Dr. Ernest A. McCulloch, a father of the stem cell research
that scientists say holds promise for the treatment of many ailments, died on
Jan. 20 in Toronto. He was 84.
His death was announced by the University of Toronto, where he was an emeritus
university professor.
Dr. McCulloch died two weeks short of the 50th anniversary of the publication of
a groundbreaking paper he wrote with Dr. James E. Till in the journal Radiation
Research. The paper had an important role in research that the two began in the
1950s and that earned them an Albert Lasker basic medical research award in 2005
for “setting the stage for all current research on adult and embryonic stem
cells.”
Such stem cells are nonspecialized but can give rise to specialized cells like
those in the brain, heart and other organs and tissues. Stem cells derived from
embryos can develop into any cell type, whether in the heart, lung or another
body part; stem cells derived from adult cells have already differentiated by
body part and can develop only into the type of cells related to them.
Many scientists now contend that with years of continued research, stem cells
may help treat, if not cure, spinal cord paralysis, cancer, diabetes,
Alzheimer’s disease, damaged hearts, kidneys and livers, and many other
ailments.
Dr. McCulloch and Dr. Till were a study in contrasts; where Dr. McCulloch was
short, stocky and rumpled, Dr. Till was tall, trim and elegantly dressed. Yet
they were the perfect research pair, balancing each other’s personalities, said
Dr. Alan Bernstein, a former president of the Canadian Institute of Health
Research, an organization analogous to the National Institutes of Health in the
United States.
“Clothes did not matter to Dr. McCulloch, and his clothes were often covered
with chalk, which he often held in his mouth, ready to draw diagrams on a
blackboard to push an idea to the extreme to see where it would take you,” said
Dr. Bernstein, who now is executive director of the Global H.I.V. Vaccine
Enterprise in New York City. “He reveled in thinking big about ideas and
encouraged speculation.”
Ernest Armstrong McCulloch was born in Toronto on April 27, 1926, and at some
point acquired the nickname Bun (for Bunny). He went directly from Upper Canada
College, a private high school in Toronto, to medical school at the University
of Toronto. (Undergraduate degrees were not required to attend medical school at
the time.) He received his medical degree with honors in 1948 and then trained
in hospitals in Toronto as a specialist in internal medicine. He had a private
practice in Toronto from 1954 to 1967.
He began his research career by studying for a year at the Lister Institute in
London. He went on to teach and conduct research in the University of Toronto’s
department of biophysics and the Ontario Cancer Institute.
From the turn of the 20th century, scientists had theorized that the body
contained cells that could renew themselves, mature and specialize in various
ways. But no one found them until Dr. McCulloch, a physician, and Dr. Till, a
biophysicist, discovered the first stem cell, one in the blood-forming system,
while conducting experiments on mice.
That discovery was a product of both planned research and serendipity. When they
began their line of research, scientists were trying to understand how and when
radiation therapy stopped cancer, and the military was seeking ways to treat
personnel exposed to radiation from nuclear weapons.
Dr. McCulloch and Dr. Till designed a system to measure bone marrow cells’
sensitivity to radiation. They observed clumps on the spleens of mice, and
through rigorous experiments showed that the spleen contained cells that divided
into the three main types of blood cells: red, white and platelets.
The findings led to a system for studying the factors that send the stem cells
down different developmental paths, and helped transform the study of blood
cells from an observational science to a more experimental one. In helping
scientists learn how and why bone marrow transplants replenish blood cells,
their work led to improvements in the procedure, one that can prolong the lives
of people with leukemia and other blood-cell cancers.
In addition to his wife, Ona, Dr. McCulloch, who lived in Toronto, is survived
by four sons, James, Michael, Robert and Paul; a daughter, Cecelia E. MacIntyre;
a sister, Tot Johnson; six grandchildren; and one great-grandson.
This article has been revised
to reflect the following
correction:
Correction: February 1, 2011
An earlier version of this article carried a caption
We welcome President Obama’s decision to lift the Bush
administration’s restrictions on federal financing for embryonic stem cell
research. His move ends a long, bleak period in which the moral objections of
religious conservatives were allowed to constrain the progress of a medically
important science.
Even with this enlightened stance, some promising stem cell research will still
be denied federal dollars. For that to change, Congress must lift a separate ban
that it has imposed every year since the mid-1990s.
Mr. Obama also pledged on Monday to base his administration’s policy decisions
on sound science, undistorted by politics or ideology. He ordered his science
office to develop a plan for all government agencies to achieve that goal.
Such a pledge should be unnecessary. Unfortunately, for eight years, former
President George W. Bush did just the opposite. He chose scientific advisory
committees based on ideology rather than expertise. His political appointees
aggressively ignored, distorted or suppressed scientific findings to promote a
political agenda or curry favor with big business.
This cynical approach seriously hampered government efforts to address global
warming and encourage sound family planning practices, among other issues.
President Obama was appropriately cautious, warning that the full promise of
stem cell research remains unknown and should not be overstated. Some of the
benefits, he said, might not appear in our lifetime or even our children’s
lifetime. But scientists hope that stem cell therapies may eventually lead to
treatments or cures for a wide range of degenerative diseases, such as
Parkinson’s and diabetes, and Mr. Obama rightly promised to pursue the research
with urgency.
In one of his first acts as president, Mr. Bush restricted federal financing for
embryonic stem cell research to what turned out to be 20 or so stem cell lines
that had been created prior to his announcement. Those lines are too limited in
number, variety and quality to allow the full range of needed research.
With the end of the Bush restrictions, scientists receiving federal money will
be able to work with hundreds of stem cell lines that have since been created —
and many more that will be created in the future. The full range of additional
research allowed won’t become apparent until new guidelines governing what
research can qualify for federal support are issued by the National Institutes
of Health.
