shots of insulin a day.

“I was there when that happened,” said Melton’s former postdoc Hemmati Brivalou to author Stephen Hall in his book Merchants of Immortality, “and we went through a very scary period.” Melton stayed home from his lab for several weeks, until Sam was out of immediate danger. He then returned and gave an emotional talk to his team. He said that he would continue the lab’s work but would concentrate on finding a cure for his son and others like him. “Sam’s situation forced me to think more about how to apply biology; how to make a difference.” Melton invited venture capitalists and entrepreneurs to the lab and founded another company, Ontogeny, to work on molecular treatments for diabetes and other diseases. Ontogeny is now part of Curis. Melton also began to study how stem cells develop into healthy and unhealthy islet cells. Melton’s daughter was diagnosed later with having acquired diabetes when she was fourteen years old.

In 1999, a few months after James Thompson’s isolation of human stem cells, the issue of embryos and cloning broke into public consciousness as the Clinton administration and Congress grappled with how to handle the controversial new discoveries. Eager to help shape the debate, Melton and other leading embryologists went to Washington to testify in favor of moving ahead with stem cell research. In a pivotal Senate hearing held by the Labor Health and Human Services Subcommittee, chaired by Pennsylvania Republican Arlen Spector, he appeared on behalf of the Juvenile Diabetes Research Foundation. Speaking, he said, as a parent, Melton described the exhausting regimen of being the father of a seven-year-old diabetic. “I can’t recall a single night since Sam was diagnosed when we slept peacefully, free of the worry that the balance between his food, insulin and exercise was not good enough. I’m unwilling to accept the enormity of this medical and psychological burden and I am personally devoted to bringing it to an end for Sam and all type I diabetics.”

He told the senators that stem cells offered hope for Sam and others and described the promise for producing healthy islet cells that could be transplanted into a patient, or for producing bioengineered islet cells that would not be susceptible to an attack by a patient’s immune system. He talked about the ethical quandaries but said that he and the diabetes foundation “feel that appropriate safeguards can and should be established,” suggesting, as other proponents do, that stem cell research should be federally funded. Soon after, he joined a task force to help form the policies of the Clinton administration, which determined in 2000 that stem cells were not embryos under an act of Congress that forbids research on human embryos. The Clinton White House—and, presumably, a succeeding Gore White House—was poised to allow broad funding of embryonic stem cell research with safeguards when George W. Bush was elected. When the Bush administration at first failed to take any action on furthering stem cell research, Melton joined James Thompson and others in a lawsuit to force action, which was obviated when President Bush announced his stem cell policy in August 2001.

In 1990, the former president George H. W. Bush, the first Bush president, summed up the idea of scientific balance in a meeting of the National Academy of Sciences. “Science, like any field of endeavor, relies on freedom of inquiry; and one of the hallmarks of that freedom is objectivity.” Under his son, President George W. Bush, and the Republican-led Congress, the pendulum in the debate between objectivity and ideology has taken a different swing. In 2003, the House of Representatives passed a bill calling for a complete ban on all forms of human cloning. The bill lumped together embryonic cloning to create stem cells with reproductive cloning, which virtually everyone believes should be banned. Under the proposed legislation, Doug Melton and his colleagues would face up to ten years in prison and fines of at least $1 million for cloning embryonic stem cells. In the 2003–2004 Congress, the Senate’s version of the bill failed to muster enough votes to pass. Proponents of a full ban and criminalization have vowed to introduce the bills again in the current Congress, which includes added numbers of conservative Republicans who are likely to support this legislation.

In the United Nations (UN), the Legal Committee of the General Assembly in 2003 defeated by one vote a measure to recommend to the full assembly a ban on all cloning, deciding to reconsider the issue in two years. Had the ban initiative reached the floor of the full assembly, a United States – led coalition advocating the ban looked likely to win, as the Bush administration claimed to have the support of 100 of 191 members. Such a ban would be nonbinding, but should it pass, it would send a loud message. The UN briefly reconsidered the measure in 2004, spurred on by the Bush administration, but again decided to postpone a vote.

I ask Melton whether he ever thought he would be jumping into the middle of a politics maelstrom like this.

“No, I never really thought much about that. It’s related to the accident of my own family history.”

“What has the experience taught you?”

