The Guardian        p. 1

2.4.2007

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

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

biology

biological

chromosome
http://www.guardian.co.uk/life/science/story/0,12996,1439545,00.html

gene
http://www.nytimes.com/2009/06/17/science/17depress.html
http://www.timesonline.co.uk/tol/comment/leading_article/article1848369.ece
http://www.guardian.co.uk/medicine/story/0,,2089635,00.html
http://www.timesonline.co.uk/tol/news/uk/health/article1647517.ece
http://www.guardian.co.uk/science/story/0,,2056262,00.html
http://www.guardian.co.uk/genes/article/0,,2028720,00.html
http://www.usatoday.com/news/world/2006-10-02-nobel-medicine_x.htm

genetics

genetically

cancer gene
http://www.timesonline.co.uk/tol/life_and_style/health/article1848437.ece
http://www.guardian.co.uk/genes/article/0,,2028720,00.html

rogue genes
http://www.timesonline.co.uk/tol/life_and_style/health/article1848437.ece

genome
http://www.nytimes.com/2010/06/20/opinion/l20genome.html
http://www.nytimes.com/2010/06/15/business/15genome.html
http://www.nytimes.com/2010/06/13/health/research/13genome.html
http://www.guardian.co.uk/genes/article/0,,2028720,00.html

gene therapy > Parkinson's disease
http://www.guardian.co.uk/science/story/0,,1924702,00.html

Huntington’s disease

deoxyribonucleic acid        DNA
http://www.nature.com/nsu/DNA50
http://www.time.com/time/time100/scientist/profile/watsoncrick.html

DNA test

DNA analysis for diseases such as cancer and Alzheimer's
http://www.guardian.co.uk/lifeandstyle/2008/dec/09/healthandwellbeing-medicalresearch

New laws on body tissue ban secret DNA testing        2006
http://www.guardian.co.uk/science/story/0,,1861652,00.html

mouse egg

divide

cell

sickle cell disease
http://www.nytimes.com/2010/04/15/us/15ranney.html

hematologist
http://www.nytimes.com/2010/04/15/us/15ranney.html

stem cell
http://www.guardian.co.uk/science/2009/mar/01/stem-cells-breakthrough
http://www.nytimes.com/2009/01/23/business/23stem.html
http://www.guardian.co.uk/medicine/story/0,,2048062,00.html
http://observer.guardian.co.uk/uk_news/story/0,,1879891,00.html
http://www.guardian.co.uk/science/story/0,,1878057,00.html
http://www.guardian.co.uk/science/story/0,,1791259,00.html
http://www.guardian.co.uk/medicine/story/0,11381,1653838,00.html
http://www.nytimes.com/2005/10/17/health/17stem.html
http://www.nytimes.com/2005/06/02/national/02embryo.html
http://www.nytimes.com/2005/05/21/politics/21stem.html

stem cell research
http://education.guardian.co.uk/higher/research/story/0,9865,1324790,00.html
http://www.guardian.co.uk/genes/article/0,2763,535023,00.html

grow
http://www.guardian.co.uk/medicine/story/0,,2048062,00.html

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.timesonline.co.uk/tol/news/science/biology_evolution/article7132299.ece
http://www.timesonline.co.uk/tol/news/science/biology_evolution/article7132316.ece
http://www.timesonline.co.uk/tol/news/science/genetics/article7128357.ece
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

J. Craig Venter
http://www.guardian.co.uk/science/venter
http://topics.nytimes.com/top/reference/timestopics/people/v/j_craig_venter/index.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/people/profiles/dr-craig-venter-so-doctor-how-does-it-feel-to-have-created-artificial-life-1978873.html

Scientists turn dead cells into live tissue        2006
http://observer.guardian.co.uk/uk_news/story/0,,1879891,00.html

First sperm from stem cells        2006
http://www.guardian.co.uk/science/story/0,,1817401,00.html

artificial sperm        2006
http://www.timesonline.co.uk/article/0,,2-2264104,00.html

mouse embryonic stem cells
http://www.guardian.co.uk/science/story/0,,1817401,00.html

new techniques to derive embryonic stem cells in mice
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
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. 40

23.5.2007

cancer
http://www.guardian.co.uk/science/cancer
http://health.nytimes.com/health/guides/disease/cancer/overview.html

http://www.nytimes.com/2010/06/06/health/research/06cancer.html
http://www.guardian.co.uk/science/2007/dec/28/medicalresearch.health
http://www.usatoday.com/news/health/2007-01-17-cancer_x.htm
http://www.usatoday.com/news/health/2007-01-17-cancer_x.htm
http://sport.guardian.co.uk/snooker/story/0,,1891787,00.html
http://www.economist.com/agenda/displaystory.cfm?story_id=4504790
http://society.guardian.co.uk/cancer/0,8145,393631,00.html

First cancer genome sequences reveal how mutations lead to disease        16 December 2009
http://www.guardian.co.uk/science/2009/dec/16/cancer-genome-sequences-genetic-mutations

rare cancer
http://www.nytimes.com/packages/html/nyregion/1-in-8-million/index.html#/mary_elizabeth_odonnellmoore

cancer researcher        USA
http://www.nytimes.com/2009/06/28/health/research/28cancer.html

cancer treatment        USA
http://www.nytimes.com/2010/06/06/health/research/06cancer.html
http://www.nytimes.com/2010/03/01/opinion/l01cancer.html
http://www.nytimes.com/2010/02/22/health/research/22trial.html
http://www.nytimes.com/2009/06/30/opinion/l30cancer.html
http://www.nytimes.com/2009/06/29/health/research/29drug.html

medicines to deter cancers         USA
http://www.nytimes.com/2009/11/13/health/research/13prevent.html

