Developmental Biology of the Endoderm and Pancreas

Summary: Doug Melton's laboratory is interested in the genes and stem cells that give rise to the pancreas and insulin-producing beta cells, with possible therapeutic implications for diabetes.


Research in our laboratory focuses on the developmental biology of the pancreas. We wish to understand how the pancreas normally develops and use that information to grow and develop pancreatic cells (islets of Langerhans) in culture. One goal of this project is to establish how vertebrates make an organ from undifferentiated embryonic cells. A longer-term goal has practical significance: if our studies are successful, it should be possible to apply our conclusions to human cells and provide a source of insulin-producing 帣 cells for transplantation into diabetics.

Our main challenge is to understand the precursor, or stem, cells that give rise to the pancreas and to characterize the key gene products that specify cell fates and functions during organogenesis. To this end, we use several vertebrate organisms, including frogs, chickens, and zebrafish, but the majority of our studies are done with mice and human embryonic stem cells. We use a wide variety of techniques, including functional genomics and gene arrays for gene discovery, tissue explants and grafting for analyzing inductive signals, and developmental genetics for direct assays of gene function. The aim of all our experiments is to understand the genes, cells, and tissues that direct pancreatic organogenesis.

Development of the Endoderm and Pancreas
The pancreas develops as an evagination from the embryonic endoderm. In mice and humans, two independent buds form. One of the first steps required for pancreatic development is an inductive interaction between the endoderm and adjacent mes/ectoderm. This interaction sets up a prepattern in the endoderm for various organ-forming regions, including the pancreas, but pancreatic-specific genes are not turned on at this stage. One possibility is that soluble factors secreted by the mes/ectoderm or endoderm itself set up the prepattern in the endoderm.

Subsequent inductive interactions occur between the notochord and the endodermal epithelium. These permissive inductions allow the pancreatic buds to emerge and continue development. About this time, the first pancreatic-specific genes are expressed, including Pdx1. When the epithelial sheet folds up to make a tube, the two lateral regions fuse to form the site where the ventral bud will emerge. The middle region forms the dorsal pancreatic bud. The two pancreatic buds require interactions with adjacent mesenchyme for further pancreatic growth and differentiation. As development continues, the two buds merge to form one organ while exocrine and endocrine cytodifferentiation proceeds. For each of these steps we aim to identify the genes that regulate development.

Pancreatic Stem Cells
In addition to work on genes that regulate pancreatic organogenesis, our laboratory has several projects aimed at the identification of cells capable of producing or turning into pancreatic islets. In embryos there are precursor or stem cells that give rise to the pancreatic lineage, and these cells are being intensely studied. In addition, embryonic stem cells (ES cells) can function as a general precursor for many kinds of cells, including 帣 cells. In the adult, studies show that new pancreatic 帣 cells are not formed by the differentiation of a precursor or stem cell, but rather by the simple process of self-duplication from pre-existing 帣 cells.

At each step of the development from an egg or stem cell to a functional pancreas, decisions are made that affect the fate of cells. For example, an embryonic stem cell can be directed to one of the three germ layers, ectoderm, mesoderm, or endoderm; the latter is the germ layer that will give rise to the pancreas. Subsequently, the endoderm is subdivided into different organ regions, including the thymus, lung, liver, stomach, intestines, and pancreas. Once cells are set aside to form the pancreas, additional decisions are made to parse cells into the ductal, exocrine, or endocrine lineages. The islet of Langerhans is a kind of "mini" endocrine organ consisting of various cell types, including the insulin-producing 帣 cells. If we can understand the gene products that signal cells to become islets, this information could also be used to treat patients directly by stimulating growth and differentiation of new 帣 cells in vivo.

