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Vocapedia > Health > Genetics > Stem cells, Growing organs, Chimeras

 

 

 

The very first attempts at xenotransplantation,

in the nineteenth century,

focused on pig organs - in this case the cornea -

because they were thought to be most like human organs.

 

Photograph: Enrique Marcarian/REUTERS

 

Human-pig chimeras

and the history of transplanting from animals

G

Tuesday 7 June 2016    08.45 BST

Last modified on Tuesday 7 June 2016    09.06 BST

https://www.theguardian.com/science/the-h-word/2016/jun/07/human-pig-chimeras-history-xenotransplantation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

WHAT CAN STEM CELLS DO?        Life Noggin        27 April 2015

 

 

 

 

WHAT CAN STEM CELLS DO?        Life Noggin        27 April 2015

 

You may have heard of stem cells before,

but there is a lot of mystery about what they actually … do.

Why is this such a promising new field?

 

YouTube

https://www.youtube.com/watch?v=K7D6iA7bZG0

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stem Cells        SciShow        30 April 2013

 

 

 

 

Stem Cells        SciShow        30 April 2013

 

Hank gives you the facts on stem cells

- what they are, what they're good for,

where they come from,

and how they're used in medicine.

 

YouTube

https://www.youtube.com/watch?v=jF2iXpoG5j8

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

laboratory-grown organs        UK

https://www.theguardian.com/science/2015/jul/08/
laboratory-grown-organs-transform-lives

 

 

 

 

grow human organs inside pigs        UK

https://www.theguardian.com/science/2016/jun/05/
organ-research-scientists-combine-human-stem-cells-and-pig-dna

 

 

 

 

human-pig embryos        UK

http://www.theguardian.com/lifeandstyle/ng-interactive/2016/jun/08/
oink-the-future-of-human-pig-embryos-cartoon

 

 

 

 

grow human heart valve from stem cells        UK

http://www.theguardian.com/science/2007/apr/02/
stemcells.genetics

 

 

 

 

grow primitive human kidneys 

http://www.npr.org/sections/health-shots/2015/10/07/
446351273/scientists-grow-primitive-human-kidneys-in-a-dish

http://www.npr.org/sections/health-shots/2015/10/07/
446351273/scientists-grow-primitive-human-kidneys-in-a-dish

 

 

 

 

grow human livers in mice

http://www.guardian.co.uk/science/video/2013/jul/05/
stem-cell-livers-grown-in-mice-video

http://www.nytimes.com/2013/07/04/
health/scientists-fabricate-rudimentary-human-livers.html

http://www.npr.org/sections/health-shots/2013/07/04/
198110553/scientists-grow-simple-human-liver-in-a-petri-dish

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

chimeras

 

make embryos

that are part human, part animal.

http://www.npr.org/sections/health-shots/2016/08/04/
488387729/nih-plans-to-lift-ban-on-research-funds-for-part-human-part-animal-embryos

http://www.npr.org/2016/08/04/
488637607/nih-reviews-moratorium-on-funding-controversial-chimera-research

http://www.npr.org/sections/health-shots/2016/05/18/
478212837/
in-search-for-cures-scientists-create-embryos-that-are-both-animal-and-human

http://www.dailymail.co.uk/sciencetech/article-3599408/
Researchers-reveal-controversial-experiments-grow-animal-human-
Frankenstein-organs-transplant-patients-going-on.html - 19 May 2016

 

http://www.npr.org/sections/health-shots/2015/11/06/
454693391/should-human-stem-cells-be-used-to-make-partly-human-chimeras

http://www.npr.org/sections/health-shots/2015/10/07/
446351273/scientists-grow-primitive-human-kidneys-in-a-dish

 

 

 

 

 

Simple eye grown from stem cells        UK        2011

 

Embryonic stem cells from mice

have been transformed into a rudimentary eye,

raising hopes of growing parts of the human eye

to investigate and treat blindness

http://www.guardian.co.uk/science/2011/apr/06/
simple-eye-stem-cells

 

 

 

 

