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Son's disease propels a stem cell pioneer

CAMBRIDGE -- Douglas Melton was building a brilliant career in science, enraptured with the mysteries of early frog development, when he had the kind of day that every parent fears.

His son, Sam, just 6 months old, woke up sick one morning 14 years ago, breathing fast and throwing up. By the afternoon, Melton and his wife, Gail, were at Children's Hospital in Boston, watching as their little boy slipped toward unconsciousness. The doctors could not figure out what was wrong.

Gail asked if the boy would survive.

''Honey," she remembered one doctor replying, ''I don't think so."

Harvard provost approves cell cloning program, guidelines. A29.

Then a quick-thinking nurse saved his life. After Sam urinated, the nurse grabbed a test strip and put it in the puddle, providing the key clue: Sam's urine was filled with sugars, indicating his body was not making enough insulin. The doctors worked frantically, reeling Sam back from the brink.

In the year after, Melton abandoned the work that had brought him tenure as a biologist at Harvard University and set out to cure juvenile diabetes, the disease that nearly took his son. ''I have done," Melton said, ''what any father would do."

But this father's quest has landed Melton, 51, and Harvard in the center of an intense controversy. Melton is part of a team that wants to clone human cells to create specialized embryonic stem cells that might reveal the secrets of juvenile diabetes and other maladies.

After a yearlong review, Harvard's provost recently decided the project can go forward, pending the approval of a committee charged with protecting the volunteers who will donate cells. Governor Mitt Romney has said the work should be illegal, and called it unethical. The Harvard team will not be attempting to create cloned babies, an idea known as ''reproductive cloning," which virtually all scientists consider horrific -- and which the Harvard scientists would like to see outlawed.

Rather, the Harvard experiments would give scientists a unique window into some diseases. For the first time, researchers will be able to watch as human cells, afflicted with whatever subtle genetic differences underlie the diseases, develop from their embryonic state to become mature cells, such as neurons. In theory, charting this progress will yield insights into the developmental biology of the diseases, and also provide new ways to design and test drugs to treat them.

Yet the proposal also raises weighty moral issues, involving the potential alleviation of human suffering and the very beginnings of life. To create embryonic stem cells, scientists must destroy human embryos, which critics say is taking human lives. Melton and others have used frozen embryos from fertility clinics that otherwise would have been destroyed. However, scientists also want to create embryonic stem cells that have the genes for specific diseases, and in many cases this is not possible using embryos from fertility clinics.

But the project, in a cramped, unmarked Harvard laboratory whose location is kept secret for fear of protesters, does not resemble the descriptions from activists on either side.

The scientists here are not poised to cure any disease: The initial experiments could easily take two years, said Melton, and they will be only a first step into unknown territory. Nor does this laboratory, where researchers quietly shuffle petri dishes with cells too small to see, bear any resemblance to the frightening images evoked by the mere mention of the word ''cloning."

Using a technique called somatic cell nuclear transfer, the team will take the nucleus of a skin cell from a volunteer who has juvenile diabetes or Parkinson's disease and place it into a human egg cell that has had its own nucleus removed. This will then be stimulated to grow in a laboratory dish for several days, until it becomes a nearly featureless ball of about 200 cells known as a blastocyst. The researchers will then tease it apart and create a new batch of embryonic stem cells.

The Harvard proposal has set powerful political forces against each other. On one hand are patient advocacy organizations such as the Juvenile Diabetes Research Foundation, which reject the critics' view of when an embryo becomes a human life, and see the work as a great hope. On the other are groups like the US Conference of Catholic Bishops who see the research as part of a slide down a slippery moral slope, toward a dark future with little regard for human life.

''I believe that Harvard is one of our premier research institutions, and that makes it doubly tragic that they are going down this avenue and sacrificing their moral credibility," said the Rev. Tadeusz Pacholczyk, who earned a doctorate in neuroscience from Yale University and is director of education for the National Catholic Bioethics Center in Philadelphia.

For Melton, the criticism has been difficult, but so has the science: It has also been frustratingly slow, with flashes of insight but an increasingly overwhelming sense of how little is known. And, just as he had begun to make progress, life brought another cruel twist.