Work from our laboratory and others has identified genes involved in the various steps of pancreatic development. Yet we still do not know all the genes or steps needed to drive cells from an immature embryonic state to a fully formed 帣 cell. As this information accumulates, we are focusing much of our effort on directing the differentiation of embryonic stem cells, including both mouse and human embryonic stem cells, into pancreatic islets and 帣 cells. If we can direct the differentiation of human cells into functional 帣 cells, we will extend our findings to clinical applications for the treatment of diabetes.

http://www.hhmi.org/research/investigators/melton.html

Researchers Devise New Technique for Creating Human Stem Cells


The image shows human embryonic stem cells stained for a characteristic marker protein (Tra1-60, red dots). When adult skin cells are fused with embryonic stem cells, the hybrid cells (not shown) re-express this marker, suggesting that the cells have reverted to the embryonic state.

Researchers have developed a new technique for creating human embryonic stem cells by fusing adult somatic cells with embryonic stem cells. The fusion causes the adult cells to undergo genetic reprogramming, which results in cells that have the developmental characteristics of human embryonic stem cells. The new technique may permit scientists to derive new human embryonic stem cell lines without the need to use human embryos.

This approach could become an alternative to somatic cell nuclear transfer (SCNT), a method that is currently used to produce human stem cells. SCNT involves transferring the nuclei of adult cells, called somatic cells, into oocytes in which scientists have removed the nuclei.


“The long term goal for this experiment was to do cell fusion in a way that would allow the elimination of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell.”
Douglas A. Melton

The researchers said that — while the technique might one day be used along with SCNT, which involves the use of unfertilized human eggs — technical hurdles must be cleared before the new technique sees widespread use. It is more likely that the new technique will see immediate use in helping to accelerate understanding of how embryonic cells “reprogram” somatic cells to an embryonic state.

The researchers published their findings in the August 26, 2005, issue of the journal Science. Senior author Kevin Eggan and Howard Hughes Medical Institute investigator Douglas A. Melton, both at Harvard University, led the research team, which also included Harvard colleagues Chad Cowan and Jocelyn Atienza.

In theory, researchers can induce embryonic stem cells to mature into a variety of specialized cells. For that reason, many researchers believe stem cells offer promise for creating populations of specialized cells that can be used to rejuvenate organs, such as the pancreas or heart, that are damaged by disease or trauma. Stem cells also provide a model system in which researchers can study the causes of genetic disease and the basis of embryonic development.

Eggan, Melton and their colleagues decided to pursue their alternative route after other researchers had shown that genetic reprogramming can occur when mouse somatic cells are fused to mouse embryonic stem cells. The scientists knew that if their studies were successful, it would provide the research community with a new option for producing reprogrammed cells using embryonic stem cells, which are more plentiful and easier to obtain than unfertilized human eggs.

In the studies published in Science, the researchers combined human fibroblast cells with human embryonic stem cells in the presence of a detergent-like substance that caused the two cell types to fuse. The researchers demonstrated that they had achieved fusion of the two cell types by searching the fused cells for two distinctive genetic markers present in the somatic fibroblast and stem cells. The researchers were also able to further confirm that fusion occurred by studying the chromosomal makeup of the fused cells. Their analyses showed that the hybrid cells were “tetraploid” - meaning they contained the combined chromosomes of both the somatic cells and the embryonic stem cells.

One of the key findings from the study was that the fusion cells have the characteristics of human embryonic stem cells. “Our assays showed that the hybrid cells, unlike adult cells, showed the development potential of embryonic stem cells,” said Eggan. “We found they could be induced to mature into nerve cells, hair follicles, muscle cells and gut endoderm cells. And, since these cell types are derived from three different parts of the embryo, this really demonstrated the ability of these cells to give rise to a variety of different cell types.”

Furthermore, Eggan noted that genetic analyses of the fused cells revealed that the somatic cell genes characteristic of adult cells had all been switched off, while those characteristic of embryonic cells had been switched on. “With the exception of a few genes one way or the other — which is perhaps because these cells are now tetraploid — the hybrid cells are indistinguishable from human embryonic stem cells,” he said.

“The long term goal for this experiment was to do cell fusion in a way that would allow the elimination of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell,” said Melton. “This paper reports only the first step toward that goal, because we end up with a tetraploid cell. So, while this does not obviate the need for human oocytes, it demonstrates that this general approach of cell fusion is an interesting one that should be further explored.”

