August 2008 Archives
Scientists Reprogram Adult Cells' Function
Advance Stirs Up Debate on EmbryosBy Rob Stein
Washington Post Staff Writer
Thursday, August 28, 2008; A01
Scientists have transformed one type of fully developed adult cell directly into another inside a living animal, a startling advance that could lead to cures for a variety of illnesses and sidestep the political and ethical quagmires
associated with embryonic stem cell research.
Through a series of painstaking experiments involving mice, the Harvard biologists pinpointed three crucial molecular switches that, when flipped, completely convert a common cell in the pancreas into the more precious insulin-producing ones that diabetics need to survive.
The experiments, detailed online yesterday in the journal Nature, raise the prospect that patients suffering from not only diabetes but also heart disease, strokes and many other ailments could eventually have some of their cells reprogrammed to cure their afflictions without the need for drugs, transplants or other therapies.
"It's kind of an extreme makeover of a cell," said Douglas A. Melton, co-director of the Harvard Stem Cell Institute, who led the research. "The goal is to create cells that are missing or defective in people. It's very exciting."
The work was hailed as a welcome development even by critics of research involving embryonic stem cells, which can be coaxed to become any tissue in the body but are highly controversial because they are obtained by destroying embryos.
"I see no moral problem in this basic technique," said Richard Doerflinger of the U.S. Conference of Catholic Bishops, a leading opponent of embryonic stems cell research. "This is a 'win-win' situation for medicine and ethics."
Researchers in the field, who have become accustomed to rapid advances, said they, too, were surprised by the advance.
"I'm stunned," said Robert Lanza, chief scientific officer of Advanced Cell Technology in Worcester, Mass., a developer of stem cell therapies. "It introduces a whole new paradigm for treating disease."
Melton and other researchers cautioned that many years of research lay ahead to prove whether the development would translate into cures.
"It's an important proof of concept," said Lawrence Goldstein, a stem cell researcher at the University of California at San Diego. "But these things always look easier on the blackboard than when you have to do them in actual patients."
Although the experiment involved mice, Melton and other researchers were optimistic that the approach would work in people.
"You never know for sure -- mice aren't humans," said George Q. Daley, a stem cell researcher at Children's Hospital in Boston. "But the biology of pancreatic development is very closely related in mice and humans."
Melton has already started experimenting with human cells in the laboratory and hopes that within a year he can start planning the first studies involving people with diabetes. "I would say within five years, we could be ready to start human trials," Melton said.
Other scientists have begun trying the approach on other cells, including those that could be used to treat spinal cord injuries and neurogenerative disorders such as Lou Gehrig's disease.
"The idea to be able to reprogram one adult neuron type into another for repair in the nervous system is very exciting," said Paola Arlotta, who is working in the Center for Regenerative Medicine at Massachusetts General Hospital-Harvard Medical School in Boston.
The research is the latest development in the explosive field of regenerative medicine, which seeks to create replacement tissues and body parts tailored to patients. That objective appeared within reach after scientists discovered stem cells. But stem cell research has been hampered by objections from President Bush and others who believe that the earliest stages of human life have moral standing.
Scientists last year shocked the field when they announced they had discovered how to manipulate the genes of adult cells to turn them back into the equivalent of embryonic cells -- entities dubbed "induced pluripotent stem" or "iPS" cells -- which could then be coaxed into any type of cell in the body.
The new work takes further advantage of the increasing ability scientists have developed in harnessing the once-mysterious inner workings of cells -- this time to skip the intermediary step of iPS cells and directly transform adult cells.
"This experiment proves you don't have to go all the way back to an embryonic state," Daley said. "You can use a related cell. That may be easier to do and more practical to do."
Doerflinger argued that the discovery was the latest evidence that research involving human embryos is no longer necessary. "This adds to the large and growing list of studies helping to make embryonic stem cells irrelevant to medical progress," Doerflinger wrote in an e-mail.
But other researchers disputed that, saying it remains unclear which approach will ultimately prove most useful.
"Embryonic stem cells offer a unique window in human disease and remain a key to the long-term progress of regenerative medicine," Melton said.
For their work, Melton and his colleagues systematically studied cells from the pancreas of adult mice, slowly winnowing the list of genes necessary to make a "beta" cell that produces insulin. After narrowing the candidate genes to nine, the researchers genetically engineered viruses known as adenoviruses to ferry the genes into other pancreatic cells, known as exocrine cells, which normally secrete enzymes to help digest food. That finally enabled the researchers to identify the three crucial genes needed take control of the rest of the cell's genes to convert an exocrine cell into a beta cell.