Painstaking searchGail likens the intensive care ward of Children's Hospital to hiking a thin ridge line, high in the mountains. On one side, she said, you see life. On the other, you look down at death.

As the doctors worked on Sam over several days, and Gail tried to comfort him with lullabies, the couple had to deal with a new reality. Their son had a disease, with potentially severe effects that can be treated but not cured.

In juvenile diabetes, which affects more than a million Americans, the body's immune system attacks a specialized group of cells in the pancreas, called beta cells, which make the body's insulin. Nobody knows why this happens, though the disease can run in families, so it is thought there is a genetic factor of some kind.

Today, the once-lethal disease can be managed with constant insulin injections, but there are still serious, long-term risks, such as blindness and organ failure, as spikes in blood-sugar levels hammer away at the body.

Every day with juvenile diabetes is a difficult juggling act of blood tests, insulin injections, and trying to foresee the future. Food raises blood sugar. Insulin allows the body to turn blood sugar into energy, bringing blood-sugar levels back down. Exercise demands more energy.

Normally, the body keeps constant watch, producing insulin as needed, but in juvenile diabetes the pancreas cannot do its job.

If scientists can find a way to replace a patient's beta cells with new ones, then they might be able to cure the disease, said Melton, who is a professor at Harvard and whose work is supported by the Howard Hughes Medical Institute. Already, doctors have given patients beta cells purified from pancreases taken from cadavers, curing the patients to the point where they don't need insulin. But this treatment is not the answer: The effect often is not permanent, patients must stay on powerful immune-suppressant medications, and there are only enough organ donors to help a tiny fraction of of sufferers.

Since Sam's diagnosis, Melton has focused his work on trying to discover how the beta cells develop in the body, in the hope that this might reveal a way to grow new ones.

But it is a dizzyingly complex problem. Every person began life as a single, fertilized egg cell. After the embryo has implanted in the walls of the uterus, the embryo begins to develop three distinct layers of cells. As more time passes, the cells from one layer, called the endoderm, specialize -- some into little buds of tissue that will become the pancreas. With this tissue, then, cells go through further specialization, with only a very small proportion becoming the beta cells that make insulin.

One of the Melton lab's contributions has been to help decipher the signals that tell cells what to specialize into. His goal -- still unmet -- is to map each of the crucial decisions a cell must make in the path it takes from primitive embryonic cell to fully functional beta cell.

Such a map could make it possible to create beta cells that could be transplanted into patients, using human embryonic stem cells to make a virtually unlimited supply of beta cells. Or, perhaps, it could be used to take beta cells from cadavers and expand their numbers, so they could help more patients. Or, perhaps, it could lead to drugs that would allow patients to grow more of their own beta cells.

Any of these solutions would still leave the problem of the immune system's attack on the beta cells, but it would represent an enormous step forward.

It has been slow, painstaking work. And two of Melton's most important findings have been disappointments. In one, the Melton lab found a crucial flaw in an experiment that seemed to show it was possible to easily convert embryonic stem cells into beta cells in a dish.

In another, published last year in the prestigious journal Nature, the lab found that there are no stem cells in the adult pancreas capable of creating beta cells. This finding has been controversial, because other scientists say they have evidence of the adult stem cells Melton claims do not exist, but Melton's Nature paper suggested that an entire avenue of diabetes research -- the quest for adult stem cells that can replace beta cells -- could be doomed to fail.

In 2001, in the midst of his work, came another bad day for the Melton family. Doug's other child, 14-year-old Emma, mentioned to Gail that she felt like she was thirsty all the time, which can be a symptom of high blood sugar. They decided to use Sam's monitor to check Emma's blood sugar. Sam, by then a vibrant 10-year-old, was there, and they were all giggling, Gail said.

Then she looked down. The blood sugar was wildly high. They checked again. Gail struggled to keep her composure. It could mean only one thing: Now, both children had juvenile diabetes.

Joining forcesAround the same time, a young scientist from the Massachusetts Institute of Technology had come to Melton's lab to give a talk, and afterward the two sat in his office and discussed a radical approach to studying complex diseases.