The researchers also performed fusion experiments using pelvic bone cells as the somatic cells and a different human embryonic cell line, to demonstrate that their technique was not restricted to one adult cell type or embryonic cell line.

In both cases, the researchers observed extensive reprogramming of the somatic cells. “We were surprised at how complete the reprogramming was,” said Eggan. “I think we were expecting that there would be more 'memory' of the adult state than the embryonic in the hybrid cells. It was quite clear that when we looked at these hybrid cells, they had completely reverted to an embryonic state.”

Melton said that the remaining technical hurdle is figuring out a way to eliminate the embryonic stem cell nucleus in the hybrid cell, causing it to have a normal number of chromosomes. One problem, said Melton, is that the nucleus in stem cells is large, occupying nearly the entire cell. Thus, it is not practical to physically extract the nucleus, as is currently done with oocytes, which have a relatively small nucleus. An alternative approach of destroying the embryonic stem cell nucleus with chemicals or radiation would induce the cell's suicide program, called apoptosis, he said.

Melton emphasized that “at this stage in our understanding, the hard fact is that the only way to create an embryonic stem cell from a somatic cell is by nuclear transfer into oocytes. Taking advantage of this current capability — such as colleagues in South Korea and other countries are doing — is critical if we are to maintain the progress necessary to realize the extraordinary clinical potential of this technology.”

Eggan added that the most realistic current promise of the fusion technique is in studying the machinery of genetic reprogramming of somatic cells by embryonic cells. “It is extremely difficult to study the reprogramming process using eggs, because in the case of humans it is very difficult to obtain eggs in any quantity and difficult or impossible to genetically manipulate them,” he said. “But embryonic stem cells can be grown in large quantities. We can isolate the components of the reprogramming machinery, and we can genetically manipulate the cells to analyze the reprogramming process.”

Image: Chad A. Cowan, HHMI at Harvard University, for Science

http://www.hhmi.org/news/melton6.html

The Issues: Stem Cell Research

CAMBRIDGE, Mass., July 8, 2004
Prof. Doug Melton �(CBS)



(CBS) CBS News continues a month-long series titled "What Does It Mean To You?" focused on where the presidential candidates stand on major issues and how a vote for one or the other candidate might affect average people's lives.

In this report, CBS News Correspondent Elizabeth Kaledin examines the political controversy over stem cell research.
http://www.cbsnews.com/stories/2004/07/08/eveningnews/main628171.shtml

Prof. Doug Melton is on a mission to harness the power of embryonic stem cells. Considered by many to be the building blocks of life, the hope is that embryonic stem cells can be programmed to reverse, even cure, diseases like Parkinson's, Alzheimer's and Doug Melton's specialty, type 1 diabetes.

But there's a catch: Embryonic stem cells come from embryos - mostly frozen leftovers slated to be thrown away from fertility clinics. But many in this country regard those embryos as human life and consider their use in research immoral. President Bush's policy is an attempt to acknowledge those views while allowing research to go forward.

"Embryonic stem cell research is at the leading edge of a series of moral hazards," Mr. Bush has said.

"This issue forces us to consider the fundamental questions about the beginnings of life."

In a 2001 speech, the president outlined the position he is sticking with in the current campaign: Researchers getting government money can only use existing supplies of embryonic stem cells -- so no new embryos will be destroyed.

Few scientific endeavors are as much affected by politics as embryonic stem cell research. What happens in November could have a profound impact not only on Doug Melton's work at Harvard, but in his personal life as well.

Both of Melton's children have type 1 diabetes, a chronic disease that can lead to blindness and kidney failure. Melton shifted his research focus after his son's diagnosis.

"I'm no different than any other parent. Any parent whose child gets diabetes says, 'What am I going to do about this?'" Melton said.

But Mr. Bush's embryonic stem cell policy has created obstacles for Melton. Though he favors regulation, there are not enough existing cells, he says, to make meaningful progress.

"Someone has described it as trying to do research with one hand held behind your back," he said.

