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Doug Melton: Crossing Boundaries

FROM THE JUNE 2005 ISSUE

Doug Melton: Crossing Boundaries

By David Ewing Duncan|Sunday, June 05, 2005

RELATED TAGS: STEM CELL RESEARCH, HEALTH POLICY

Harvard embryologist Doug Melton argues that efforts to outlaw embryonic stem cell research are rooted in archaic notions of what is natural. "You know, people once thought cutting into the body was a sin," he says. "Now it's normal. Society's increase in knowledge and practices and beliefs can have a serious effect on what's natural."

Katherine Wolkoff

Doug Melton
Born: September 26, 1953
Mother: Betty Melton, court reporter
Father: A. Melton, grocery store manager
Ph.D. thesis: Gene injections into amphibian oocytes

Sitting in Doug Melton's Harvard University office on a spring day, I look at the faces of his children in photographs on the desk. Sam is 14 years old now, with short hair and a slightly awkward smile; Emma has long, dark hair and serious eyes. A college freshman, Emma once wrote in an essay that she wants to become an embryologist like her father. "I am also interested in becoming a member of Congress and petitioning for a cure that way," she wrote. Her father says, "I just hope she gets the chance."

Inside Sam and Emma is an immune system that has destroyed cells called islets that are responsible for producing insulin in the pancreas. Insulin is an enzyme that helps transport sugars from the blood into cells for use as fuel. Without it, sugars gum up in the blood vessels as sugar does in a gas tank, causing an untreated diabetic to go into shock and die. Most diabetics today are saved by frequent shots of synthetic insulin, but the balance between blood sugar and injected insulin is a crude calculation. Diabetics receive either too much or too little insulin each day, which causes damage to organs and muscles. For Melton's children, this imbalance is most likely an early death sentence, unless, of course, their father can discover a stem cell fix for pancreatic cells in diabetics that are inexplicably attacked by the body's immune system.

Melton's Prometheus-like resolve to give the embryological equivalent of fire to his children is evident from the floor plan of his office. Unlike the offices of most senior science professors here and at other elite institutions, which can resemble those of the world headquarters of a corporation, Melton's digs are nondescript. As I sit with him at a small table near his desk, it's clear where he would rather be—in his adjacent personal lab, also unusual for a superstar scientist. "I don't want to waste any time," he says.

Melton's determination and humble earnestness are immediately clear. With undergraduate degrees in both biology and philosophy and a Ph.D. in molecular biology, he seems to love nothing more than a passionate, long-winded argument.

But his arguments can be surprising. For instance, he wonders—just an intellectual puzzle, he assures me, that he would never want to do—What would happen if scientists injected human stem cells into a monkey embryo? What would grow? A human heart, a human brain, a toe? "That," he says, "is a kind of new biology that I find a million times more interesting than these specious arguments over whether life begins at fertilization."

I suggest that an experiment like that might seem bizarre to many people. He agrees but argues that it will seem normal one day. "There was a time when surgery was abnormal," he says, when it was considered a violation of the body as the sacred vessel of the soul. He is intrigued by what is seen as normal or abnormal. Like many scientists, he likes to live in a space at the edge of what is possible.

Doug Melton grew up on the South Side of Chicago. 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 high school. "I went to a rather difficult high school," he says. "It was right after Martin Luther King had been killed.

At the University of Illinois, Melton discovered biology. "For the first time in my life, I felt myself part of an intellectual world," he says. He excelled and won a Marshall Scholarship to study at the University of Cambridge in England, where he earned his second undergraduate degree in history and philosophy of science at Trinity College. He stayed on to earn his Ph.D. in molecular biology at Cambridge, training under the legendary geneticist John Gurdon, whose breakthroughs in the 1950s and 1960s were key to the experiments performed by Ian Wilmut, a Gurdon student who cloned Dolly the sheep in 1997.

Other leading scientists leave the details of basic research to graduate students or postdocs, but Melton spends as much time as possible working at a private lab bench adjacent to his office. He prefers to do his lab research alone because he does not want any distractions. Melton's ultimate goal is to discover how embryonic stem cells grow into special cells called islets in the pancreas. Islets produce insulin in a healthy person but shut down and stop functioning in someone who has diabetes.