Other important embryonic research is still being hobbled by the so-called
Dickey-Wicker amendment. The amendment, which is regularly attached to
appropriations bills for the Department of Health and Human Services, prohibits
the use of federal funds to support scientific work that involves the
destruction of human embryos (as happens when stem cells are extracted) or the
creation of embryos for research purposes.
Until that changes, scientists who want to create embryos — and extract stem
cells — matched to patients with specific diseases will have to rely on private
or state support. Such research is one promising way to learn how the diseases
develop and devise the best treatments. Congress should follow Mr. Obama’s lead
and lift this prohibition so such important work can benefit from an infusion of
federal dollars.
In a research milestone, the federal government will allow the world’s first
test in people of a therapy derived from human embryonic stem cells.
Federal drug regulators said that political considerations had no role in the
decision. Nevertheless, the move coincided with the inauguration of President
Obama, who has pledged to remove some of the financing restrictions placed on
the field by President George W. Bush.
The clearance of the clinical trial — of a treatment for spinal cord injury — is
to be announced Friday by Geron, the biotechnology company that first applied to
the Food and Drug Administration to conduct the trial last March. The F.D.A. had
first said no, asking for more data.
Thomas B. Okarma, Geron’s chief executive, said Thursday that he did not think
that the Bush administration’s objections to embryonic stem cell research played
a role in the F.D.A.’s delaying approval.
“We really have no evidence,” Dr. Okarma said, “that there was any political
overhang.”
But others said they suspected it was more than a coincidence that approval was
granted right after the new administration took office.
“I think this approval is directly tied to the change in administration,” said
Robert N. Klein, the chairman of California’s $3 billion stem cell research
program. He said he thought the Bush administration had pressured the F.D.A. to
delay the trial.
Mr. Klein called the approval of the first human trial of this sort “an
extraordinary benchmark.”
Stem cells derived from adults and fetuses are already being used in some
clinical trials, but they generally have less versatility than embryonic stem
cells in terms of what tissue types they can form.
The F.D.A. approval comes a little more than 10 years after the first human
embryonic stem cells were isolated at the University of Wisconsin, in work
financed by Geron.
Because the cells can turn into any type of cell in the body, the theory is they
may one day be able to provide tissues to replace worn-out organs or
nonfunctioning cells to treat diabetes, heart attacks and other diseases. The
field is known as regenerative medicine.
The Bush administration restricted federal financing for research on embryonic
stem cells because creation of the cells entails the destruction of human
embryos.
Geron’s trial will involve 8 to 10 people with severe spinal cord injuries. The
cells will be injected into the spinal cord at the injury site 7 to 14 days
after the injury occurs, because there is evidence the therapy will not work for
much older injuries.
The study is a so-called Phase I trial, aimed mainly at testing the safety of
the therapy. There would still be years of testing and many hurdles to overcome
before the treatment would become routinely available to patients.
Geron, which is based in Menlo Park, Calif., said that it had identified up to
seven medical centers for the trial but that those sites must first get
permission from their own internal review boards to participate.
Even as some researchers hailed the onset of clinical trials, others expressed
trepidation that if the therapy proves unsafe — or even if it is safe but does
not work — it could cause a backlash that would set the field back for years.
“It would be a disaster, a nightmare, if we ran into these kinds of problems in
this very first trial,” said Dr. John A. Kessler, the chairman of neurology and
director of the stem cell institute at Northwestern University.
Dr. Kessler, whose own daughter was paralyzed from the waist down in a skiing
accident, said he thought Geron’s therapy was not the ideal candidate for the
first trial. He said results showing the therapy worked in moderately injured
animals might not apply to more seriously injured people.
“We really want the best trial to be done for this first trial, and this might
not be it,” he said.
Dr. Okarma of Geron emphasized that the purpose of the first trial was safety,
so that lack of efficacy should not be a problem. While researchers will also
look for signs the treatment works, he said, the best that could be hoped for
would be some slight restoration of function that could then be enhanced through
physical therapy.
“We don’t expect to take someone who is completely paralyzed from the waist down
and have them dance six months later,” he said. If the first trial shows safety,
the company would then hope to test higher doses of cells and treat patients
with less severe injuries, he said.
Geron’s therapy involves using various growth factors to turn embryonic stem
cells into precursors of neural support cells called oligodendrocytes, which are
then injected into the spinal cord at the site of the injury.
The hope is that the injected cells will help repair the insulation, known as
myelin, around nerve cells, restoring the ability of some nerve cells to carry
signals. There is also some hope that growth factors produced by the injected
cells will spur damaged nerve cells to regenerate.
The therapy was developed in collaboration with Hans Keirstead of the University
of California, Irvine. He has shown videos of paralyzed rats that were able to
walk again, albeit imperfectly, after receiving the therapy. Those videos helped
persuade California voters to approve the $3 billion stem cell research program
in 2004.
The main safety concern is that if raw embryonic cells are put into the body,
they can form tumors. Even though most such tumors do not spread like other
cancers, any unwanted growth in the spinal cord can further damage nerves.
“It’s not ready for prime time, at least not in my mind, until we can be assured
that the transplanted stem cells have completely lost the capacity for
tumorogenicity,” said Dr. Steven Goldman, chairman of neurology at the
University of Rochester. He was a member a committee convened by the F.D.A. last
April to examine the safety aspects of trials using therapies from embryonic
stem cells.
Dr. Okarma said Geron had done numerous studies showing that its cells did not
contain residual embryonic cells and did not form tumors in animals even after a
year. It submitted 22,000 pages of data to the F.D.A., perhaps the largest
application ever for permission to begin a clinical trial.
The embryonic stem cell line used by Geron is one of the oldest ones and was
therefore eligible for federal financing under the Bush administration’s policy,
Dr. Okarma said.
Nevertheless, Geron paid for its own work, spending $45 million to prepare its
F.D.A. application.
Geron, which was formed in 1990 as an antiaging company, is still in the
development stage and is not yet profitable, having lost about $500 million
since its inception. Besides working on stem cells, it is testing drugs for
cancer that influence telomeres, the caps on the ends of chromosomes that help
control the aging of cells. Geron’s market value is about $400 million.