“I was so naïve about the political process,” he says, “about how important policy decisions are made. I found that shocking. So I started to speak out, particularly against bioethicists, who I think are self-appointed priests of certain political views, saying to them, ‘I don’t know why you think you have the right to say what is ethical and what isn’t, and that my own views should have as much validity as theirs.’ I find that when most people say ethics what they really mean is ‘moral,’” he adds, “and that it has to do with their religious beliefs. No one’s really trying to do unethical things.”

He is dismissive of most of the bioethicists appointed by Bush to the President’s Council of Bioethics, a committee that is supposed to base its decisions on scientific findings but has been criticized by Melton and others for undue partisanship. He finds the chairman of the council, the University of Chicago physician and bioethicist Leon Kass, to be “extremely political.” Kass is a strident opponent of many genetic therapies that might be used to enhance or alter humans. He opposes efforts to extend life span by using genetics, and although he supports some stem cell research for medical treatments, he opposes the destruction of embryos to secure stem cells.

I ask Melton what he thinks the role of government should be for something like stem cells.

“I think the government needs to create the conditions for what I would call an informed debate,” he says. “And it’s not easy for someone sitting in my position to say that without sounding arrogant, but the simple fact is that our Congress doesn’t often think about the things that they’re trying to legislate on. They don’t educate themselves on what is the basic biology. And I can give numerous examples. A wonderful question was asked to people who are writing legislation on AIDS, if they know the difference between a cell and a virus. Most didn’t.”

4

In Melton’s office he shows me his personal bench, telling me it’s a little unusual for a principal investigator in a large lab to do basic experiments. Typically, these are done by graduate students and post-doctoral students. He also points out that he intentionally has no windows here to prevent distractions. He tells me that the lab is using frogs, chickens, and zebrafish, but primarily mice for their experiments. The lab has tracked the phases of development of a pancreas from embryonic stem cells that form the endoderm and then go through a complicated series of steps involving the activation of genes and proteins that cause different organs to develop according to a programmed schedule in their DNA. Melton says that researchers have learned a great deal but still don’t know all of the genes and steps needed to drive stem cells from their undifferentiated state to fully formed islet cells.

“What are you actually doing in your lab?” I ask.

“In here now, mostly what we’re doing is trying to turn embryonic stem cells into pancreatic beta [islet] cells that make insulin,” he says. “And so we do that with two approaches: one is to take the human ES cells and just try to make them do that, and the other is to study how mice and chickens and frogs normally make a beta cell, and then use that to inform our thinking about humans.”

“So you actually have some stem cells right here in this lab?”

“They’re in the incubator down the hall.”

“And you’re using private money?”

“It’s a mix. I’ve had Howard Hughes money but more than half my lab’s funding comes from the federal government. But we’re not allowed to use the federal funds on these human ES cells.”

I ask him why he thinks people fear this sort of research.

“I think that’s a deeply interesting subject. What is the source of that fear and maybe to take a digression on it, I would tell you that my own view is that there is an innate fear to crossing boundaries; people feel secure with boundaries. Why have ideas of chimeras fascinated man for millennia? Minotaurs and mermaids? Why is that so intriguing? If you think about it, the whole idea of classifying animals, which must have been invented in about the eighteenth century, that you could find a thing called ‘species,’ gave one a sort of stamp of approval on the idea that there is a natural order, there are boxes, there are shelves where everything has its so-called natural place. What is natural and what is antinatural changes with time, and is a very difficult subject. I’m thinking of offering an undergraduate course on the concept of nature.”

“But you now have the ability to create real chimeras—a human brain in a dog, or something,” I say. “This is upsetting to some people.”

“People get the heebie-jeebies when you talk to them about putting a human brain into a dog,” says Melton. “In fact, I would suggest that there are two contexts where I think there might be an interesting connection. There is something like a natural double-take when you see a person who’s seriously deformed. People mostly say, when you see a burn victim or a person who’s had an arm amputated, that the reason you’re drawn to look, or to stare, at these poor people is the fear that it could happen to you. I actually think it’s something deeper than that. I think it has something to do with an affront to this idea of the natural order of—that person doesn’t fit into this box. I hate to say this, and it might get me into trouble, but that’s what I suspect.

“Look at the literature about science,” he says. “What was the significance of Mary Shelley’s Frankenstein? Why was Frankenstein considered an important book? Certainly not in the same way we think of Harry Potter as some kind of cheap science fiction. It wasn’t just science fiction. It was, in my view, because it addressed what is the essence of being human.