Katherine Wolkoff

After Cambridge, Melton went to Harvard, where he threw himself into developmental biology, working to catalog growth-factor proteins called morphogens that control the development of organs. In one experiment, one of Melton's postdocs, Ali Hemmati-Brivanlou, knocked out the growth factor activin just after a frog e gg was fertilized. The result was surprising: The embryo failed. On closer inspection, Hemmati-Brivanlou realized that the lack of activin had stopped the development of the mesoderm, a layer of tissue in an embryo that eventually develops into muscle, bone, and connective tissue. Nearly all the cells in the stalled embryo had turned into brain cells, simply because a single protein had been stopped.

"For some years I studied what happens right after fertilization that is important for telling cells what to become," says Melton. "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.

"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."

One night in 1991, Melton's 6-month-old son, Sam, started vomiting. What seemed like a virus grew worse. When Sam went limp, Melton and his wife, Gail, rushed the baby to the emergency room at Children's Hospital in Boston. Sam nearly died before doctors finally realized he had diabetes, the youngest person ever diagnosed with the disease at Children's Hospital. Sam recovered, but his illness launched the Meltons into an overwhelming regimen of keeping an infant diabetic alive—blood tests every few hours, a closely controlled diet, up to five shots of insulin a day.

"I was there when that happened," said Melton's former postdoc Hemmati-Brivanlou to the author Stephen S. Hall in his book Merchants of Immortality, "and we went through a very scary period." Melton stayed home from his lab for weeks, until Sam seemed out of immediate danger. Then he returned and gave an emotional talk to his team. He said that he would continue the work in the lab but would concentrate on finding a cure for his son and others like him. Melton began to study how stem cells turn into either healthy or unhealthy islet cells. Later Melton's daughter was diagnosed with diabetes when she was 14.

Mouse embryos: Scientists first found embryonic stem cells in mice in the 1970s, but an understanding of the critical role they play in cell differentiation only emerged years later. "While they're useful for studying gene function in an animal, they also have their own inherent interest," Melton says. "Could you make body parts, tissues, ex vivo? That's the field I'm very excited about, but we're way behind."

Katherine Wolkoff

Look at the literature about science," he says. "What was the significance of Mary Shelley's Frankenstein? Why was Frankenstein considered an important book? It was, in my view, because it addressed what is the essence of being human.

"So this relates to embryonic stem 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 embryonic stem cells, and not, and whether cloning should be allowed."

I ask if he has 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 embryonic stem cells opened the door to."

I nod as he makes the shift 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 are a consequence more of nature or more of nurture. One of these is public education. 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, 2 million people are incarcerated in the United States.

In his book Madness and Civilization, Michel Foucault says that one way to characterize a society is to hold a mirror up to it," Melton adds. "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. So if you were to accept this, 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?

In his quest to find a cure for diabetes, Melton sometimes has to hang up his lab coat and be an activist. In 2001, after President Bush limited federally funded research to 69 existing embryonic stem cell lines, Melton launched a private fund-raising crusade and developed 17 new lines that are now available to any reputable stem cell researcher. "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," says Melton. "The fact is, scientists that I know are trying to do good for people."

Katherine Wolkoff

"Now, bear with me as I tell you about 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 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. And now let's do an experiment where we clone animals so that 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 those of humans.

"So that's what I want my experiment to be—to clone gorillas or chimpanzees. 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 mangoes?

"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 embryonic stem cell, and we inject it into a monkey blastocyst [the first 130 or so cells in a newly formed embryo]. Now you know that if you take a mouse embryonic stem 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. So it might have a blue liver and some blue muscle cells.

"Now let's do it with the human embryonic stem cell into a monkey. This is different from cloning now. We're purposely trying to make a chimera—100 chimeras. 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 embryonic stem 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."

I am beginning to wonder how far he will go with an idea that is close to Frankenstein territory given today's ethics. He assures me that he has no plans to do this experiment for real.