While the Bush administration’s policy did not impede the company’s application
at the F.D.A., Dr. Okarma said, it did slow progress for the field in general by
making it hard for academics to do research.
“It is the private sector that has kept the technology alive so that it can see
the light of day in a clinical trial,” he said.
Mr. Klein of the California stem cell program said he thought the next trial
might be of a treatment for macular degeneration, an eye disease, that is being
developed in Britain.
In the last couple of years, some attention has turned away from embryonic stem
cells to a newer technique that allows a patient’s own skin cells to be turned
into a cell resembling such embryonic cells.
That might do away with the need for embryos. And the resulting tissue made from
those cells would match the patient, doing away with the need for immune
suppression to prevent rejection of the transplant. Geron said its trial would
require only temporary use of low doses of immune-suppressing drugs.
But the newer technique involves putting genes into the skin cells using
viruses, which also raises a risk of cancer.
Medicine’s
dream of growing new human hearts and other organs to repair or replace damaged
ones received a significant boost Sunday when University of Minnesota
researchers reported success in creating a beating rat heart in a laboratory.
Experts not involved in the Minnesota work called it “a landmark achievement”
and “a stunning” advance. But they and the Minnesota researchers cautioned that
the dream, if it is ever realized, was still at least 10 years away.
Dr. Doris A. Taylor, the head of the team that created the rat heart, said she
followed a guiding principle of her laboratory: “give nature the tools, and get
out of the way.”
“We just took nature’s own building blocks to build a new organ,” Dr. Taylor
said of her team’s report in the journal Nature Medicine.
The researchers removed all the cells from a dead rat heart, leaving the valves
and outer structure as scaffolding for new heart cells injected from newborn
rats. Within two weeks, the cells formed a new beating heart that conducted
electrical impulses and pumped a small amount of blood.
With modifications, scientists should be able to grow a human heart by taking
stem cells from a patient’s bone marrow and placing them in a cadaver heart that
has been prepared as a scaffold, Dr. Taylor said in a telephone interview from
her laboratory in Minneapolis. The early success “opens the door to this notion
that you can make any organ: kidney, liver, lung, pancreas — you name it and we
hope we can make it,” she said.
Todd N. McAllister of Cytograft Tissue Engineering in Novato, Calif., said,
“Doris Taylor’s work is one of those maddeningly simple ideas that you knock
yourself on the head, saying, ‘Why didn’t I think of that?’ ” Dr. McAllister’s
team has used a snippet of a patient’s skin to grow blood vessels in a
laboratory, and then implanted them to restore blood flow around a patient’s
damaged arteries and veins.
The field of tissue engineering has been growing rapidly. For many years,
doctors have used engineered skin for burn patients. Engineered cartilage is
used for joint repairs. Researchers are investigating the use of stem cells to
repair cardiac muscle damaged by heart attacks. Also, new bladders grown from a
patient’s own cells are being tested in the same patients.
Dr. Taylor is a newcomer to tissue regeneration. She began her professional
career at the Albert Einstein College of Medicine in the Bronx investigating
gene therapy and then cell therapy. She said she switched to tissue regeneration
when she realized the limiting step in trying to generate an organ was not the
number of cells needed, but the complexity of creating a three-dimensional
structure.
“The heart is a beautiful organ,” Dr. Taylor said, “and it’s not one that I
thought I’d ever be able to build in a dish.”
Her view changed about three years ago when she recalled that cells were removed
from human and pig heart valves before they were used to replace damaged human
ones. As she contemplated replacing the old rat cells with new ones, Dr. Taylor
followed another of her mantras: “Trust your crazy ideas.”
Progress came in fits and starts. “We made every mistake known, did every
experiment wrong and had to go back and do them right,” Dr. Taylor said.
She poured detergents like those in shampoos in the rat’s arteries to wash out
the heart cells and then injected neonatal cardiac cells. The first two
detergents she tested failed. But a third concoction led to a clear, translucent
scaffold that retained the heart’s architecture.
After injecting the young rat heart cells into a scaffold, she stimulated them
electrically and created an artificial circulation as the equivalent of blood
pressure to make the heart pump and produce a pulse. The steps also helped the
cells mature. Tests like examining slices of the heart under a microscope showed
they were living cells.
To test the biological compatibility of the new hearts, the team transplanted
them into the abdomen of unrelated live rats. The hearts were not immediately
rejected. A blood supply developed. The hearts beat regularly. And cells from
the host rats moved in and began to reline the blood vessels, even growing in
the wall of the hearts.
Dr. Taylor is now conducting similar experiments on pigs as a step toward human
work. “Working out the details in a pig heart made a lot more sense” because the
anatomy of the porcine heart is the closest to humans and pigs are plentiful,
she said.
“The next goal will be to see if we can get the heart to pump strongly enough
and become mature enough that we can use it to keep an animal alive” in a
replacement transplant, Dr. Taylor said.
As for human hearts, the best-case situation would be to obtain them from
cadavers, remove their cells to make a scaffold and then inject bone marrow,
muscle or young cardiac cells from a patient. The process of repopulating the
scaffold with new cells would take a few months, she said.
The body replaces its proteins every few months, so the hope is that the body
will create a matrix that it recognizes as its own.
One potential problem is that antirejection drugs might be required to prevent
adverse immune reactions from the scaffold. In that case, Dr. Taylor hopes such
therapy would be needed only temporarily.
Many things that work in experiments on animals fail in humans because of the
species barrier. Dr. McAllister said that in Dr. Taylor’s case “the principal
problem in escalating it to humans is one of scale, not of cell biology, and
that is an easier problem to solve potentially.”
Dr. Taylor said, “If it works, it means that there will be many more organs
available for transplants.”