M. D. Anderson Cancer Center        Houston, Texas        USA
http://www.mdanderson.org/
http://www.nytimes.com/2009/10/25/health/research/25anderson.html

The Boston Globe > The Big Picture > Childhood Cancer Awareness Month        USA        2008
http://www.boston.com/bigpicture/2008/09/childhood_cancer_awareness_mon.html

spread
http://www.guardian.co.uk/science/2007/dec/28/medicalresearch.health

tumor

malignant brain tumor
http://www.nytimes.com/aponline/us/AP-Kennedy.html

have cancer

cancer sufferer

battle with cancer

esophageal cancer
http://www.nytimes.com/reuters/2009/03/16/arts/entertainment-us-silver.html

lung cancer
http://www.guardian.co.uk/lifeandstyle/lung-cancer

http://www.nytimes.com/aponline/2009/12/08/arts/AP-US-TV-Gumbel-Cancer.html

Skin cancer (melanoma)
http://www.nytimes.com/2010/03/01/opinion/l01cancer.html
http://www.nytimes.com/2010/02/22/health/research/22trial.html
http://www.guardian.co.uk/lifeandstyle/skin-cancer-melanoma

leukemia
http://www.nytimes.com/2009/11/10/sports/basketball/10rhoden.html

Acute Myeloid Leukemia        AML
http://health.nytimes.com/health/guides/disease/acute-myeloid-leukemia/overview.html
http://www.nytimes.com/2009/11/03/science/03conv.html

Chronic Myelogenous Leukemia        CML
http://health.nytimes.com/health/guides/disease/chronic-myelogenous-leukemia-cml/overview.html
http://www.nytimes.com/2009/11/03/science/03conv.html

testicular cancer
http://www.guardian.co.uk/lifeandstyle/video/2009/nov/05/testicular-cancer-guide

breast cancer
http://www.guardian.co.uk/lifeandstyle/breast-cancer
http://health.nytimes.com/health/guides/disease/breast-cancer/overview.html

http://www.independent.co.uk/life-style/health-and-families/health-news/
dramatic-advance-in-treatment-of-breast-cancer-1992682.html
http://www.nytimes.com/2009/10/18/opinion/l18mammo.html
http://www.nytimes.com/2009/10/10/opinion/10DeVries.html
http://www.guardian.co.uk/lifeandstyle/2008/nov/30/breast-cancer-health-family-pregnancy
http://society.guardian.co.uk/health/news/0,,1766299,00.html
http://observer.guardian.co.uk/international/story/0,6903,1489606,00.html
http://society.guardian.co.uk/cancer/story/0,8150,1298662,00.html

breast cancer awareness
http://www.guardian.co.uk/music/2010/mar/28/kylie-minogue-breast-cancer-campaign

be genetically prone to breast cancer
http://www.nytimes.com/2007/09/16/health/16gene.html

mammography        USA
http://health.nytimes.com/health/guides/test/mammography/overview.html

http://www.nytimes.com/2009/11/20/opinion/20fri1.html

mammogram        USA
http://www.nytimes.com/2009/12/01/health/research/01cancer.html
http://www.nytimes.com/2009/11/20/opinion/20fri1.html
http://www.nytimes.com/2009/11/17/health/17cancer.html
http://www.nytimes.com/2007/09/16/health/16gene.html

Cagle cartoons > No more mammograms        USA        2009
http://www.cagle.com/news/Mammograms/main.asp

mammologists        USA
http://www.nytimes.com/2009/10/10/opinion/10DeVries.html
 

mastectomy        USA
http://www.nytimes.com/2007/09/16/health/16gene.html

cervical cancer
http://health.nytimes.com/health/guides/disease/cervical-cancer/overview.html

http://www.nytimes.com/2009/11/20/health/20pap.html
http://www.timesonline.co.uk/tol/news/uk/health/article2745159.ece
http://www.timesonline.co.uk/tol/news/uk/health/article2746187.ece
http://www.guardian.co.uk/news/2007/oct/26/uknews.health
http://www.guardian.co.uk/society/2007/oct/26/health.medicineandhealth
http://www.guardian.co.uk/medicine/story/0,,2042653,00.html
http://www.usatoday.com/news/health/2006-06-08-cervical-cancer-vaccine_x.htm

Q&A: Cervical cancer vaccination
http://www.timesonline.co.uk/tol/news/uk/health/article2746187.ece
http://www.timesonline.co.uk/tol/news/uk/health/article2745159.ece
http://www.guardian.co.uk/news/2007/oct/26/uknews.health

cervical screening tests

Medullary carcinoma of the thyroid / cancer of the thyroid gland
http://health.nytimes.com/health/guides/disease/medullary-carcinoma-of-thyroid/overview.html

brain cancer
http://www.nytimes.com/2009/11/17/health/17tumor.html

prostate cancer
http://www.guardian.co.uk/lifeandstyle/2009/nov/17/darcus-howe-surviving-prostate-cancer
http://health.nytimes.com/health/guides/disease/cancer/overview.html

cancer screening
http://www.nytimes.com/2009/10/26/opinion/l26cancer.html
http://www.nytimes.com/2009/10/21/health/21cancer.html
http://www.nytimes.com/2009/07/27/opinion/l27cancer.html
http://www.nytimes.com/2009/07/17/health/17screening.html
http://www.independent.co.uk/life-style/health-and-wellbeing/
health-news/fears-of-rise-in-breast-cancer-as-more-women-decline-screenings-1222846.html
http://www.timesonline.co.uk/tol/life_and_style/health/article1848435.ece
http://www.timesonline.co.uk/tol/life_and_style/health/article1848434.ece
http://www.timesonline.co.uk/tol/comment/leading_article/article1848369.ece