John Kerry, on the other hand, is promising to increase federal funding and open up the field.

"We must lift those barriers that stand in the way of stem cell research in America," Kerry has said.

If there's a change in administration policy it will speed discovery and lead to cures faster. There's no doubt that the present policy is hampering research.

Regardless of the outcome of the election, Doug Melton will continue toiling away. He has already created his own supply of embryonic stem cells using private funding. But this accomplished scientist feels his life will be a failure if he can't help his kids.

Melton was asked if could separate his professional and personal lives - the scientist from the father.

"I try not to. I mean for me, my life is those two things. When I go home, of course I enjoy my children as any parent does, but I'm waking up in the morning thinking about how to find a cure" he said.


和MIV, CBS Broadcasting Inc. All Rights Reserved.

Science Test: Biggest Struggles In Stem-Cell Fight May Be in the Lab


The Wall Street Journal
August 12, 2004

Science Test: Biggest Struggles In Stem-Cell Fight May Be in the Lab
In Quest for a Diabetes Cure, Dr. Melton Tries to Make Insulin-Producing Tissue Guided by a Jellyfish Gene

By MICHAEL WALDHOLZ and ANTONIO REGALADO
Staff Reporters of THE WALL STREET JOURNAL

CAMBRIDGE, Mass. -- In a laboratory near Harvard Square, batches of stem cells harvested from human embryos steadily multiply inside glass incubators and petri dishes filled with pink-red fluid.

The cells result from almost five years of work by a team of Harvard scientists led by 50-year-old Douglas Melton, a self-assured former frog biologist. Dr. Melton's two teen-age children have type-1 diabetes, and he is dedicating his career to using stem cells to cure it. Over time the disease, which affects about one million Americans, can ravage its victims, causing blindness, kidney failure and limb amputation.

Driven by personal anguish as well as scientific expertise, Dr. Melton has become one of the most influential scientists in a debate that is now a campaign issue in the presidential race. Along the way, he has skirted U.S. government rules restricting the use of human embryos and helped raise $5 million from private donors to create a stem-cell institute at Harvard University. While a relentless advocate of stem-cell research, he has also crossed scientists in his field, persistently criticizing stem-cell research he thinks is headed in the wrong direction.

Stem cells literally form the foundation for human life as they divide into cells that eventually become every human tissue and organ. In the laboratory, when stem cells are plucked from embryos, the cells haven't yet formed into a specific type. The trick is to get them to grow into specialized cells -- insulin-making cells to treat diabetes, brain neurons to treat Parkinson's disease or motor nerves to cure spinal-cord paralysis.

This is what Dr. Melton and a few dozen other laboratories around the world are struggling to do. Yet, despite all his efforts, Dr. Melton has yet to accomplish his goal of producing insulin-making cells in the lab. "We are convinced we can do it," he says. "We just don't know how."

Some groups oppose stem-cell research because it involves the destruction of human embryos. In a much-debated compromise, the White House three years ago permitted federal funding for embryonic cell research -- but only for cells created on or before Aug. 9, 2001. The idea was to prohibit the use of federal money from encouraging the destruction of more embryos. The cells available for study come from embryos that were donated by couples for whom extra embryos were created during in vitro fertility treatments.

Many scientists complain that the restrictions on stem-cell research are impeding progress. But Dr. Melton's efforts show that some of the greatest barriers to turning the cells into promising new therapies remain those that scientists encounter in the lab.

"Anyone who says new therapy is around the corner, or even a few years away, is just wrong," says Ronald McKay, a leading researcher at the National Institute of Neurological Disorders and Stroke in Bethesda, Md.

With some conditions, such as Alzheimer's disease, science has yet to understand what goes wrong. Simply replacing damaged brain cells with new ones grown in the lab from stem cells isn't yet feasible and may not be for decades, researchers say.

But in diabetes, doctors are reporting early success with an experimental cell-replacement therapy. The treatment involves taking insulin-producing cells, called islets, from the pancreas of cadavers and transplanting them into diabetics. Since 2000, when the first successful islet transplants were performed at the University of Alberta in Edmonton, Canada, about 300 of these procedures have been carried out.