Because the components of the biologic matrix differ for every organ, Dr. Taylor
expects that scientists will be able to do tests to answer two fundamental
questions: Can a stem cell be placed anywhere in the body and still produce a
heart, kidney or other organ? Or must a stem cell be placed in its anatomic
position to do so?
Such tests might include taking stem cells from one organ, for example a kidney,
and putting them in a kidney, liver or heart to begin to understand if the stem
cells are innately committed to produce kidneys or whether they will convert to
produce livers or hearts.
Beginning Jan. 15, Adam Liptak’s column, “Sidebar,”
November
22, 2007
The New York Times
By GINA KOLATA
If the stem
cell wars are indeed nearly over, no one will savor the peace more than James A.
Thomson.
Dr. Thomson’s laboratory at the University of Wisconsin was one of two that in
1998 plucked stem cells from human embryos for the first time, destroying the
embryos in the process and touching off a divisive national debate.
And on Tuesday, his laboratory was one of two that reported a new way to turn
ordinary human skin cells into what appear to be embryonic stem cells without
ever using a human embryo.
The fact is, Dr. Thomson said in an interview, he had ethical concerns about
embryonic research from the outset, even though he knew that such research
offered insights into human development and the potential for powerful new
treatments for disease.
“If human embryonic stem cell research does not make you at least a little bit
uncomfortable, you have not thought about it enough,” he said. “I thought long
and hard about whether I would do it.”
He decided in the end to go ahead, reasoning that the work was important and
that he was using embryos from fertility clinics that would have been destroyed
otherwise. The couples whose sperm and eggs were used to create the embryos had
said they no longer wanted them. Nonetheless, Dr. Thomson said, announcing that
he had obtained human embryonic stem cells was “scary,” adding, “It was not
known how it would be received.”
But he never anticipated the extent and rancor of the stem cell debate. For
nearly a decade now, the issue has bitterly divided patients and politicians,
religious groups and researchers.
Now with the new technique, which involves adding just four genes to ordinary
adult skin cells, it will not be long, he says, before the stem cell wars are a
distant memory. “A decade from now, this will be just a funny historical
footnote,” Dr. Thomson said in the interview.
As for the science behind it, the thrill of discovery, he said, “Surprisingly,
there is no ‘Wow’ moment,” either from 1998 or now. Both times, the discovery
came after he had spent months rigorously testing the cells to be sure they
really were stem cells, worrying all the while that they could die or be lost to
contamination. When he knew he had succeeded, the suspense was gone.
“Imagine holding your breath for a few months,” Dr. Thomson said. When he was
done, he said, “I felt mostly a sense of relief.”
But he knows what he wrought. Stem cells, universal cells that can turn into any
of the body’s 220 cell types, normally emerge only fleetingly after a few days
of embryo development. Scientists want to use them to study complex human
diseases like Alzheimer’s or Parkinson’s in a petri dish, finding causes and
treatments. And, they say, it may be possible to use the cells to grow
replacement tissues for patients.
The problem until now had been the source of the cells — human embryos.
The topic, says R. Alta Charo, a University of Wisconsin ethicist, “took on an
almost iconic quality the same way Roe v. Wade has.”
In the meantime, many leading scientists decided not to get into the stem cell
field. There was a stigma attached, Dr. Thomson says. And, he adds, “Most
scientists don’t like controversial things.”
A native of Oak Park, Ill., James Alexander Thomson, 48, did not set out to
throw bioethical bombs. All he wanted, he said, was to answer the most basic
scientific questions about cellular development.
First there was a degree in biophysics from the University of Illinois. As a
graduate student, Dr. Thomson began working with mouse embryonic stem cells and
then, with federal support, he extracted stem cells from monkey embryos. After
earning two doctorates from the University of Pennsylvania, one in veterinary
medicine and one in molecular biology, he continued research at his own
laboratory at the University of Wisconsin.
Eventually he realized, though, that studying mice and monkeys could take him
only so far. If he wanted to understand how human embryos develop and why their
development sometimes goes awry, he needed human stem cells. But, he says, he
hesitated.
In 1995, he began consulting with two ethicists at his university, Dr. Norman
Fost, a physician, and Ms. Charo, a law professor. He wanted to anticipate what
the ethical problems might be and what the criticisms might be.
Dr. Fost was impressed.
“It is unusual in the history of science for a scientist to really want to think
carefully about the ethical implications of his work before he sets out to do
it,” Dr. Fost said. “The biggest problem in ethics is not anticipating
problems.”
But Dr. Fost and Dr. Thomson guessed wrong about what would bother people most.
They thought it would be what Dr. Fost termed “the technological power” of stem
cells. What if someone put human stem cells into the brain of a rat, for
example?
“I thought at the time that this was possibly the biggest issue,” Dr. Fost said.
“It was unprecedented in the history of biology. It’s the ‘Help, get me out of
here’ scenario. Let’s say the rat brain turns out to be entirely human cells.
What’s going on in there? Is it a human brain? And how would you study it — you
can’t ask the rat.”
Meanwhile, as Dr. Thomson was planning his effort to obtain human embryonic stem
cells, another discovery changed his entire view of development. In 1997, Ian
Wilmut, a scientist in Scotland, announced the creation of the first cloned
mammal, Dolly, cloned from frozen udder cells from a long-dead sheep.
Dr. Wilmut had slipped an udder cell — a cell that normally would never be
anything but an udder cell — into an egg whose genetic material had been
removed. The egg somehow brought the udder cell’s chromosomes back to the state
they had been in when embryo development first began.
“Dolly changed the way I thought about developmental biology,” Dr. Thomson says.
“Development was reversible.”
Four years ago he and, independently, Shinya Yamanaka of Kyoto University set
out to figure out a way to mimic what an egg can do. Both succeeded and both
discovered that all they had to do was add four genes to the cells and the cells
would turn into what look, so far, just like stem cells.
“It is actually fairly straightforward to repeat what we have done,” Dr. Thomson
said.