"It was a mixture of work, luck and guessing," Melton said. "We achieved a complete transformation, or re-purposing, of cells from one type to another. We were delighted."
When the scientists tried the approach on diabetic mice, the animals became able to control their blood sugar levels.
"It didn't cure the mouse, but they were able to reduce their blood sugar levels to near-normal," Melton said.
Melton and others said it remains to be seen whether it will be necessary to use genetically engineered viruses, which could face obstacles obtaining regulatory approval because of concerns about unforeseen risks, or whether chemicals might be found to do the same thing.
If preliminary studies in the laboratory are promising, Melton said he might first try converting liver cells to insulin-producing pancreatic cells, because that would be safer than using the pancreas. An alternative strategy would be to use the approach to grow beta cells in the laboratory and transplant them into patients.
Lanza said he is optimistic.
"One day, this may allow the doctor to replace the scalpel with a sort of genetic surgery," Lanza said. "If this can be perfected, it would represent one of the holy grails of medicine."
Scientists produce stem cells for 10 diseases
NEW YORK (AP) -- Harvard scientists say they have created stems cells for 10 genetic disorders, which will allow researchers to watch the diseases develop in a lab dish.
This early step, using a new technique, could help speed up efforts to find treatments for some of the most confounding ailments, the scientists said.
The new work was reported online Thursday in the journal Cell, and the researchers said they plan to make the cell lines readily available to other scientists.
Dr. George Daley and his colleagues at the Harvard Stem Cell Institute used ordinary skin cells and bone marrow from people with a variety of diseases, including Parkinson's, Huntington's and Down syndrome to produce the stem cells.
The new cells will allow researchers to "watch the disease progress in a dish, that is, to watch what goes right or wrong," Doug Melton, co-director of the institute, said during a teleconference.
"I think we'll see in years ahead that this opens the door to a new way to treating degenerative diseases," he said.
The new technique reprograms cells, giving them the chameleon-like qualities of embryonic stem cells, which can morph into all kinds of tissue, such as heart, nerve and brain. As with embryonic stem cells, the hope is to speed medical research.
Research teams in Wisconsin and Japan were the first to report last November that they had reprogrammed skin cells, and that the cells had behaved like stem cells in a series of lab tests. Just last week, another Harvard team of scientists said they reprogrammed skin cells from two elderly patients with ALS, or Lou Gehrig's disease, and grew them into nerve cells.
Melton said the new disease-specific cell lines "represent a collection of degenerative diseases for which there are no good treatments and, more importantly, no good animal models for the most part in studying them."
A new laboratory has been created to serve as a repository for the cells, and to distribute them to other scientists researching the diseases, Melton said.
"The hope is that this will accelerate research and it will create a climate of openness," said Daley.
He expects stem cell lines to be developed for many more diseases, noting, "this is just the first wave of diseases." Other diseases for which they created stem cells are Type 1, or juvenile, diabetes; two types of muscular dystrophy, Gaucher disease and a rare genetic disorder known as the "bubble boy disease."
Daley stressed that the reprogrammed cells won't eliminate the need or value of studying embryonic stem cells.
"At least for the foreseeable future, and I would argue forever, they are going to be extremely valuable tools," he said.
The reprogramming work was funded by the National Institutes of Health and private contributions to the Harvard Stem Cell Institute.
On the Net:
- Harvard Stem Cell Institute: http://www.hsci.harvard.edu
What place do "saviour siblings" have in paediatric transplantation: establishing the role of pre-implantation genetic diagnosis with HLA typing
Background: Not all children in need of a haematopoietic stem cell transplant have a suitable relative or unrelated donor available. Recently, in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) tissue typing has been used to selectively transfer an IVF embryo in order to produce a child who may provide umbilical cord blood for transplantation to an ill sibling. Such children are sometimes called "saviour siblings".
Objective: To examine the published clinical and epidemiological evidence relevant to the use of this technology, with the aim of clarifying those situations where IVF and PGD for HLA-typing should be discussed with parents of an ill child.
Design: A critical analysis of published literature on: comparative studies of umbilical cord blood versus other sources of stem cells for transplantation; comparative studies of matched unrelated donor versus matched related donor transplantation; and the likelihood of finding an unrelated stem cell donor.