Researchers Say They Created a ‘Synthetic Cell’        2010

http://www.nytimes.com/2010/05/21/science/21cell.html

http://www.guardian.co.uk/science/2010/may/20/craig-venter-synthetic-life-form

http://www.guardian.co.uk/science/2010/may/20/craig-venter-synthetic-life-genome

http://www.guardian.co.uk/science/video/2010/may/20/craig-venter-new-life-form

http://www.guardian.co.uk/commentisfree/andrewbrown/2010/may/20/craig-venter-life-god

http://www.guardian.co.uk/science/gallery/2010/may/20/first-synthetic-cell

http://www.guardian.co.uk/science/2010/may/20/creation-bacterial-cell-craig-venter

http://www.independent.co.uk/news/science/
synthetic-cell-is-a-giant-leap-for-science-and-could-be-bigger-still-for-mankind-1978869.html

http://www.independent.co.uk/news/people/profiles/
dr-craig-venter-so-doctor-how-does-it-feel-to-have-created-artificial-life-1978873.html

http://www.independent.co.uk/opinion/commentators/
dr-tom-wakeford-a-thrilling-breakthrough-but-also-a-frightening-one-1978870.html

 

 

 

 

play God        USA

http://www.npr.org/sections/health-shots/2016/05/18/
478212837/in-search-for-cures-scientists-create-embryos-that-are-both-animal-and-human

 

 

 

 

J. Craig Venter

https://www.theguardian.com/science/venter

http://www.nytimes.com/topic/person/craig-venter 

 

http://www.guardian.co.uk/science/2010/may/20/craig-venter-synthetic-life-form

http://www.guardian.co.uk/science/2010/may/20/craig-venter-synthetic-life-genome

http://www.guardian.co.uk/science/video/2010/may/20/craig-venter-new-life-form

http://www.guardian.co.uk/commentisfree/andrewbrown/2010/may/20/craig-venter-life-god

http://www.guardian.co.uk/science/gallery/2010/may/20/first-synthetic-cell

http://www.guardian.co.uk/science/2010/may/20/creation-bacterial-cell-craig-venter

http://www.independent.co.uk/news/people/profiles/
dr-craig-venter-so-doctor-how-does-it-feel-to-have-created-artificial-life-1978873.html

 

 

 

 

biotech company        UK

http://www.guardian.co.uk/science/2013/apr/21/
using-genetics-to-fight-disease

 

 

 

 

Scientists turn dead cells into live tissue        UK        2006

http://www.theguardian.com/science/2006/sep/24/
highereducation.research

 

 

 

 

human stem cells

 

basic cells that can be transformed

into types that are specific to tissues

like liver or lung.

http://www.nytimes.com/2012/09/16/
health/research/scientists-make-progress-in-tailor-made-organs.html

 

http://www.npr.org/sections/health-shots/2015/11/06/
454693391/should-human-stem-cells-be-used-to-make-partly-human-chimeras

 

http://www.nytimes.com/2012/09/16/
health/research/scientists-make-progress-in-tailor-made-organs.html

 

 

 

 

First sperm from stem cells        2006

 

 

 

 

mouse embryonic stem cells

 

 

 

new techniques

to derive embryonic stem cells in mice        USA

http://www.nytimes.com/2005/10/17/
health/17stem.html

 

 

 

 

converts a patient's skin cell into embryonic cells

and then new tissues to repair the body        USA

http://www.nytimes.com/2005/10/17/
health/17stem.html

 

 

 

 

break open the embryo

before it implants in the uterus,

a stage at which it is called a blastocyst,

and take out the inner cell mass,

whose cells form all the tissues in a human body

 

 

 

 

let a fertilized mouse egg divide three times

until it contained eight cells,

a stage just before

the embryo becomes a blastocyst

 

 

 

 

seven-cell embryo

 

 

 

 

be implanted in the mouse uterus

 

 

 

 

grow successfully to term

 

 

 

 

remove

 

 

 

 

grow

 

 

 

 

tissue

 

 

 

 

glassware

 

 

 

 

embryo

 

 

 

 

product of a clinic embryo

 

 

 

 

test-tube babies

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The Guardian        p. 1        2 April 2007

http://www.theguardian.com/science/2007/apr/02/stemcells.genetics

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Man Who Helped Start Stem Cell War May End It        NYT        22.11.2007
http://www.nytimes.com/2007/11/22/science/22stem.html

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stem Cell Test Tried on Mice Saves Embryo

By NICHOLAS WADE        NYT        October 17, 2005
http://www.nytimes.com/2005/10/17/health/17stem.html

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ernest McCulloch,

Crucial Figure

in Stem Cell Research,

Dies at 84

 

February 1, 2011

The New York Times

By LAWRENCE K. ALTMAN

 

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

that misidenfied the person in the photograph.

It was Dr. James E. Till ,

Dr. McCulloch's work partner.

Ernest McCulloch, Crucial Figure in Stem Cell Research, Dies at 84,
NYT, 1.2.2011,
http://www.nytimes.com/2011/02/01/health/research/01mcculloch.html

 

 

 

 

 

Researchers Say

They Created a ‘Synthetic Cell’

 

May 20, 2010

The New York Times

By NICHOLAS WADE

 

The genome pioneer J. Craig Venter has taken another step in his quest to create synthetic life, by synthesizing an entire bacterial genome and using it to take over a cell.