More work remains, but he is confident that the path ahead is clear.
“Isn’t it great to start a field and then to end it,” he said.
November
21, 2007
The New York Times
By GINA KOLATA
Two teams
of scientists are reporting today that they turned human skin cells into what
appear to be embryonic stem cells without having to make or destroy an embryo —
a feat that could quell the ethical debate troubling the field.
All they had to do, the scientists said, was add four genes. The genes
reprogrammed the chromosomes of the skin cells, making the cells into blank
slates that should be able to turn into any of the 220 cell types of the human
body, be it heart, brain, blood or bone. Until now, the only way to get such
human universal cells was to pluck them from a human embryo several days after
fertilization, destroying the embryo in the process.
The reprogrammed skin cells may yet prove to have subtle differences from
embryonic stem cells that come directly from human embryos, and the new method
includes potentially risky steps, like introducing a cancer gene. But stem cell
researchers say they are confident that it will not take long to perfect the
method and that today’s drawbacks will prove to be temporary.
Researchers and ethicists not involved in the findings say the work should
reshape the stem cell field. At some time in the near future, they said, today’s
debate over whether it is morally acceptable to create and destroy human embryos
to obtain stem cells should be moot.
“Everyone was waiting for this day to come,” said the Rev. Tadeiusz Pacholczyk,
director of education at the National Catholic Bioethics Center. “You should
have a solution here that will address the moral objections that have been
percolating for years,” he added.
The two independent teams, from Japan and Wisconsin, note that their method also
creates stem cells that genetically match the donor without having to resort to
the controversial step of cloning. If stem cells are used to make replacement
cells and tissues for patients, it would be invaluable to have genetically
matched cells because they would not be rejected by the immune system. Even more
important, scientists say, is that genetically matched cells from patients will
enable them to study complex diseases, like Alzheimer’s, in the lab.
Until now, the only way to get embryonic stem cells that genetically matched an
individual would be to create embryos that were clones of that person and
extract their stem cells. Just last week, scientists in Oregon reported that
they did this with monkeys, but the prospect of doing such experiments in humans
has been ethically fraught.
But with the new method, human cloning for stem cell research, like the creation
of human embryos to extract stem cells, may be unnecessary.
“It really is amazing,” said Dr. Leonard Zon, director of the stem cell program
at Harvard Medical School’s Children’s Hospital.
And, said Dr. Douglas Melton, co-director of the Stem Cell Institute at Harvard
University, it is “ethically uncomplicated.”
For all the hopes invested in it over the past decade, embryonic stem cell
research has not yet produced any cures or major therapeutic discoveries. Stem
cells are so malleable that they may pose risk of cancer, and the new method of
obtaining stem cells includes steps that raise their own safety concerns.
Still, the new work could allow the field to vault significant problems,
including the shortage of human embryonic stem cells and restrictions on federal
funding for such research. Even when scientists have other sources of funding,
they report that it is expensive and difficult to find women who will provide
eggs for such research.
The new discovery is being published online today in Cell, in a paper by Shinya
Yamanaka of Kyoto University and the Gladstone Institute for Cardiovascular
Disease in San Francisco, and in Science, in a paper by James Thomson and his
colleagues at the University of Wisconsin.
While both groups used just four genes to reprogram human skin cells, two of the
four genes used by the Japanese scientists were different from two of the four
used by the American group. All the genes in question, though, act in a similar
way – they are master regulator genes whose role is to turn other genes on or
off.
The reprogrammed cells, the scientists report, appear to behave exactly like
human embryonic stem cells.
“By any means we test them they are the same as embryonic stem cells,” Dr.
Thomson says.
He and Dr. Yamanaka caution, though, that they still must confirm that the
reprogrammed human skin cells really are the same as stem cells they get from
embryos. And while those studies are underway, Dr. Thomson and others say, it
would be premature to abandon research with stem cells taken from human embryos.
Another caveat is that , so far, scientists use a type of virus, a retrovirus,
to insert the genes into the cells’ chromosomes. Retroviruses slip genes into
chromosomes at random, sometimes causing mutations that can make normal cells
turn into cancers.
In addition, one of the genes that the Japanese scientists insert actually is a
cancer gene.
The cancer risk means that the resulting stem cells would not be suitable for
replacement cells or tissues for patients with diseases, like diabetes, in which
their own cells die. They would, though, be ideal for the sort of studies that
many researchers say are the real promise of this endeavor — studying the causes
and treatments of complex diseases.
For example, researchers want to make embryonic stem cells from a person with a
disease like Alzheimer’s and turn the stem cells into nerve cells in a petri
dish. Then, scientists hope, they may be able to understand what goes awry in
Alzheimer’s patients when their brain cells die and how to prevent or treat the
disease.
But even the retrovirus drawback may be temporary, scientists say. Dr. Yamanaka
and several other researchers are trying to get the same effect by adding
chemicals or using more benign viruses to get the genes into cells. They say
they are starting to see success.
It is only a matter of time until retroviruses are not needed, Dr. Melton
predicted.
“Anyone who is going to suggest that this is just a side show and that it won’t
work is wrong,” Dr. Melton said.
The new discovery was preceded by work in mice. Last year, Dr. Yamanaka
published a paper showing that he could add four genes to mouse cells and turn
them into mouse embryonic stem cells.
He even completed the ultimate test to show that the resulting stem cells could
become any type of mouse cell. He used them to create new mice, whose every cell
came from one of those stem cells. Twenty percent of those mice, though,
developed cancer, illustrating the risk of using retroviruses and a cancer gene
to make cells for replacement parts.
Scientists were electrified by the reprogramming discovery, Dr. Melton said.
“Once it worked, I hit my forehead and said, ‘it’s so obvious,’ ”he said. “But
it’s not obvious until it’s done.”
Some were skeptical about Dr. Yamanaka’s work and questioned whether such an
approach would ever work in humans.