American Cancer Society        USA
http://topics.nytimes.com/top/reference/timestopics/organizations/a/american_cancer_society/index.html

chemotherapy
http://www.nytimes.com/2009/07/21/health/21canc.html
http://www.guardian.co.uk/lifeandstyle/2009/apr/21/chemotherapy-cancer-chemobrain
http://www.nytimes.com/aponline/us/AP-Kennedy.html
http://www.usatoday.com/news/health/2006-10-05-chemo-fog_x.htm

radiotherapy
http://society.guardian.co.uk/health/news/0,,1716003,00.html

radiation
http://www.nytimes.com/2010/01/31/opinion/l31radiation.html
http://www.nytimes.com/2010/01/24/health/24radiation.html
http://www.nytimes.com/aponline/us/AP-Kennedy.html

infertility caused by cancer treatment
http://society.guardian.co.uk/cancer/story/0,8150,1312010,00.html

brain tumour
http://www.guardian.co.uk/medicine/story/0,,1925765,00.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

Grant System Leads Cancer Researchers to Play It Safe

June 28, 2009
The New York Times
By GINA KOLATA

Among the recent research grants awarded by the National Cancer Institute is one for a study asking whether people who are especially responsive to good-tasting food have the most difficulty staying on a diet. Another study will assess a Web-based program that encourages families to choose more healthful foods.

Many other grants involve biological research unlikely to break new ground. For example, one project asks whether a laboratory discovery involving colon cancer also applies to breast cancer. But even if it does apply, there is no treatment yet that exploits it.

The cancer institute has spent $105 billion since President Richard M. Nixon declared war on the disease in 1971. The American Cancer Society, the largest private financer of cancer research, has spent about $3.4 billion on research grants since 1946.

Yet the fight against cancer is going slower than most had hoped, with only small changes in the death rate in the almost 40 years since it began.

One major impediment, scientists agree, is the grant system itself. It has become a sort of jobs program, a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.

“These grants are not silly, but they are only likely to produce incremental progress,” said Dr. Robert C. Young, chancellor at Fox Chase Cancer Center in Philadelphia and chairman of the Board of Scientific Advisors, an independent group that makes recommendations to the cancer institute.

The institute’s reviewers choose such projects because, with too little money to finance most proposals, they are timid about taking chances on ones that might not succeed. The problem, Dr. Young and others say, is that projects that could make a major difference in cancer prevention and treatment are all too often crowded out because they are too uncertain. In fact, it has become lore among cancer researchers that some game-changing discoveries involved projects deemed too unlikely to succeed and were therefore denied federal grants, forcing researchers to struggle mightily to continue.

Take one transformative drug, for breast cancer. It was based on a discovery by Dr. Dennis Slamon of the University of California, Los Angeles, that very aggressive breast cancers often have multiple copies of a particular protein, HER-2. That led to the development of herceptin, which blocks HER-2.

Now women with excess HER-2 proteins, who once had the worst breast cancer prognoses, have prognoses that are among the best. But when Dr. Slamon wanted to start this research, his grant was turned down. He succeeded only after the grateful wife of a patient helped him get money from Revlon, the cosmetics company.

Yet studies like the one on tasty food are financed. That study, which received a grant of $100,000 over two years, is based on the idea that since obesity is associated with an increased risk of cancer, understanding why people have trouble losing weight could lead to better weight control methods, which could lead to less obesity, which could lead to less cancer.

“It was the first grant I ever submitted, and it was funded on the first try,” said the principal investigator, Bradley M. Appelhans, an assistant professor of basic medical sciences and psychology at the University of Arizona. Dr. Appelhans said he realized it would hardly cure cancer, but hoped that “it will provide knowledge that will incrementally contribute to more effective cancer prevention strategies.”

Even top federal cancer officials say the system needs to be changed.

“We have a system that works over all pretty well, and is very good at ruling out bad things — we don’t fund bad research,” said Dr. Raynard S. Kington, acting director of the National Institutes of Health, which includes the cancer institute. “But given that, we also recognize that the system probably provides disincentives to funding really transformative research.”

The private American Cancer Society follows a similarly cautious path. Last year, it awarded $124 million in new research grants, with some money coming from large donors but most from events like walkathons and memorial donations.

Dr. Otis W. Brawley, chief medical officer at the cancer society, said the whole cancer research effort remained too cautious.

“The problem in science is that the way you get ahead is by staying within narrow parameters and doing what other people are doing,” Dr. Brawley said. “No one wants to fund wild new ideas.”

He added that the problem of getting money for imaginative but chancy proposals had worsened in recent years. There are more scientists seeking grants — they surged into the field in the 1990s when the National Institutes of Health budget doubled before plunging again.

That makes many researchers, who need grants not just to run their labs but also sometimes to keep their faculty positions, even more cautious in the grant proposals they submit. And grant review committees become more wary about giving scarce money to speculative proposals.

Philanthropies, which helped some researchers try outside-the-box ideas, are now having financial problems. And advances in technology have made research more expensive.

“Scientists don’t like talking about it publicly,” because they worry that their remarks will be viewed as lashing out at the health institutes, which supports them, said Dr. Richard D. Klausner, a former director of the National Cancer Institute.

But, Dr. Klausner added: “There is no conversation that I have ever had about the grant system that doesn’t have an incredible sense of consensus that it is not working. That is a terrible wasted opportunity for the scientists, patients, the nation and the world.”