“So this relates to—if I can get this back to where I started—we were talking about ES cells and why the nation is so excited about where they come from. This issue is one that I have of necessity delved into quite a bit. It would take too long to talk about the various religious views of why one should isolate ES cells and not and whether cloning should be allowed.”

“Have you written about that?”

“No, but I have to talk publicly about it often, like with Catholic priests and with the Board of Overseers of Harvard. So I actually have educated myself quite a lot on the various religious views. I don’t really want to get into it, and the reason is I don’t think it’s fundamentally interesting. It largely has to do with the trivial concern of trying to put a tag on when life begins. What I do think is deeply interesting is this issue of chimeras. So bear with me for a minute on a couple of very broad themes that I think human ES cells opened the door to.”

I nod as he shifts from biologist to impassioned philosopher.

“Let’s say that, at a minimum, there are two areas of behavior in which our government spends an enormous amount of money. Both of them indirectly struggle with the question of whether phenotypes for the final product is a consequence more of nature or more or nurture. One of these is public education. So if you think about the whole philosophy of it, the idea which I think is a commendable one is that everyone has equal potential, and given equal opportunity will produce results. The other has to do with criminal behavior. I heard on the news this morning that for the first time now, two million people—one percent of our population—is incarcerated. It’s a number I find fascinating.

“In the book Madness in Civilization, by Foucault, he says that one way to characterize a society is to hold a mirror up to it. And that mirror is, who does the society contend is nuts? It’s a very interesting thesis. You learn more about the reflection of a society not by talking about their kings and queens and the middle class, but whom the society is fearful of. Because that defines them in a way. So if you were to accept this—and I can think of better examples—that the government spends wads of money addressing indirectly this question of nature and nurture through incarcerating people. Now, is this our genotype driving this, or our environment?

“Now bear with me as I tell you two kinds of experiments that will give hard numbers on what I’m saying. I’m not suggesting that this will answer the question. What I’m saying is it’s going to give hard, factual information that will be useful. So the first one is these identical twin studies done with humans that were separated at birth. I find that fascinating, principally because it says there’s more to the genes than you want to imagine.

(#ulink_7c788087-f267-598e-87d5-7663308642a1) And now let’s do an experiment where we clone animals so we have twins, genetically identical individuals. And let’s take an animal that has interesting behavior. It’s hard to argue that gorillas and/or chimpanzees don’t have behaviors that are very similar to humans.

“So that’s what I want my experiment to be. To clone gorillas or chimpanzees. It’s expensive, but that’s why I introduced it with the cost we spend on prisons. And now we have behavioral tests, and I don’t actually care what the tests are. In the identical twin studies, they were ‘what’s your favorite color?’ Which is a very interesting question because it’s so meaningless and stupid, and yet the fact that identical twins had an 80 percent correlation coefficient on that, even though they’d been separated at birth, I find fascinating. So let’s take gorillas. What do they like to eat better, bananas or mangos? How do they do that test? How did they do on visual acuity?

“So what you get as a result of that is numbers, hard numbers on the extent to which behavior is modified by a gene. Now, for the more interesting experiment. We take a human ES cell and we inject it into a monkey blastocyst [the first cells in a newly formed embryo]. Now you know that if you take a mouse ES cell that is, say, labeled so all of the developed cells will be blue, and you inject it into a mouse blastocyst, you’ll get a chimera where different parts of the mouse will be derived from the injected ES cell. So it might have a blue liver and some blue muscle cells, and that’s what I mean by a chimera.”

“That’s something you do today?” I ask.

“Yes. But now let’s do it with the human ES cells into a monkey, and we make chimeras. This is different from cloning now. We’re purposely trying to make a chimera—one hundred chimeras from one hundred monkeys. And now we’re going to look through their bodies and we’re going to look to see what parts of the body the human ES cell makes. Now, there’ll be a monkey where the only thing that was made that is human is the big toe. That’s completely uninteresting; no one will argue about that. No one will say that’s an experiment you shouldn’t do. And then we’ll have a monkey with a human heart. Three centuries ago, if we found a monkey whose heart was human, people would have freaked out because the seat of the soul was the heart. Now, no one really thinks that.”