“They said, ‘That’s very good with mice. But let’s see if you can do it with a
human,”’ Dr. Zon recalled.
But others set off in what became an international race to repeat the work with
human cells.
“Dozens, if not hundreds of labs, have been attempting to do this,” said Dr.
George Daley, associate director of the stem cell program at Children’s
Hospital.
Few expected Dr. Yamanka would succeed so soon. Nor did they expect that the
same four genes would reprogram human cells.
“This shows it’s not an esoteric thing that happened in the mouse,” said Rudolf
Jaenisch, a stem cell researcher at M.I.T.
Ever since the birth of Dolly the sheep, scientists knew that adult cells could,
in theory, turn into embryonic stem cells. But they had no idea how to do it
without cloning, the way Dolly was created.
With cloning, researchers put an adult cell’s chromosomes into an unfertilized
egg whose genetic material was removed. The egg, by some mysterious process,
then does all the work. It reprograms the adult cell’s chromosomes, bringing
them back to the state they were in just after the egg was fertilized. Those
reprogrammed genes then direct the development of an embryo. A few days later, a
ball of stem cells emerges in the embryo. Since the embryo’s chromosomes came
from the adult cell, every cell of the embryo, including its stem cells, are
exact genetic matches of the adult.
The abiding question, though, was, How did the egg reprogram the adult cell’s
chromosomes? Would it be possible to reprogram an adult cell without using an
egg?
About four years ago, Dr. Yamanaka and Dr. Thomson independently hit upon the
same idea. They would search for genes that are being used in an embryonic stem
cell that are not being used in an adult cell. Then they would see if those
genes would reprogram an adult cell.
Dr. Yamanaka worked with mouse cells and Dr. Thomson worked with human cells
from foreskins.
The researchers found more than 1,000 candidate genes. So both groups took
educated guesses, trying to whittle down the genes to the few dozen they thought
might be the crucial ones and then asking whether any combinations of those
genes could turn a skin cell into a stem cell.
It was laborious work, with no guarantee of a payoff.
“The number of factors could have been one or ten or 100 or more,” Dr. Yamanaka
said in a telephone interview from his lab in Japan.
If many genes were required, the experiments would have failed, Dr. Thomson
said, because it would be impossible to test all the gene combinations.
The mouse work went more quickly than Dr. Thomson’s work with human cells. As
soon as Dr. Yamanaka saw that the mouse experiments succeeded, he began trying
the same brute force method in human skin cells that he ordered from a
commercial laboratory. Some were face cells from a 36 year old white woman and
others were connective tissue cells from joints of a 69 year old white man.
Dr. Yamanaka said he thought it would take a few years to find the right genes
and the right conditions to make the human experiments work. Feeling the hot
breath of competitors on his neck, he was in his lab every day for 12 to 14
hours a day, he said.
A few months later, he succeeded.
“We did work very hard,” Dr. Yamanaka said. “But we were very surprised.”
November
20, 2007
Filed at 9:59 a.m. ET
By THE ASSOCIATED PRESS
The New York Times
NEW YORK
(AP) -- Scientists have made ordinary human skin cells take on the
chameleon-like powers of embryonic stem cells, a startling breakthrough that
might someday deliver the medical payoffs of embryo cloning without the
controversy.
Laboratory teams on two continents report success in a pair of landmark papers
released Tuesday. It's a neck-and-neck finish to a race that made headlines five
months ago, when scientists announced that the feat had been accomplished in
mice.
The ''direct reprogramming'' technique avoids the swarm of ethical, political
and practical obstacles that have stymied attempts to produce human stem cells
by cloning embryos.
Scientists familiar with the work said scientific questions remain and that it's
still important to pursue the cloning strategy, but that the new work is a major
coup.
''This work represents a tremendous scientific milestone -- the biological
equivalent of the Wright Brothers' first airplane,'' said Dr. Robert Lanza,
chief science officer of Advanced Cell Technology, which has been trying to
extract stem cells from cloned human embryos.
''It's a bit like learning how to turn lead into gold,'' said Lanza, while
cautioning that the work is far from providing medical payoffs.
''It's a huge deal,'' agreed Rudolf Jaenisch, a prominent stem cell scientist at
the Whitehead Institute in Cambridge, Mass. ''You have the proof of principle
that you can do it.''
There is a catch. At this point, the technique requires disrupting the DNA of
the skin cells, which creates the potential for developing cancer. So it would
be unacceptable for the most touted use of embryonic cells: creating transplant
tissue that in theory could be used to treat diseases like diabetes,
Parkinson's, and spinal cord injury.
But the DNA disruption is just a byproduct of the technique, and experts said
they believe it can be avoided.
The new work is being published online by two journals, Cell and Science. The
Cell paper is from a team led by Dr. Shinya Yamanaka of Kyoto University; the
Science paper is from a team led by Junying Yu, working in the lab of in
stem-cell pioneer James Thomson of the University of Wisconsin-Madison.
Both reported creating cells that behaved like stem cells in a series of lab
tests.
Thomson, 48, made headlines in 1998 when he announced that his team had isolated
human embryonic stem cells.
Yamanaka gained scientific notice in 2006 by reporting that direct reprogramming
in mice had produced cells resembling embryonic stem cells, although with
significant differences. In June, his group and two others announced they'd
created mouse cells that were virtually indistinguishable from stem cells.
For the new work, the two men chose different cell types from a tissue supplier.
Yamanaka reprogrammed skin cells from the face of an unidentified 36-year-old
woman, and Thomson's team worked with foreskin cells from a newborn. Thomson,
who was working his way from embryonic to fetal to adult cells, said he's still
analyzing his results with adult cells.
Both labs did basically the same thing. Each used viruses to ferry four genes
into the skin cells. These particular genes were known to turn other genes on
and off, but just how they produced cells that mimic embryonic stem cells is a
mystery.
''People didn't know it would be this easy,'' Thomson said. ''Thousands of labs
in the United States can do this, basically tomorrow.''