"But the brain is different," he says. "These days, if we're forced to pick a body part where our soul is, we say it's connected to our mind, which is connected to our brain. And that comes back to this idea of what is natural. So now we have our 100 monkeys, one of them has a blue big toe, another one has a human heart. But now the interesting part of the experiment is that we can make chimeras, which have different parts of our human brains and different parts of a monkey brain.

"And one of the first-level questions we might ask is: What part of a monkey has to be human in order to have speech? I find it really intriguing, as in the movie Planet of the Apes, to walk into a lab here at Harvard and have one of the monkeys say hello to you. That makes you wonder immediately: What does this monkey think? So what you want to know first, is this just mimicry, like a parrot? And it gets back to Wittgenstein, who talked about the relationship between language and thought. So you ask me what am I excited about? That's it."

He pauses, and I tell him this would give me the heebie-jeebies: "A human brain in a monkey that is conscious; it would be a horrible freak."

"I'm not suggesting that this chimera would have the intelligence of a human."

"But how do you know it won't?"

"It's an interesting question; I find it highly unlikely that this would happen. I don't think it would. There would be just parts of the brain that were human."

"It still sounds dangerous," I say.

"What we consider to be natural is largely a function of time. Natural childbirth, natural conception, natural, natural, natural. Now let me say two things to you about this. One is, what I find people don't ask themselves about enough is: If everything is supposed to be about controlling man's intervention, why do people take antibiotics?

"Let me explain a trick, a kind of philosopher's game about natural conception. If you look at the legislation that's been proposed in most countries, they have to rule out making a genetically identical individual as a reason to ban cloning because of the existence of twins. If you didn't do this, you would be obliged to kill one of two twins. So what they're left with is that it's medically unsafe, which is absolutely true. I suggest to you that this reason is really a surrogate for a fear of doing something where they don't know the consequence, by which I mean they are afraid. Here's my puzzle. Right now, in natural childbirth, a certain percentage of all natural fertilization events end in something we call diseased or abnormal. So if you go to Massachusetts General Hospital over here, for a certain small percentage of all children, the child has a heart defect problem. So now let's look ahead: Fast-forward two generations from now, and I will contend that it will be possible, by medical advances, to make cloning [a child] by nuclear transfer safer than natural childbirth—that the cloned embryos will have a defect rate, let's call it, of less than 1 percent.

"I'm not saying this will really happen, or that it should, but let's say 20 years from now. Let's suppose the failure rate is below what you and I call the natural birthrate. Here's the puzzle: Would the government then be justified in telling the population you can no longer create children by what you and I call natural childbirth because the probability of defect is higher than it is by cloning?

"There is another point, which comes up in my discussions with the Catholic Church: There is something called natural abortion—where biology removes fertilized events by not allowing them to implant."

"You mean spontaneous abortions, or miscarriages."

"Yes. I have a hard time finding the number because books seem to give different numbers, but people have agreed on a surprisingly high number. If you take 100 fertilized eggs, let's say only 20 percent of them are going to implant and make a baby. Of the fertilization events, most of them fail. If that's true, the Catholic Church has a major problem that they fail to face up to if life begins at fertilization. Let's assume there are 10 million Catholic couples trying to have babies for their families. This would mean there are tens of thousands of fertilized eggs that do not result in the birth of a baby, and this poses a problem in terms of the Catholic Church holding funerals for all of those fertilized eggs. And when I pointed this out, they find this to be a puzzle that they don't know how to answer. One answer is that this is God's will, and that's fine, but then that gets you into this really complicated business of, is it not then God's will to have a person like me wanting to work on human embryonic stem cells?"

Later, on the phone, I ask Melton if there is any instance he can imagine that would simply cause him to halt a stem cell experiment.

"I think it's uninteresting to live in a society where one is so afraid of the unknown that you won't try new things. I'll think about the dangers, because I haven't thought about them enough. I should think about why one shouldn't do that experiment."

Adapted from The Geneticist Who Played Hoops With My DNA...And Other Masterminds from the Frontiers of Biotech by David Ewing Duncan, to be published in May 2005 by William Morrow. Copyright 2005 by David Ewing Duncan. All Rights Reserved.