Gary Kleiman, a 51-year-old Miami resident, has had type-1, or juvenile-onset, diabetes, since age 7. By 1982, the disease -- in which the pancreas is unable to produce sufficient insulin -- had destroyed his kidneys, requiring him to get a transplanted one from his mother. By 2002, that kidney was also ravaged, and he received another one from his brother. By this time, he had also lost sight in one eye.

In November 2002, Mr. Kleiman was among the first Americans to receive an islet transplant. Since then, he hasn't required daily insulin injections, and the disease is no longer attacking his organs. As long as the islets keep working, he is cured, although since the underlying disease still exists, he may require additional transplants at some time.

"It's been unbelievable," says Mr. Kleiman, who is married and has two young children. "I didn't realize the stress that had been integrated into my entire life."

Stem-cell proponents say the main obstacle to making the diabetes treatment more widely available is the shortage of transplantable islets.

"Cadavers will never provide enough islets to meet the need," says Robert Goldstein, director of research at the Juvenile Diabetes Research Foundation, one of several groups lobbying against the federal funding restrictions. Last month, in testimony before Congress, Dr. Goldstein said: "We have good reason to believe that embryonic stem cells will one day be able to grow large amounts of insulin-producing cells for transplant."

Until the late 1990s, Dr. Melton wasn't well known outside academia. As an embryologist interested in understanding how organisms develop, he centered his career on the Xenopus species of frog. The frog's embryos develop outside the womb. Because the embryos are translucent, scientists can watch organs develop and see which biochemical signals are responsible for turning cells into specific tissues.

In November 1998, everything changed. Scientists at the University of Wisconsin reported they had isolated stem cells from human embryos. Suddenly, scientists who had been studying organ development in embryos of mice, frogs and chickens could examine human development.

Dr. Melton decided to try techniques used in studying frog embryos to investigate how the pancreas is formed. He hoped the research might reveal a way to regenerate islets -- the insulin-making cells inside the pancreas that are destroyed in type-1 diabetes -- as a way to find a cure for his son's disease.

In 1999, Dr. Melton entered the public arena with testimony before a Senate hearing on whether to provide federal funding for stem-cell research. He said the need to constantly check his seven-year-old son Sam's blood sugar was taking "a heavy toll on the rest of the family." He noted that his wife was regularly up late checking Sam's blood, worried that if the sugar level dropped too low, the child might slip into a coma.

"I can't recall a night since Sam was diagnosed when we slept peacefully," Dr. Melton said. Arguing that stem cells extracted from embryos might hold the key to a cure, he said: "I am unwilling to accept the enormity of this medical and psychological burden and I am personally devoted to bringing it to an end."

He also displayed his sharp elbows. When the University of Wisconsin demanded that those who wanted to work with its new cells agree to commercial and scientific restrictions, Dr. Melton attacked the conditions as "unacceptable and ridiculous," saying the cells should be made available without interference.

When Wisconsin refused to budge, Dr. Melton obtained cells from a research team in Israel that had participated in the original project but was now also feuding with the university.

Collaborating with researchers in Israel, Dr. Melton tested the effects of various growth factors on the cells. He found these chemical signals would push the stem cells in one direction or another. Some became immature nerves, others resembled muscle. But the Israeli-American team soon recognized that its ability to control the direction the cells took was sharply limited. Stem cells proved extraordinarily difficult to manipulate. Rather than respond to the scientists' commands, Dr. Melton said, they often behaved ike "popcorn," spontaneously morphing into a variety of cell types.

The next year, the Meltons' daughter, Emma, then 12, also developed type-1 diabetes. Spurred by the plight of his children, he decided he could get faster results by isolating his own set of stem cells from human embryos, even though that was sure to generate more controversy. Over the next two years, in a collaboration with Boston IVF, a fertility clinic, his lab was sent liquid-nitrogen packed, stainless-steel bottles containing 344 frozen embryos donated from couples who had given permission for their unused embryos to be used in research. The embryos otherwise would be discarded.