The Wisconsin Alumni Research Foundation, which holds three patents for
Thomson's work, is applying for patents involving his new research, a
spokeswoman said. Two of the four genes he used were different from Yamanaka's
recipe.
Scientists prize embryonic stem cells because they can turn into virtually any
kind of cell in the body. The cloning approach -- which has worked so far only
in mice and monkeys -- should be able to produce stem cells that genetically
match the person who donates body cells for cloning.
That means tissue made from the cells should be transplantable into that person
without fear of rejection. Scientists emphasize that any such payoff would be
well in the future, and that the more immediate medical benefits would come from
basic research in the lab.
In fact, many scientists say the cloning technique has proven too expensive and
cumbersome in its current form to produce stem cells routinely for transplants.
The new work shows that the direct reprogramming technique can also produce
versatile cells that are genetically matched to a person. But it avoids several
problems that have bedeviled the cloning approach.
For one thing, it doesn't require a supply of unfertilized human eggs, which are
hard to obtain for research and subjects the women donating them to a surgical
procedure. Using eggs also raises the ethical questions of whether women should
be paid for them.
In cloning, those eggs are used to make embryos from which stem cells are
harvested. But that destroys the embryos, which has led to political opposition
from President Bush, the Roman Catholic church and others.
Those were ''show-stopping ethical problems,'' said Laurie Zoloth, director of
Northwestern University's Center for Bioethics, Science and Society.
The new work, she said, ''redefines the ethical terrain.''
Richard Doerflinger, deputy director of pro-life activities for the U.S.
Conference of Catholic Bishops, called the new work ''a very significant
breakthrough in finding morally unproblematic alternatives to cloning. ... I
think this is something that would be readily acceptable to Catholics.''
Another advantage of direct reprogramming is that it would qualify for federal
research funding, unlike projects that seek to extract stem cells from human
embryos, noted Doug Melton, co-director of the Harvard Stem Cell Institute.
Still, scientific questions remain about the cells produced by direct
reprogramming, called ''iPS'' cells. One is how the cells compare to embryonic
stem cells in their behavior and potential. Yamanaka said his work detected
differences in gene activity.
If they're different, iPS cells might prove better for some scientific uses and
cloned stem cells preferable for other uses. Scientists want to study the roots
of genetic disease and screen potential drug treatments in their laboratories,
for example.
Scottish researcher Ian Wilmut, famous for his role in cloning Dolly the sheep a
decade ago, told London's Daily Telegraph that he is giving up the cloning
approach to produce stem cells and plans to pursue direct reprogramming instead.
Other scientists said it's too early for the field to follow Wilmut's lead.
Cloning embryos to produce stem cells remains too valuable as a research tool,
Jaenisch said.
Dr. George Daley of the Harvard institute, who said his own lab has also
achieved direct reprogramming of human cells, said it's not clear how long it
will take to get around the cancer risk problem. Nor is it clear just how direct
reprogramming works, or whether that approach mimics what happens in cloning, he
noted.
So the cloning approach still has much to offer, he said.
Daley, who's president of the International Society for Stem Cell Research, said
his lab is pursuing both strategies.
''We'll see, ultimately, which one works and which one is more practical.''
November
20, 2007
Filed at 9:20 a.m. ET
By THE ASSOCIATED PRESS
The New York Times
Embryonic
stem cells can develop into all kinds of tissue. Scientists have long sought to
find a way to create such cells that are genetically matched to patients,
because of the potential for new ways to treat disease and injury.
They've pursued this through cloning, which uses embryos. But through a new
method, ''direct reprogramming,'' scientists have found a way to produce cells
that appear virtually identical to stem cells, without using embryos.
Q: How big a breakthrough is this?
A: Huge. One researcher compared it to the Wright Brothers' airplane. Ian
Wilmut, who cloned Dolly the sheep, said he is dropping the cloning approach for
stem cells to begin testing this new method.
Q: What's so great about this new approach?
A: It doesn't require women's unfertilized eggs to make embryos; human eggs are
in short supply for research. And it doesn't involve the destruction of embryos,
which is required to harvest stem cells from within them. That destruction has
led some groups to oppose the cloning approach for ethical and religious
reasons.
Q: Does this mean scientists will no longer need human eggs or embryos?
A: No. Scientists say research should continue on embryonic stem cells. But this
new development will likely reduce the demand.
Q: How does the new method work?
A: Four genes were inserted into each skin cell. Scientists knew these
particular genes turn other genes on and off, but how the combination converted
skin cells into mimics of stem cells remains a mystery.
Q: Are these cells so-called ''adult stem cells?''
A: No. That term refers to cells found in the body that already have the ability
to morph into a variety of cell types. They don't need the four-gene treatment.
Q: Are there any drawbacks to this new approach?
A: At this early stage, the technique being used disrupts the DNA of the skin
cells, which leads to a potential for cancer. For now, that makes it
unacceptable as a way to create stem cells for disease treatment. But the DNA
disruption is just a byproduct of the technique, and experts believe there is a
way to avoid it.
Q: What does it mean for average people? Can we expect to see new treatments
anytime soon?
A: Not for years. Besides overcoming the cancer obstacle, scientists still have
to answer basic questions about these cells. In medicine, these cells would
probably be used first for lab studies like screening potential drugs.
In a surprising advance that sidesteps the ethical debates
surrounding stem cell biology, researchers have come much closer to a major goal
of regenerative medicine, the conversion of a patient’s cells into specialized
tissues that might replace those lost to disease.
The advance is an easy-to-use technique for reprogramming a skin cell of a mouse
back to the embryonic state. Embryonic cells can be induced in the laboratory to
develop into many of the body’s major tissues.
If the technique can be adapted to human cells, it would let scientists use a
patient’s skin cell to generate new heart, liver or kidney cells that might be
transplantable and would not be rejected by the patient’s immune system.