Conclusion: IVF and PGD for HLA-typing is only applicable when transplantation is non-urgent and parents are of reproductive age. Discussions regarding this technology may be appropriate where no suitable related or unrelated donor is available for a child requiring a transplant, or where no suitable related donor is available and transplantation is only likely to be entertained with a matched sibling donor. Discussion may also be considered in the management of any child lacking a matched related donor who requires a non-urgent transplant or may require a transplant in the future.
Should baby be risked for sister?
By Vivienne Parry
Radio 4's Inside the Ethics CommitteeCatherine is a little girl condemned by genetic disease to a gruelling regime of treatment.
She could be released from it by a sibling, but the sibling is not yet conceived.
And can one child's health ever be put at risk to save another's?
When Catherine, the first child of Charles and Clara, was born in 2001, she seemed healthy - but not for long.
"She was very listless and would fall asleep in the middle of a feed," said her mother.
"When she was 11 weeks old, she was pretty much pure white, you couldn't even see her lips. We took her into A&E."
Tests revealed that Catherine had virtually no red blood cells.
She was eventually diagnosed with Diamond Blackfan Anaemia (DBA), a genetic disease in which few if any red blood cells are produced by the bone marrow, producing anaemia.
DBA can be treated with day long monthly transfusions.
However, every transfusion adds iron to the body which will cause irreversible organ damage unless removed.
Removal involves giving a drug given as a continuous transfusion through a needle, all through the night, five nights a week.
"Catherine hated it, screaming 'I don't want it, I don't want it'," said Clara.
"She got used to it, but often said: 'Why can't I be normal'."
Risk of early death
DBA carries a one in four chance of early death because of organ damage and an increased risk of childhood cancer.
"Once we saw what her quality of life was and the problems that she might have in the future, we started saying is there something else we can do?", said Clara.
A bone marrow transplant was the only option.
One from an unrelated donor carried up to a 30% risk of death for Catherine, one from a related donor a 5% risk.
Charles and Clare had intended having another baby anyway and hoped that a baby brother or sister would be a tissue match.
With each pregnancy there is the same one in four chance of a match.
But it is possible to use a technique normally used in pre-implantation genetic diagnosis (PGD), in which a cell from the three-day-old embryo is taken to screen out serious genetic disease, for tissue typing, to guarantee that a sibling is a tissue match, before being replaced.
The uncertainty of IVF gives a one in 10 chance of successful pregnancy with such a match.
Spontaneous mutation
There was however a major problem: DBA can be inherited or arise as a spontaneous mutation.
Which sort did Catherine have?
There was no family history of the condition. Tests on Catherine showed she didn't have any of the known mutations that cause DBA, but there are some as yet uknown.
It meant that no-one could test whether another baby had the condition or not.
Not being able to rule out DBA was a major ethical issue.
So Clara and Charles decided to have a baby naturally. But the new baby wasn't a match.
By this time, Catherine was three and the couple were acutely aware that her condition was deteriorating.
She had to have a transplant before she became too sick to survive the procedure.
They decided to go for tissue typing. To do this they needed to have a licence from the Human Fertilisation and Embryology Authority.
But at the time, the HFEA only allowed PGD to be used for tissue typing where a disease could be screened out. This was not possible in Catherine's case.
So the couple went to the US, where it was permitted. But two attempts failed.
They were psyching themselves up for a third attempt, when they read about a UK couple in the same situation as themselves, who had been given a licence by the HFEA following a judicial review.
They decided to try for a 'saviour sibling' using PGD.
Devastating blow
The procedure of taking stem cells for a bone marrow transplant would not harm Catherine's sibling, because they could be obtained from cord blood at birth.
When baby sister, McKenzie was born, not enough stem cells could be collected for a transplant.
It was a devastating blow - but at least she was free from DBA.
"Every picture I took of them together had added meaning because Catherine was looking at her lifeline," said Clara.
A much more invasive collection of bone marrow from McKenzie involving 90 minutes of general anaesthesia was now required.
There is no benefit to the donor, and McKenzie was not able to provide consent.
The chances of success for Catherine were getting less as time went on, but the younger McKenzie was, the greater the risks of anaesthesia for her.
Competing interests
Here the ethical issues are the competing 'best interests' of the sisters.
There is also the issue that the donation will only cure Catherine's symptoms, not rid her of the condition.
There is a good chance it could fail. How would McKenzie feel later knowing that her donation failed to save her sister?
And should Catherine's kidneys fail, then once again, McKenzie would be the first choice of donor.
The Clinical Ethics Committee decided that the bone marrow transplant should go ahead. It took place 18 months ago.
It was a success and Catherine continues to do well.