In August 2001, with conservatives pressing for a ban on any funding of embryo stem-cell research, President Bush struck a compromise. He ruled federal grants could be used to study only stem cells already taken from embryos. No U.S. money could be used to create new stem cells or to study new ones, which Dr. Melton was already set on doing. Dr. Melton immediately joined other scientists protesting the policy, saying the existing cell supplies identified by the administration were too few for research.

Although the administration initially disputed that, earlier this year, government scientists conceded that of the 78 batches of stem cells approved for study in 2001, only about 20 of the so-called cell lines are actually available or useful.

In March, Dr. Melton announced that his lab had created 17 new populations of embryo stem cells. He used money from the Howard Hughes Medical Institute, which funded much of his earlier animal research, and from Harvard, the Juvenile Diabetes Research Foundation and private donors he says wish to remain anonymous. He says he has since used private money to create five more lines of embryo stem cells.

In a conference call to reporters across the U.S. and overseas, Dr. Melton described the logistics dictated by the government rules. In order not to violate the law, Dr. Melton had to create a separate lab that didn't contain equipment acquired with federal funds. Lab tools bought with nongovernment money were segregated into boxes with red stickers.

"It was like making four dishes for dinner and making one of these with its own salt, pepper and other ingredients," he said. Noting he planned to provide the cells for a minimal fee to others who might want to use them for growing nerves or muscle cells, he said his lab was focused solely on turning the cells into islets.

By this time, Dr. Melton's early hope of quick success had slipped away. Initially, it looked as if growing islets from the embryo stem cells might be relatively easy. In 2001, Dr. McKay, the government scientist, published a paper showing that mouse stem cells could be transformed in the lab to insulin-producing cells. That was followed by claims from other researchers that they had turned human stem cells into insulin producers.

Embryo-research advocates have used these reports to argue that stem cells will solve the islet shortage, citing the experiments in fund-raising letters and political lobbying statements. In his testimony to Congress in July, Dr. Goldstein of the Juvenile Diabetes Foundation repeated the claims, saying "recent studies have demonstrated the ability to coax embryonic stem cells into insulin-producing cells in the lab."

But despite receiving a significant amount of money from the foundation, for which he says he is "extremely grateful," Dr. Melton says Dr. Goldstein and the researchers who reported the early results are wrong. In published reports and at numerous science meetings over the past two years, Dr. Melton has criticized the findings. He says that in their attempts to grow islets, the research teams used chemical growth factors, including insulin. Dr. Melton says the insulin in the mix confused the results.

The researchers believe they have succeeded in growing insulin-producing cells but are quick to concede their method is inefficient and better techniques must be developed.

One indication of Dr. Melton's growing influence is that his criticism has brought some research to a halt. Don Wolf, a researcher at Oregon Regional Primate Center working with monkey stem cells, says Dr. Melton's critique, while justified, has "affected people's ability to write and fund grants and continue their work." The National Academy of Sciences recently refused to publish a paper from his lab, Dr. Wolf says, citing concerns expressed by Dr. Melton and others. The academy says it doesn't comment on papers under review.

Dr. Melton is unsympathetic to such complaints. He argues -- and some others in the field agree -- that in order to grow islets in the lab, scientists need to identify the precise genes that create islets. The trial-and-error methods previously used aren't readily reproducible and don't provide a basic understanding of how nature works, he says. His critiques are meant to encourage the field to do what he is attempting: figure out how to rigorously copy in a lab dish what occurs in the developing fetus.

Islets belong to a family of cells called endoderm, which make up organs such as the liver, stomach and pancreas. Researchers have yet to uncover the genetic signals that turn stem cells into endoderm.

This is frustrating because other labs have reported success in getting stem cells to divide into neurons and even beating heart cells. In the lab, these appear to grow from stem cells spontaneously, without much coaxing. Scientists speculate that might be because the embryo early on needs blood and nerve connections to grow, while endoderm-based organs aren't needed until later.