A Big Idea Without a Backer

For 25 years, Eileen K. Jaffe received federal grants to run her lab. As a senior scientist at the Fox Chase Cancer Center, with a long list of published papers in prestigious journals, she is a respected, established researcher.

Then Dr. Jaffe stumbled upon results that went against textbook explanations, suggesting that it might be possible to find an entirely new class of drugs that could disable proteins that fuel cancer cells. Now she wants to find chemicals that might be developed into such drugs.

But her grant proposal was rejected out of hand by the institutes of health, not even discussed by a review panel. She had no preliminary data showing that the idea was likely to work, something reviewers always want to see, and the idea was just too unprecedented.

Dr. Jaffe epitomizes the scientist who realizes that if she were to single-mindedly pursue her unorthodox idea, her “career may be ruined in the process,” in the words of Dr. Brawley of the American Cancer Society.

Dr. Jaffe is just conceiving her project; it is much to soon to know whether it will result in a revolutionary drug. And even if she does find potential new drugs, it is not clear that they will be effective. Most new ideas are difficult to prove, and most potential new drugs fail.

So Dr. Jaffe was not entirely surprised when her grant application to look for such cancer drugs was summarily rejected.

“They said I don’t have preliminary results,” she said. “Of course I don’t. I need the grant money to get them.”

Dr. Young, chancellor at Fox Chase, said Dr. Jaffe’s situation showed why people with bold new ideas often just give up.

“You can’t prove it will work in advance,” he said. “If you could, it wouldn’t be a high-risk idea.”

It is a long haul, Dr. Jaffe knows. And she has already had to downsize her lab. But, she said, she will persist.

Angels Outside Government

At the Dana-Farber Cancer Institute in Boston, Dr. Ewa T. Sicinska knew she would have a similar problem with her research. She wanted to grow human cancers in mice. Unlike Dr. Jaffe, though, Dr. Sicinska did not even apply for government money.

It is not that the project was unimportant.

“Rather than have to start a human clinical trial to test new drugs, we want to test them first in mice with real human tumors,” said Dr. George D. Demetri, who leads the research group supporting Dr. Sicinska.

Researchers have studied mouse cancers but, they acknowledge, they are just not the same as human cancers — they are much easier to treat, and drugs that cure mice often do nothing in people. So, over the years, scientists have tried to implant human cancer cells in mice, but with little success.

“Everyone told us that if you take tumors out of patients and put them in mice, they don’t grow,” Dr. Demetri said. The tumor cells usually were put in a plastic dish before being implanted in mice. “We said — wait a minute. The cells are not growing in the plastic dish. They probably are dying. What if we bypass the dish?’”

With that idea in mind, Dr. Demetri, convinced it was too speculative to get federal money, tapped an unusual source, the Ludwig Fund. Endowed by Daniel K. Ludwig, one of the world’s richest men in the 1960s and 1970s, the fund supports unfettered cancer research at six medical centers in the United States, including Dana-Farber, to be used at the institutes’ discretion. That put Dr. Sicinska in a very different position from that of Dr. Jaffe. She could try something chancy without a grant.

Dr. Sicinska used a quarter of a million dollars of Ludwig money for this project, buying mice without immune systems, which meant they could not reject human tumors, and housing them in a germ-free basement lab. She spent months learning to implant tumors in the mice and enlisted geneticists to study the implanted tumors, making sure they did not mutate beyond recognition.

She spends her days in the lab, using a miniature ultrasound machine to scan the mice, hairless creatures with prominent ears. Four types of sarcomas — cancers of fat, muscle or bone — are growing in them and look genetically identical to the tumors removed from patients.

Dr. Elias A. Zerhouni, former director of the National Institutes of Health, said he was not sure that a grant for the project would have been turned down. The N.I.H., he said, does finance research on mouse models for human cancer.

But Dr. Demetri said he did not apply “because we have lots of experience in what’s fundable.” His mouse work, he said, is exploratory, and he cannot predict what he will find or when. He certainly could not lay out a road map of what he would do and promise results in a few years.

Studies With a Different Goal

Researchers like Dr. Appelhans, who is studying weight control and tasty foods, do not expect to change the outlook for cancer patients anytime soon. But, they say, that does not mean their work is unimportant.

Dr. Appelhans will study 85 overweight or obese women, measuring how much the tastes and textures of food drive their eating. Then they will be given a weight loss diet and nutritional counseling. Dr. Appelhans will ask whether those who are most tempted by the tastes and textures also have the most trouble following the diet.

As for the grant to assess a Web-based program to improve food choices, it is predicated on studies indicating that what people eat in childhood and adolescence may have an impact on cancer risk in middle and old age, said the grant recipient, Karen Weber Cullen, associate professor of pediatrics at Baylor College of Medicine. Some studies have found that people who reported having eaten fruits and vegetables when they were younger and maintaining a healthy weight were less likely to have cancer.

Of course, it would not be feasible to follow participants for 30 or 40 years to see if their cancer risk was altered, Dr. Cullen noted. But, she added, “we try to achieve improvements in diet and physical activity behaviors that become permanent and will make a difference in later years.”

In the study asking whether a molecular pathway that spurs the growth of colon cancer cells also encourages the growth of breast cancer cells, the principal investigator ultimately wants to find a safe drug to prevent breast cancer. She received a typical-size grant of a little more than $1 million for the five-year study.

The plan, said the investigator, Louise R. Howe, an associate research professor at Weill Cornell Medical College, is first to confirm her hypothesis about the pathway in breast cancer cells. But even if it is correct, the much harder research would lie ahead because no drugs exist to block the pathway, and even if they did, there are no assurances that they would be safe.