Dr. Venter calls the result a “synthetic cell” and is presenting the research as a landmark achievement that will open the way to creating useful microbes from scratch to make products like vaccines and biofuels. At a press conference Thursday, Dr. Venter described the converted cell as “the first self-replicating species we’ve had on the planet whose parent is a computer.”

“This is a philosophical advance as much as a technical advance,” he said, suggesting that the “synthetic cell” raised new questions about the nature of life

Other scientists agree that he has achieved a technical feat in synthesizing the largest piece of DNA so far — a million units in length — and in making it accurate enough to substitute for the cell’s own DNA.

But some regard this approach as unpromising because it will take years to design new organisms, and meanwhile progress toward making biofuels is already being achieved with conventional genetic engineering approaches in which existing organisms are modified a few genes at a time.

Dr. Venter’s aim is to achieve total control over a bacterium’s genome, first by synthesizing its DNA in a laboratory and then by designing a new genome stripped of many natural functions and equipped with new genes that govern production of useful chemicals.

“It’s very powerful to be able to reconstruct and own every letter in a genome because that means you can put in different genes,” said Gerald Joyce, a biologist at the Scripps Research Institute in La Jolla, Calif.

In response to the scientific report, President Obama asked the White House bioethics commission on Thursday to complete a study of the issues raised by synthetic biology within six months and report back to him on its findings. He said the new development raised “genuine concerns,” though he did not specify them further.

Dr. Venter took a first step toward this goal three years ago, showing that the natural DNA from one bacterium could be inserted into another and that it would take over the host cell’s operation. Last year, his team synthesized a piece of DNA with 1,080,000 bases, the chemical units of which DNA is composed.

In a final step, a team led by Daniel G. Gibson, Hamilton O. Smith and Dr. Venter report in Thursday’s issue of the journal Science that the synthetic DNA takes over a bacterial cell just as the natural DNA did, making the cell generate the proteins specified by the new DNA’s genetic information in preference to those of its own genome.

The team ordered pieces of DNA 1,000 units in length from Blue Heron, a company that specializes in synthesizing DNA, and developed a technique for assembling the shorter lengths into a complete genome. The cost of the project was $40 million, most of it paid for by Synthetic Genomics, a company Dr. Venter founded.

But the bacterium used by the Venter group is unsuitable for biofuel production, and Dr. Venter said he would move to different organisms. Synthetic Genomics has a contract from Exxon to generate biofuels from algae. Exxon is prepared to spend up to $600 million if all its milestones are met. Dr. Venter said he would try to build “an entire algae genome so we can vary the 50 to 60 different parameters for algae growth to make superproductive organisms.”

On his yacht trips round the world, Dr. Venter has analyzed the DNA of the many microbes in seawater and now has a library of about 40 million genes, mostly from algae. These genes will be a resource to make captive algae produce useful chemicals, he said.

Some other scientists said that aside from assembling a large piece of DNA, Dr. Venter has not broken new ground. “To my mind Craig has somewhat overplayed the importance of this,” said David Baltimore, a geneticist at Caltech. He described the result as “a technical tour de force,” a matter of scale rather than a scientific breakthrough.

“He has not created life, only mimicked it,” Dr. Baltimore said.

Dr. Venter’s approach “is not necessarily on the path” to produce useful microorganisms, said George Church, a genome researcher at Harvard Medical School. Leroy Hood, of the Institute for Systems Biology in Seattle, described Dr. Venter’s report as “glitzy” but said lower-level genes and networks had to be understood first before it would be worth trying to design whole organisms from scratch.

In 2002 Eckard Wimmer, of the State University of New York at Stony Brook, synthesized the genome of the polio virus. The genome constructed a live polio virus that infected and killed mice. Dr. Venter’s work on the bacterium is similar in principle, except that the polio virus genome is only 7,500 units in length, and the bacteria’s genome is more than 100 times longer.

Friends of the Earth, an environmental group, denounced the synthetic genome as “dangerous new technology,” saying that “Mr. Venter should stop all further research until sufficient regulations are in place.”

The genome Dr. Venter synthesized is copied from a natural bacterium that infects goats. He said that before copying the DNA, he excised 14 genes likely to be pathogenic, so the new bacterium, even if it escaped, would be unlikely to cause goats harm.