Previously, the only way scientists knew they were likely to get such cells is
by nuclear transfer, the insertion of an adult cell’s nucleus into an egg whose
own nucleus has been removed. The egg somehow reprograms the nucleus back to
embryonic state.
The new technique, developed by Shinya Yamanaka of Kyoto University, depends on
inserting just four genes into a skin cell. These accomplish the same
reprogramming task as the egg, or at least one very similar.
The technique is much easier to apply than nuclear transfer, does not involve
the expensive and controversial use of human eggs, and should avoid all or
almost all of the ethical criticism directed at the use of embryonic stem cells.
“From the point of view of moving biomedicine and regenerative medicine faster,
this is about as big a deal as you could imagine,” said Irving Weissman, a
leading stem cell biologist at Stanford University.
David Scadden, a stem cell biologist at the Harvard Medical School, said the
finding that cells could be reprogrammed with simple biochemical techniques “is
truly extraordinary and frankly something most assumed would take a decade to
work out.”
The new technique seems likely to be welcomed by many who have opposed human
embryonic stem cell research. It “raises no serious moral problem, because it
creates embryonic-like stem cells without creating, harming or destroying human
lives at any stage,” said Richard Doerflinger, a spokesman on stem cell issues
for the United States Conference of Catholic Bishops. In themselves, embryonic
stem cells “have no moral status,” and the bishops’ objections to embryonic stem
cell research rest solely on the fact that human embryos must be harmed or
destroyed to obtain them, he said.
Ronald Green, an ethicist at Dartmouth College, said it would be “very hard for
people to say that what is created here is a nascent form of human life that
should be protected.” The new technique, if adaptable to human cells, “will be
one way this debate could end,” he said.
Ever since the creation of Dolly, the first cloned mammal, scientists have
sought to lay hands on the mysterious chemicals with which an egg will reprogram
a mature cell nucleus injected into it and set the cell on the same path of
embryonic development as when egg and sperm combine.
Years of patient research have identified many of the genes that are active in
the embryonic cell and maintain its pluripotency, or ability to morph into many
different tissues. Last year Dr. Yamanaka and his colleague Kazutoshi Takahashi,
both at Kyoto University, published a remarkable report relating how they had
guessed at 24 genes that seemed responsible for maintaining pluripotency in
mouse embryonic stem cells.
When they inserted all 24 genes into mouse skin cells, the cells showed signs of
pluripotency. The Kyoto team then subtracted genes one by one until they had a
set of four genes that were essential. The genes are inserted into viruses that
infect the cell and become active as the virus replicates. The skin cell’s own
copies of these genes are repressed since they would interfere with its
function. “We were very surprised” that just four genes are sufficient to
reprogram the skin cells, Dr. Yamanaka said.
Dr. Yamanaka’s report riveted the attention of biologists elsewhere. Two teams
set out to repeat and extend his findings, one led by Rudolf Jaenisch of the
Whitehead Institute and the other by Kathrin Plath of the University of
California, Los Angeles, and Konrad Hochedlinger of the Massachusetts General
Hospital. Dr. Yamanaka, too, set about refining his work.
In articles being published in Nature and a new journal, Cell-Stem Cell, the
three teams show that injection of the four genes identified by Dr. Yamanaka can
make mouse cells revert to cells that are indistinguishable from embryonic stem
cells. Dr. Yamanaka’s report of last year showed that only some properties of
embryonic stem cells were attained.
This clear confirmation of Dr. Yamanaka’s recipe is exciting to researchers
because it throws open to study the key process of multicellular organisms, that
of committing cells to a variety of different roles, even though all carry the
same genetic information.
Recent studies have shown that the chromatin, the complex protein material that
clads the DNA in chromosomes, is not passive packaging material but highly
dynamic. It contains systems of switches that close down large suites of genes
but allow others to be active, depending on the role each cell is assigned to
perform.
Dr. Yamanaka’s four genes evidently reset the switch settings appropriate for a
skin cell to ones that specify an embryonic stem cell. The technique is easy to
use and “should revolutionize the field since every small lab can work on
reprogramming,” said Alexander Meissner, a co-author of Dr. Jaenisch’s report.
An immediate issue is whether the technique can be reinvented for human cells.
One problem is that the mice have to be interbred. Another is that the cells
must be infected with the gene-carrying virus, which is not ideal for cells to
be used in therapy. A third issue is that two of the genes in the recipe can
cause cancer. Indeed 20 percent of Dr. Yamanaka’s mice died of the disease.
Nonetheless, several biologists expressed confidence that all these difficulties
will be sidestepped somehow.
“The technical problems seem approachable — I don’t see anyone running into a
brick wall,” said Owen Witte, a stem cell biologist at the University of
California, Los Angeles. In a Web cast about the research, Dr. Jaenisch
predicted that the problems of adapting the technique to human cells will be
solvable but he did not know when.
If a human version of Dr. Yamanaka’s recipe is developed, one important research
use, Dr. Weissman said, will be to reprogram diseased cells from patients so as
to study the molecular basis of how their disease develops.
Beyond that is the hope of generating cells for therapy. Researchers have
learned how to make embryonic cells in the laboratory develop into neurons,
heart muscle cells and other tissues. In principle these might be injected into
a patient to replace or supplement the cells of the diseased tissue, without
fear of immune rejection. No one really knows if the new cells would succumb to
the same disease process, or if they would be well behaved, given that they
developed in a laboratory dish without recapitulating the exact succession of
environments they would have experienced in the embryo.
Still, repairing the body with its own cells should in principle be a superior
form of medicine to the surgeon’s knife and the oncologists’ poisons.
But the first fruit of the new technique will be in figuring out how cells work.
This and other methods will lead to an explosion of information that will “open
the door for understanding how cells program and re-program their fate,” Dr.
Scadden predicted. If and when applicable to human cells, he said, the four-gene
approach “will have profound implications for new biology, regenerative medicine
and will change the ethical debate around stem cells.” fetical