Dr. Howe said she hoped that she would find such drugs, or that companies would. Then she wants to develop a way to selectively deliver the drugs to precancerous breast cells. If it all works and the treatment is safe, women with precancerous conditions could avoid developing cancer.

Dr. Howe has reviewed grants for the cancer institute herself, she said, and realizes that, among other things, those that get financed must have “a novel hypothesis that is credible based on what we know already.”

Trying to Change the System

The National Institutes of Health has started “pilot experiments” to see if there is a better way of getting financing for innovative projects, its acting director, Dr. Kington, said.

They include “pioneer awards,” begun in 2004 for “ideas that have the potential for high impact but may be too novel, span too diverse a range of disciplines or be at a stage too early to fare well in the traditional peer review process.” But only 3 percent to 5 percent of the applicants get funded. Now the institutes have decided to set aside up to $25 million for “transformative R01 grants,” described as “proposing exceptionally innovative, high risk, original and/or unconventional research with the potential to create or overturn fundamental paradigms.”

About 700 proposals have come in, but only a small number are expected to be financed, according to Dr. Keith R. Yamamoto, a molecular biologist and executive vice dean of the school of medicine at the University of California, San Francisco, and co-chairman of the committee that reviewed the proposals last week.

“From reading the applications so far, there are really some fantastic things,” Dr. Yamamoto said.

There also is new money from the federal economic stimulus package passed by Congress, which gives the National Institutes of Health $200 million for “challenge grants” lasting two years or less.

But the N.I.H. has received about 21,000 applications for 200 challenge grants, and researchers who have applied concede there is not much hope.

“I did submit one of these challenge grants recently, like the rest of the lemmings,” said Dr. Chi Dang, professor of medicine, cell biology, oncology and pathology at the Johns Hopkins University School of Medicine. But, he added, “there are many, many more applications than slots.”

Some experienced scientists have found a way to offset the problem somewhat. They do chancy experiments by siphoning money from their grants.

“In a way, the system is encrypted,” Dr. Yamamoto said, allowing those in the know to wink and do their own thing on the side.

Great discoveries have been made with N.I.H. financing without manipulating the system, Dr. Klausner said.

“But,” he added, “I actually believe that by and large it is despite, rather than because of, the review system.”

    Grant System Leads Cancer Researchers to Play It Safe, NYT, 28.6.2009, http://www.nytimes.com/2009/06/28/health/research/28cancer.html

Cancer Patients Challenge the Patenting of a Gene

May 13, 2009
The New York Times
By JOHN SCHWARTZ

When Genae Girard received a diagnosis of breast cancer in 2006, she knew she would be facing medical challenges and high expenses. But she did not expect to run into patent problems.

Ms. Girard took a genetic test to see if her genes also put her at increased risk for ovarian cancer, which might require the removal of her ovaries. The test came back positive, so she wanted a second opinion from another test. But there can be no second opinion. A decision by the government more than 10 years ago allowed a single company, Myriad Genetics, to own the patent on two genes that are closely associated with increased risk for breast cancer and ovarian cancer, and on the testing that measures that risk.

On Tuesday, Ms. Girard, 39, who lives in the Austin, Tex., area, filed a lawsuit against Myriad and the Patent Office, challenging the decision to grant a patent on a gene to Myriad and companies like it. She was joined by four other cancer patients, by professional organizations of pathologists with more than 100,000 members and by several individual pathologists and genetic researchers.

The lawsuit, believed to be the first of its kind, was organized by the American Civil Liberties Union and filed in federal court in New York. It blends patent law, medical science, breast cancer activism and an unusual civil liberties argument in ways that could make it a landmark case.

Companies like Myriad, based in Salt Lake City, have argued that the patent system promotes innovation by giving companies the temporary monopoly that rewards their substantial investment in research and development.

Richard Marsh, Myriad’s general counsel, said company officials would not be able to comment on the lawsuit until they had fully reviewed the complaint.

The coalition of plaintiffs argues that gene patents actually restrict the practice of medicine and new research.

“With a sole provider, there’s mediocrity,” said Wendy K. Chung, the director of clinical genetics at Columbia University and a plaintiff in the case.

Dr. Chung and others involved with the suit do not accuse Myriad of being a poor steward of the information concerning the two genes at issue in the suit, known as BRCA1 and BRCA2, but they argue that BRCA testing would improve if market forces were allowed to work.

Harry Ostrer, director of the human genetics program at the New York University School of Medicine and a plaintiff in the case, said that many laboratories could perform the BRCA tests faster than Myriad, and for less money than the more than $3,000 the company charged.

Laboratories like his, he said, could focus on the mysteries still unsolved in gene variants. But if he tried to offer such services today, he said, he would be risking a patent infringement lawsuit from Myriad.

Christopher A. Hansen, senior national staff counsel for the civil liberties union, said the problem was with the patent office, not the company. He recalled that when he first heard that the office had granted a patent for a gene, “I said that can’t be true.”

As the A.C.L.U. explored the restrictions on competition that companies like Myriad had put in place — blocking alternatives to the patented tests, and even the practice of interpreting or comparing gene sequences that involved those genes — the restrictions started to look like not just a question of patent law, Mr. Hansen said, but of the First Amendment’s guarantee of free speech as well.

“What they have really patented,” he said, “is knowledge.”

A patent was also granted to a single company for genetic testing on long QT syndrome, which can lead to heart arrhythmias and sudden death, and to the HFE gene, linked to hereditary hemochromatosis, a condition in which iron accumulates in the blood and can cause organ damage. Doctors and scientists have complained about both patents.

On the other hand, the company that owns the patent to the gene CFTR, which has been linked to cystic fibrosis, has licensed the testing to dozens of laboratories, drawing praise from the medical world.