Using techniques developed in his frog research, Dr. Melton and his colleagues devised a color-coded system to track whether stem cells in lab dishes are becoming endoderm or some other tissue. The colors are derived from genes that create bright fluorescent lights in certain aquatic animals. For instance, in the mid-1990s, researchers isolated a gene responsible for creating a flashing green light that jellyfish native to Puget Sound use to communicate.

Researchers in Dr. Melton's lab have attached the green-light gene next to genes that become active only when a stem cell turns into endoderm. Yellow and blue light genes are attached to other tissues. "We call them tutti frutti cells," Dr. Melton says. The job ahead is to isolate the exact chemical signals that are present when cells turn green.

But this is time-consuming. It took more than a year to create the color-tracking system. While other labs are now using a similar approach, "the search would go much faster with more labs involved, " Dr. Melton says.

Since the spring, Harvard has sent out frozen vials of Dr. Melton's cells to more than 25 research groups, and 80 others have asked for them, according to the university. Lawrence Goldstein, a biologist at University of California, San Diego, who plans to study some of the Melton cells with nongovernment funds, says federal rules are discouraging young scientists from entering the field. "It looks too difficult, too complicated, too tangled up," he says, noting that young researchers depend on federal money to get started.

To speed the process in his lab, Dr. Melton says he needs robots that can conduct numerous experiments at once. Because of government restrictions, he is blocked from using robots paid for under existing federal grants. One solution is to use equipment at nearby labs, bought with expired federal grants.

Dr. Melton continues to be outspoken in efforts to keep the few other U.S. labs focused on what he believes is the best way to create islets. He recently caused another stir with a new report saying stem cells can't be derived from existing pancreas tissue. Some mature organs, such as blood marrow, contain stem cells that naturally divide as a way to replenish cells in the body. Critics of embryo stem-cell research say these so-called adult stem cells can be studied as a way to avoid research using embryos.

Although several prominent research groups, such as those at the Joslin Diabetes Center in Boston, say they believe they have turned up evidence of adult stem cells in the pancreas, Dr. Melton is unmoved. "It's a waste of precious time and effort," he says.
ref

November 11, 2004 link
The 2004 Scientific American 50 Award: Policy Leaders

Image: JEFF JOHNSON Hybrid Medical Animation
STEM CELLS from human embryos, such as the one above, are at the center of a debate over scientific research.
Douglas Melton’s finding that adult stem cells do not give rise to insulin-forming cells undercuts the rationale for a ban on research with embryonic stem cells.

POLICY LEADER OF THE YEAR
Douglas A. Melton
Thomas Dudley Cabot Professor of the Natural Sciences, Harvard University, and investigator, Howard Hughes Medical Institute

Advocated and enabled more extensive studies of embryonic stem cells.

Last year Douglas Melton made a discovery that both advanced the understanding of diabetes and cast doubt on an argument the Bush administration had used to defend its tight restrictions on federally funded research into embryonic stem cells. He has used this result to advance his strong opposition to the policy and to mobilize still more private resources to keep the field alive in this country.

Melton found evidence that the insulin-forming beta cells of the pancreas reproduce by simple division in the mature phase rather than descending from a progenitor, the adult stem cell. The finding was extraordinarily important for diabetes research, which is looking for sources of beta cells that will be accepted by the immune systems of patients with type 1 diabetes who lack such cells and must therefore inject insulin. Now it seems that workers in search of transplantable tissue will have to culture either fully mature cells or fully immature ones--that is, embryonic stem cells. The discovery therefore undermines the administration's argument that adult stem cells could readily fill in for the embryonic kind.

Melton's scientific eminence has made him a particularly effective opponent of the administration's near ban on funding embryo research. Not only has he argued against it in congressional testimony and other public media, he has found ways to work around it. In March he announced the establishment of 17 new lines of embryonic cells, a feat that nearly doubled the number of usable lines available since the Bush policy took effect. He has since established five more lines. The work was onerous because it had to be done with private funds he helped to raise. It was performed in new laboratories that had never received any federal support. This spring the governing authority for these endeavors was unveiled under the name of the Harvard Stem Cell Institute. Melton will serve as its co-director. His own focus, however, will be diabetes, a field which he entered after his two children were diagnosed with the disease.