Dr. Venter’s assertion that he has created a “synthetic cell” has alarmed people who think that means he has created a new life form or an artificial cell. “Of course that’s not right — its ancestor is a biological life form,” said Dr. Joyce of Scripps.

Dr. Venter copied the DNA from one species of bacteria and inserted it into another. The second bacteria made all the proteins and organelles in the so-called “synthetic cell,” by following the specifications implicit in the structure of the inserted DNA.

“My worry is that some people are going to draw the conclusion that they have created a new life form,” said Jim Collins, a bioengineer at Boston University. “What they have created is an organism with a synthesized natural genome. But it doesn’t represent the creation of life from scratch or the creation of a new life form,” he said.

    Researchers Say They Created a ‘Synthetic Cell’, NYT, 20.5.2010,
    http://www.nytimes.com/2010/05/21/science/21cell.html

 

 

 

 

 

Editorial

Science and Stem Cells

 

March 10, 2009
The New York Times

 

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.

    Science and Stem Cells, 10.3.2009,
    http://www.nytimes.com/2009/03/10/opinion/10tue1.html

 

 

 

 

 

F.D.A. Approves a Stem Cell Trial

 

January 23, 2009
The New York Times
By ANDREW POLLACK

 

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.

    F.D.A. Approves a Stem Cell Trial, NYT, 24.1.2009,
    http://www.nytimes.com/2009/01/23/business/23stem.html

 

 

 

 

Team Creates Rat Heart

Using Cells of Baby Rats

 

January 14, 2008
The New York Times
By LAWRENCE K. ALTMAN

 

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,”

will appear on Tuesdays.

Dan Barry’s column, “This Land,”

will return on Monday, Jan. 21.

    Team Creates Rat Heart Using Cells of Baby Rats, NYT, 14.1.2008,
    http://www.nytimes.com/2008/01/14/health/14heart.html

 

 

 

 

 

Man Who Helped Start Stem Cell War

May End It

 

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.

    Man Who Helped Start Stem Cell War May End It, NYT, 22.11.2007,
    http://www.nytimes.com/2007/11/22/science/22stem.html

 

 

 

 

 

New Stem Cell Method

Could Ease Ethical Concerns

 

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.”

    New Stem Cell Method Could Ease Ethical Concerns, NYT, 21.11.2007,
    http://www.nytimes.com/2007/11/21/science/21stem.html

 

 

 

 

 

Stem Cell Breakthrough Reported

 

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.''

------

On the Net:

Journal Cell: http://www.cell.com

Journal Science: http://www.sciencemag.org

    Stem Cell Breakthrough Reported, NYT, 20.11.2007,
    http://www.nytimes.com/aponline/us/AP-Stem-Cells.html

 

 

 

 

 

Questions, Answers on Stem Cells

 

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.

    Questions, Answers on Stem Cells, NYT, 20.11.2007,
    http://www.nytimes.com/aponline/us/AP-Stem-Cells-QA.html

 

 

 

 

 

Basics

Sleek, Fast and Focused:

The Cells That Make Dad Dad

 

June 12, 2007
The New York Times
By NATALIE ANGIER

 

We are fast approaching Father’s Day, the festive occasion on which we plague Dad with yet another necktie or collect phone call and just generally strive to remind the big guy of the central verity of paternity — that it’s a lot more fun to become a father than to be one. “I won’t lie to you,” said the great Homer Simpson. “Fatherhood isn’t easy like motherhood.” Yet in our insistence that men are more than elaborately engineered gamete vectors, we neglect the marvels of their elaborately engineered gametes. As the scientists who study male germ cells will readily attest, sperm are some of the most extraordinary cells of the body, a triumph of efficient packaging, sleek design and superspecialization. Human sperm are extremely compact, and they’ve been stripped of a normal cell’s protein-making machinery; but when cast into the forbidding environment of the female reproductive tract, they will learn on the job and change their search strategies and swim strokes as needed.

Sperm are also fast and as cute as tadpoles. They have chubby teardrop heads and stylish, tapering tails, and they glide, slither, bumble and do figure-eights. So while a father may not be entitled to take the same pride in his sperm as he does in his kids, it’s fair to celebrate the single-minded cellular commas that helped give those children their start.

Sperm are pretty much the tiniest cells in the human body. The head of a mature, semen-ready sperm cell spans about 5 microns, or two-thousandths of an inch, less than half the width of a white blood cell or a skin cell. And a sperm cell is absurdly dwarfed by its female counterpart, the egg, which, fittingly or not, is among the biggest cells in the body. At 30 times the width of a sperm, the egg is massive enough to be seen with the naked eye.