The decision to allow gene patents was controversial from the start; patents are normally not granted for products of nature or laws of nature. The companies successfully argued that they had done something that made the genes more than nature’s work: they had isolated and purified the DNA, and thus had patented something they had created — even though it corresponded to the sequence of an actual gene.

The argument may have convinced patent examiners, but it has long been a sore point for many scientists. “You can’t patent my DNA, any more than you can patent my right arm, or patent my blood,” said Jan A. Nowak, president of the Association for Molecular Pathology, a plaintiff in the case.

So far, however, two panels of government experts who have looked at the issue have not found significant impediments to research or medical care caused by gene patents. A 2006 report from the National Research Council found that patented biomedical research “rarely imposes a significant burden for biomedical researchers.”

That report and others, however, warn that the patent landscape “could become considerably more complex and burdensome over time.”

In the future, genetic tests are likely to involve the analysis of many genes at once, or even of a person’s full set of genes. Some 20 percent of the human genome is already included in patent claims, amounting to thousands of individual genes, says a draft report from the National Institutes of Health. The report warns that “it may be difficult for any one developer to obtain all the needed licenses” to develop the next generations of tests.

For Lisbeth Ceriani, a single mother from Newton, Mass., and a plaintiff in the case against Myriad, the biggest obstacle that gene patents present is one of cost. She has had breast cancer and a double mastectomy, but wants to have BRCA testing to determine her risk of ovarian cancer and help her decide whether to have her ovaries removed. But Myriad has refused to work with her insurance plan, Mass Health, and paying for the test herself is beyond her means.

She is reluctant to have surgery that might prove unnecessary, she said, but she also worries about her 8-year-old daughter and the inherited risk she might face. Which is why, Ms. Ceriani said, she wants to “find out if I have the mutation, so I can take the necessary steps to stay on the planet.”

“I want to be here,” she said, “to make sure she does her screening by the time she’s 30.”

    Cancer Patients Challenge the Patenting of a Gene, NYT, 13.5.2009, http://www.nytimes.com/2009/05/13/health/13patent.html?hpw

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?hp

US Cancer Deaths Rose by 5, 400 in 2005

February 20, 2008
Filed at 3:02 a.m. ET
By THE ASSOCIATED PRESS
The New York Times

ATLANTA (AP) -- U.S. cancer deaths rose by more than 5,000 in 2005, a somewhat disappointing reversal of a two-year downward trend, the American Cancer Society said in a report issued Wednesday.

The group counted 559,312 people who died from cancer.

The cancer death rate among the overall population continued to fall, but only slightly, after a couple of years of more dramatic decline.

In 2005, there were just under 184 cancer deaths per 100,000 people, down from nearly 186 the previous year. Experts said it wasn't surprising that the rate would stabilize.

The cancer death rate has been dropping since the early 1990s, and early in this decade was declining by about 1 percent a year. The actual number of cancer deaths kept rising, however, because of the growing population.

So it was big news when the rate dropped by 2 percent in both 2003 and 2004, enough to cause the total number of cancer deaths to fall for the first time since 1930.

President Bush and others hailed that as a sign that federally funded research was making strides against the disease.

But now the death rate decline is back to 1 percent. And the 2005 numbers show annual cancer deaths are no longer falling, but are up more than 5,400 since 2004.

''The declining rate was no longer great enough to overcome the increase in population,'' said Elizabeth Ward, a co-author of the cancer society report

Officials with the organization say they don't know why the decline in the death rate eased.

It may be that cancer screenings are not having as big an effect as they were a few years ago, said Dr. Peter Ravdin, a research professor in biostatistics at the University of Texas M.D. Anderson Cancer Center in Houston.

One possible example: In 2004, the largest drop in deaths among the major cancers was in colorectal cancer. Experts gave much of the credit to colonoscopy screenings that detect polyps and allow doctors to remove them before they turn cancerous. They also mentioned ''the Katie Couric effect'' -- a jump in colonoscopy rates after the ''Today'' show host had the exam on national television in 2000.

In the new report, the colorectal cancer death rate decreased by about 3 percent from 2004 to 2005, after plunging 6 percent from 2003 to 2004.

Colorectal cancer screening rates through 2003 did not show a decline. But it's possible they have fallen since then, Ravdin said.

Cancer society officials have also voiced concern that cancer deaths may increase as Americans lose health insurance coverage and get fewer screenings.

The good news is the cancer death rate is still declining, and that since the early 1990s is down more than 18 percent for men and more than 10 percent for women. Those reductions translate to more than half a million cancer deaths avoided, according to the cancer society.

Experts attribute the success to declines in smoking and to earlier detection and more effective treatment of tumors.

------

On the Net:

American Cancer Society report: www.cancer.org/statistics

    US Cancer Deaths Rose by 5, 400 in 2005, NYT, 20.2.2008, http://www.nytimes.com/aponline/us/AP-Cancer-Deaths.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?hp

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?hp

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?hp

New breast cancer genes identified

Most significant advance in decade

Monday May 28, 2007
Guardian
Polly Curtis, health correspondent

The most significant advance in the understanding of breast cancer for a decade was announced last night with the identification of a new group of common genetic markers for the disease.

Scientists have discovered four genes which, if faulty, can increase a woman's chance of developing breast cancer - by up to 60% in the case of two of the genes. This helps explain why women with a close relative with breast cancer are twice as likely to develop the disease, and offers the hope of a test in the near future. The scientists also believe the techniques used will help them unravel other cancers.

Karol Sikora, a leading cancer specialist, said of the studies published online in Nature and Nature Genetics last night: "This set of incredible papers points to the future understanding [of] the genetics of cancer."