Harvard Announces Private Project to Make Human Stem Cells

By Rick Weiss
Washington Post Staff Writer
Wednesday, June 7, 2006; Page A10

Harvard University announced yesterday the launch of a privately funded, multimillion-dollar program to create cloned human embryos as sources of medically promising stem cells.

The collaborative effort, involving several Harvard-affiliated medical research centers, the New York Stem Cell Foundation and Columbia University, marks a new phase in the long-simmering U.S. culture war over stem cell research, pitting some of the nation's most prestigious institutions against a vocal conservative movement that opposes the work.

President Bush banned the use of federal funds for studies of new human embryonic stem cell colonies in August 2001, saying the creation and destruction of human embryos for research ran counter to a "culture of life." Since then, only the University of California at San Francisco has acknowledged doing research on cloning human embryos, also using private funding.

The field lost much of its luster earlier this year when Korean claims of having done the first successful derivation of stem cells from cloned human embryos proved fraudulent.

Harvard officials said they had developed their program over a two-year period under an umbrella of new ethics rules, and hoped to boost the field without unduly offending opponents.

"While we understand and respect the sincerely held beliefs of those who oppose the research, we are equally sincere in our belief that the life-and-death medical needs of countless suffering children and adults justifies moving forward with this research," said Harvard President Lawrence H. Summers.

The work, aspects of which have already begun, involves creating embryos not by the usual fusing of sperm and egg but by fusing a patient's body cell -- such as a skin cell -- with a human egg whose DNA has been removed. The resulting embryo would be genetically identical to the patient who donated the skin cell, so stem cells derived from it and transplanted into the patient would probably not be rejected by the immune system.

In one scenario, stem cells made from a person with sickle cell disease would have the disease-causing genetic defect corrected in the lab, be coaxed to become bone marrow cells and then be reinfused into the patient's marrow. There they could churn out a lifelong supply of healthy, non-sickling blood cells.

But the more immediate aim is to conduct basic research on the underlying causes of genetically complex diseases, scientists said.

"Clinical applications may be a decade or even more away," said George Q. Daley of Children's Hospital Boston, one of the study leaders along with Douglas A. Melton and Kevin C. Eggan of the Harvard Stem Cell Institute.

Much of the ethical wrangling leading up to yesterday's announcement related to the procurement of human eggs. Under rules ultimately approved by all eight ethics review boards with jurisdiction over the experiments, women will be reimbursed for expenses they directly incur in the process of donating eggs but will not be eligible for the thousands of dollars they could get for providing eggs to a fertility clinic to help other women get pregnant.

Egg donation, which involves a one-month hormone treatment and an outpatient surgical procedure, carries a small risk of serious complications. Harvard researchers said they hoped that women with relatives who suffer from the diseases that will be the initial focus of the work -- diabetes and blood disorders and, in years to follow, neurodegenerative diseases such as Lou Gehrig's -- might volunteer.

Other experiments will use eggs and embryos left from failed fertility treatments -- materials that the researchers said may be easier to obtain but that also may be of lower quality than fresh eggs.

Robert Lanza, scientific director of Advanced Cell Technology, said yesterday that his company is very close to starting similar work, having found two potential donors after running more than 100 ads in places as distant as Virginia. The company, with its headquarters in Alameda, Calif., and labs in Worcester, Mass., is also experimenting with methods of growing human embryos without eggs -- an approach that some opponents of stem cell work find ethically acceptable.

The House passed legislation last year allowing federal funding of stem cell studies on conventional embryos slated for destruction at fertility clinics but still precluding funding of embryo cloning. Senate consideration of the bill, promised by Majority Leader Bill Frist (R-Tenn.), could happen in the next few months, according to Hill aides tracking the issue.

http://www.washingtonpost.com/wp-dyn/content/article/2006/06/06/AR2006060601290.html