The scientist was Kevin Eggan, 31, then a graduate student in the lab of MIT's Rudolf Jaenisch. Doing nuclear transfer on microscopic cells is still very much an art -- requiring specialized equipment, good hands to work with highly sensitive instruments, and almost superhuman patience -- and Eggan is one of the few people who have mastered it.

Although Eggan's interest is in neurodegenerative diseases like Parkinson's, and Melton's is in juvenile diabetes, the two shared a common frustration. In many diseases, scientists know that genetics play an important role but they do not know which genes are at fault, and suspect that there are many of them. Such diseases pose special problems for biologists, because it is not possible to genetically engineer a mouse -- a mainstay of experimentation -- with all the defective genes, because the defective genes haven't been identified.

The two talked about an attempt to solve the problem by bringing together Eggan's skills at nuclear transfer with the emerging science of human embryonic stem cells. Embryonic stem cells have the ability to become any cell in the body. Using nuclear transfer, Eggan and Melton wondered if they could transfer the genes of a patient with a disease into an egg cell and then create embryonic stem cells from this -- a so-called ''disease line" of embryonic stem cells. Such an approach would allow them to compare how particular types of cells develop when they have the genes associated with a disease.

For example, with juvenile diabetes, the team would like to take embryonic stem cells created with the genes of a patient, and push them to become beta cells -- the cells lost in the disease -- and watch for any deviation from normal development. If they do detect differences -- perhaps a subtle change that sets off the immune system attack -- this would provide important insights into the disease.

This would give all scientists -- the Harvard team said it would make the cells freely available -- a unique tool. They would be able to watch as human cells, with the precise genetic background of patients, develop into the affected cells.

While scientists say the work could prove very important, they caution that even if the project successfully creates the new human embryonic stem cells, there is no way to predict how they will develop or what the cells will reveal.

In the case of juvenile diabetes, for example, there is a crucial scientific roadblock: Nobody knows how to push human embryonic stem cells to become beta cells. Even if the team is able to do the nuclear transfer and create the embryonic stem cells, they will be of little use if they cannot create the cells involved in the disease, and for juvenile diabetes this cannot be done now.

Melton said that it will take a long time to get the nuclear transfer project to work, and said he is hopeful that, by the time it is ready, he or somebody else will have solved the beta cell problem.

''It is the first step of a long-term project," said Melton. ''We are planning for success."

With Parkinson's disease, the situation is different, because scientists know how to make the cell they will need. Thus, if Eggan is able to create embryonic stem cells that have the genes of a Parkinson's patient, he will then be able to coax these cells to become the neurons that die in patients with Parkinson's disease.

''We don't even know if the neurons of Parkinson's patients develop the same way as healthy ones," said Eggan, who is a junior fellow in the Harvard Society of Fellows. ''The point of nuclear transfer is to understand the initial causes of the disease."

Yet, even in the case of Parkinson's, there is no way to know how useful the experiments will end up being. There may be some crucial environmental event -- a virus, perhaps, or some toxin -- that sets the disease in motion in a body, and this will not happen in the dish.

''Ordinarily, we do not talk about experiments until we are confident about their conclusions," said Melton. ''But these are special kinds of experiments that have attracted the attention of the public and the Legislature and we as a group of scientists think it is very important that the public know why we are doing these experiments."

Melton and Eggan both reject the idea that there is anything morally questionable about their research, and specifically the notion that they are taking human lives. From their perspective, as biologists, they say the creation of a human being is a process, like the development of an acorn into an acorn tree. It makes no sense, they said, to think of the cells they work with as babies.

Sitting in his office late one afternoon, Melton said he has been frustrated by the way his research is sometimes portrayed, and particularly Romney's recent charge that it is unethical.

Melton is working to help his children. But, like many parents of children with chronic illnesses, Melton has also come to feel more of a connection with human suffering that once passed unnoticed.

Sometimes, he said, he will be watching television and feel deeply moved at the sight of someone in a wheelchair.

''You could almost say that there is a moral obligation to do these experiments," Melton said. ''It would be very hard to turn my back on them."

Gareth Cook can be reached at cook@globe.com.


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