It is the most significant discovery in the field since the 1990s, when scientists identified two rare genes, BRCA1 and BRCA2, which make carriers likely to develop breast cancer. An international coalition of researchers led by Cancer Research UK at Cambridge University has proved the theory that geneticists have been working on ever since: that most familial patterns of breast cancer can be explained by myriad smaller genetic effects.

Breast cancer is twice as common in those who have a close relative who develops it due to a fault in a gene, although the presence of a faulty gene does not mean that cancer will definitely occur.

The scientists trawled large parts of the genome in 800 people. They identified 11,000 "tags", or blocks of DNA which point to genes, which were more common in women with breast cancer and studied them in 8,000 more women. In the final process, which involved 40,000 women, they narrowed the search down to five tags which were significantly more common among women with breast cancer than those without. The tags pointed them to four genes which they believe are responsible for the increased breast cancer risk among the patients studied. Scientists expect that they will find a fifth.

Two of the genes identified, FGFR2 and TNRC9, are thought to increase the risk of breast cancer by about 20% in women who carry one faulty copy of a gene and by between 40% and 60% in those who carry two faulty copies. The lifetime risk for women with two faulty copies in either of these two genes would rise from one in 11 to around one in six or seven. The other two genes increase risk by 10% if there is one fault.

A maximum 10% of breast cancers have a genetic element, and the genes scientists know about so far account for 25% of these. The genes identified today account for a further 4% and are responsible for only a small number of breast cancers - up to 179 of the 44,000 diagnosed every year.

The ultimate aim is genetic screening that would band women according to risk. But scientists warn this could create an army of "worried well". They stress that the findings do not merit genetic testing immediately.

The findings do, however, hint at a different cause of familial breast cancers. Three of the new genes are involved in the control of cell growth or cell signalling, mechanisms which have never been linked to breast cancer before.

The author of the study, Douglas Easton, director of Cancer Research UK's Genetic Epidemiology Unit in Cambridge, said: "We're very excited by these results because the regions we identified don't contain previously known inherited cancer genes. This opens the door to new research directions." The techniques used are similar to those which helped identify the genes for obesity last month.

    New breast cancer genes identified, G, 28.5.2007, http://www.guardian.co.uk/medicine/story/0,,2089635,00.html

Facing Life With a Lethal Gene        NYT        18.3.2007
http://www.nytimes.com/2007/03/18/health/18huntington.html?hp

Facing Life With a Lethal Gene

March 18, 2007
The New York Times
By AMY HARMON

The test, the counselor said, had come back positive.

Katharine Moser inhaled sharply. She thought she was as ready as anyone could be to face her genetic destiny. She had attended a genetic counseling session and visited a psychiatrist, as required by the clinic. She had undergone the recommended neurological exam. And yet, she realized in that moment, she had never expected to hear those words.

“What do I do now?” Ms. Moser asked.

“What do you want to do?” the counselor replied.

“Cry,” she said quietly.

Her best friend, Colleen Elio, seated next to her, had already begun.

Ms. Moser was 23. It had taken her months to convince the clinic at NewYork-Presbyterian Hospital/Columbia University Medical Center in Manhattan that she wanted, at such a young age, to find out whether she carried the gene for Huntington’s disease.

Huntington’s, the incurable brain disorder that possessed her grandfather’s body and ravaged his mind for three decades, typically strikes in middle age. But most young adults who know the disease runs in their family have avoided the DNA test that can tell whether they will get it, preferring the torture — and hope — of not knowing.

Ms. Moser is part of a vanguard of people at risk for Huntington’s who are choosing to learn early what their future holds. Facing their genetic heritage, they say, will help them decide how to live their lives.

Yet even as a raft of new DNA tests are revealing predispositions to all kinds of conditions, including breast cancer, depression and dementia, little is known about what it is like to live with such knowledge.

“What runs in your own family, and would you want to know?” said Nancy Wexler, a neuropsychologist at Columbia and the president of the Hereditary Disease Foundation, which has pioneered Huntington’s research. “Soon everyone is going to have an option like this. You make the decision to test, you have to live with the consequences.”

On that drizzly spring morning two years ago, Ms. Moser was feeling her way, with perhaps the most definitive and disturbing verdict genetic testing has to offer. Anyone who carries the gene will inevitably develop Huntington’s.

She fought her tears. She tried for humor.

Don’t let yourself get too thin, said the clinic’s social worker. Not a problem, Ms. Moser responded, gesturing to her curvy frame. No more than two drinks at a time. Perhaps, Ms. Moser suggested to Ms. Elio, she meant one in each hand.

Then came anger.

“Why me?” she remembers thinking, in a refrain she found hard to shake in the coming months. “I’m the good one. It’s not like I’m sick because I have emphysema from smoking or I did something dangerous.”

The gene that will kill Ms. Moser sits on the short arm of everyone’s fourth chromosome, where the letters of the genetic alphabet normally repeat C-A-G as many as 35 times in a row. In people who develop Huntington’s, however, there are more than 35 repeats.

No one quite knows why this DNA hiccup causes cell death in the brain, leading Huntington’s patients to jerk and twitch uncontrollably and rendering them progressively unable to walk, talk, think and swallow. But the greater the number of repeats, the earlier symptoms tend to appear and the faster they progress.

Ms. Moser’s “CAG number” was 45, the counselor said. She had more repeats than her grandfather, whose first symptoms — loss of short-term memory, mood swings and a constant ticking noise he made with his mouth — surfaced when he turned 50. But it was another year before Ms. Moser would realize that she could have less than 12 years until she showed symptoms.