But men have the overwhelming quantitative edge in the gamete games. Whereas current evidence suggests that a human female is born with all the eggs she will have, and that only about 500 of her natal stock of one million will ever ripen and have a shot at fertilization, a male from puberty onward is pretty much a nonstop sperm bakery. Each testicle generates more than 4 million new sperm per hour, for a lifetime total of maybe 12 trillion sperm per man (although the numbers vary with the day and generally slope downward with age).

The average ejaculation consists mostly of a teaspoon’s worth of nonspermic seminal fluid, a viscous mix of sugars, citric acid and other ingredients designed to pamper and power the sperm cells and prepare them for difficult times ahead; the sperm proper account for only about 1 percent of the semen mass. Yet in that 1 percent may be found 150 million sperm, 150 million human aspirants yearning to meet their mammoth other halves.

To which one can crack, dream on. Not only are there far too few eggs to go around, but also the majority of sperm couldn’t fertilize an ovum if it were plunked down in front of them. “Only a perfectly normal sperm can penetrate an egg,” said Dr. Harry Fisch, a urologist at Columbia University Medical Center, “and the majority of sperm are abnormally shaped.” Some may have pinheads, others have two heads, some lack tails, a third don’t move at all. As a rule, Dr. Fisch said, a man is lucky if 15 percent of his sperm are serviceable. “One guy I saw had 22 percent,” he said, “but that’s rare.”

Creating sperm is a complex, multistep operation in which immature cells spend one or two months wending through a labyrinth of tubules coiled in the testes, at each stage losing a bit more of the blobby contours and yolky contents of standard cells and assuming the streamlined profile of sperm cells. The operation is a delicate one that must be performed at temperatures some 2 degrees below that of the body, which is why the testicles hang outside the body, where breezes can keep them cool; why a man hoping to become a father is advised to skip the hot baths and saunas; and why a bout of high fever can disrupt fertility for months.

The model sperm that emerges at tubule’s end has, like an insect, three basic body segments. Of crowning importance is the head, which is taken up largely by a supercondensed tangle of 23 chromosomes, half the complement of DNA found in a normal body cell and thus the right number to merge with an egg’s 23 chromosomes and begin tapping out a whole new body. At the tip of the sperm head is the acrosome, a specialized sack of enzymes that help the sperm penetrate through what Joseph S. Tash, a male fertility expert at the University of Kansas Medical Center, calls the “forest” of ancillary cells and connective tissue that surrounds the ripe, ready egg.

Below the head is the midpiece, which is packed with the tiny engines called mitochondria that lend the sperm its motility, and below the midpiece is the tail, a bundle of 11 entwined filaments that thrashes and propels a sperm forward at the estimable pace of one-twelfth of an inch per minute, the equivalent of a human striding at four miles an hour.

Sperm do not really hit their stride until they are deposited in the female reproductive tract, at which point chemical signals from the vaginal and cervical mucus seem to spark them to life. Released from the buffering folds of their seminal delivery blanket, they at first swim straight ahead, torpedo-style, “with very little back and forth of the head,” Dr. Tash said. They may linger in the cervical mucus for a couple of days, or cross the cervix and enter the uterus.

If an egg has burst from its ovarian follicle and been plucked by a fallopian tube, sperm can sense its signature, a telltale shift in calcium ions. The sperm become “hyperactivated,” said Moira O’Bryan, a sperm expert at Monash University in Australia, switching to “a crazed figure-eight motion” ideal for boring through barriers. The ovum eggs them on, signaling some to play the sacrificial kamikaze and explode their enzyme sacks prematurely, loosening the corridor for other, shapelier sperm to pass through intact. A few dozen fine-figured sperm find their way to the final barrier, the egg’s plasma membrane, where they waggle with all their crazy-eight might and beg to be chosen — but only one will be taken, will fuse with the egg and be absorbed into its rich inner sanctum.

In a fraction of a second, an electrical, ionic jolt dramatically changes the egg’s outer coat, to forestall the lethal intrusion of additional sperm.

The wheels are in motion. How do you like your new tie?

    Sleek, Fast and Focused: The Cells That Make Dad Dad, NYT, 12.6.2007,
    http://www.nytimes.com/2007/06/12/science/12angi.html

 

 

 

 

 

Scientists Move Closer to Turning Skin Cells

Into Tissues

 

June 6, 2007
The New York Times
By NICHOLAS WADE

 

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.”

Scientists Move Closer to Turning Skin Cells Into Tissues,
NYT,
6.6.2007,
http://www.nytimes.com/2007/06/06/science/06cnd-cell.html

 

 

 

 

 

 

 

 

 

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