Immediately after getting her results, Ms. Moser was too busy making plans.

“I’m going to become super-strong and super-balanced,” she vowed over lunch with Ms. Elio, her straight brown hair pulled into a determined bun. “So when I start to lose it I’ll be a little closer to normal.”

In the tumultuous months that followed, Ms. Moser often found herself unable to remember what normal had once been. She forced herself to renounce the crush she had long nursed on a certain firefighter, sure that marriage was no longer an option for her. She threw herself into fund-raising in the hopes that someone would find a cure. Sometimes, she raged.

She never, she said, regretted being tested. But at night, crying herself to sleep in the dark of her lavender bedroom, she would go over and over it. She was the same, but she was also different. And there was nothing she could do.

A Lesson in Stigma

Ms. Moser grew up in Connecticut, part of a large Irish Catholic family. Like many families affected by Huntington’s, Ms. Moser’s regarded the disease as a curse, not to be mentioned even as it dominated their lives in the form of her grandfather’s writhing body and unpredictable rages.

Once, staying in Ms. Moser’s room on a visit, he broke her trundle bed with his violent, involuntary jerking. Another time, he came into the kitchen naked, his underpants on his head. When the children giggled, Ms. Moser’s mother defended her father: “If you don’t like it, get out of my house and go.”

But no one explained what had happened to their grandfather, Thomas Dowd, a former New York City police officer who once had dreams of retiring to Florida.

In 1990, Mr. Dowd’s older brother, living in a veteran’s hospital in an advanced stage of the disease, was strangled in his own restraints. But a year or so later, when Ms. Moser wanted to do her sixth-grade science project on Huntington’s, her mother recoiled.

“Why,” she demanded, “would you want to do it on this disease that is killing your grandfather?”

Ms. Moser was left to confirm for herself, through library books and a CD-ROM encyclopedia, that she and her brothers, her mother, her aunts, an uncle and cousins could all face the same fate.

Any child who has a parent with Huntington’s has a 50 percent chance of having inherited the gene that causes it, Ms. Moser learned.

Her mother, who asked not to be identified by name for fear of discrimination, had not always been so guarded. At one point, she drove around with a “Cure HD” sign in the window of her van. She told people that her father had “Woody Guthrie’s disease,” invoking the folk icon who died of Huntington’s in 1967.

But her efforts to raise awareness soon foundered. Huntington’s is a rare genetic disease, affecting about 30,000 people in the United States, with about 250,000 more at risk. Few people know what it is. Strangers assumed her father’s unsteady walk, a frequent early symptom, meant he was drunk.

“Nobody has compassion,” Ms. Moser’s mother concluded. “People look at you like you’re strange, and ‘What’s wrong with you?’ ”

Shortly after a simple DNA test became available for Huntington’s in 1993, one of Ms. Moser’s aunts tested positive. Another, driven to find out if her own medical problems were related to Huntington’s, tested negative. But when Ms. Moser announced as a teenager that she wanted to get tested one day, her mother insisted that she should not. If her daughter carried the gene, that meant she did, too. And she did not want to know.

“You don’t want to know stuff like that,” Ms. Moser’s mother said in an interview. “You want to enjoy life.”

Ms. Moser’s father, who met and married his wife six years before Ms. Moser’s grandfather received his Huntington’s diagnosis, said he had managed not to think much about her at-risk status.

“So she was at risk,” he said. “Everyone’s at risk for everything.”

The test, Ms. Moser remembers her mother suggesting, would cost thousands of dollars. Still, in college, Ms. Moser often trolled the Web for information about it. Mostly, she imagined how sweet it would be to know she did not have the gene. But increasingly she was haunted, too, by the suspicion that her mother did.

As awful as it was, she admitted to Ms. Elio, her freshman-year neighbor at Elizabethtown College in Pennsylvania, she almost hoped it was true. It would explain her mother’s strokes of meanness, her unpredictable flashes of anger.

Ms. Moser’s mother said she had never considered the conflicts with her daughter out of the ordinary. “All my friends who had daughters said that was all normal, and when she’s 25 she’ll be your best friend,” she said. “I was waiting for that to happen, but I guess it’s not happening.”

When Ms. Moser graduated in 2003 with a degree in occupational therapy, their relationship, never peaceful, was getting worse. She moved to Queens without giving her mother her new address.

Wanting to Know

Out of school, Ms. Moser soon spotted a listing for a job at Terence Cardinal Cooke Health Care Center, a nursing home on the Upper East Side of Manhattan. She knew it was meant for her.

Her grandfather had died there in 2002 after living for a decade at the home, one of only a handful in the country with a unit devoted entirely to Huntington’s.

“I hated visiting him growing up,” Ms. Moser said. “It was scary.”

Now, though, she was drawn to see the disease up close.

On breaks from her duties elsewhere, she visited her cousin James Dowd, the son of her grandfather’s brother who had come to live in the Huntington’s unit several years earlier. It was there, in a conversation with another staff member, that she learned she could be tested for only a few hundred dollars at the Columbia clinic across town. She scheduled an appointment for the next week.

The staff at Columbia urged Ms. Moser to consider the downside of genetic testing. Some people battle depression after they test positive. And the information, she was cautioned, could make it harder for her to get a job or health insurance.

But Ms. Moser bristled at the idea that she should have to remain ignorant about her genetic status to avoid discrimination. “I didn’t do anything wrong,” she said. “It’s not like telling people I’m a drug addict.”

She also recalls rejecting a counselor’s suggestion that she might have asked to be tested as a way of crying for help.

“I’m like, ‘No,’ ” Ms. Moser recalls replying. “ ‘I’ve come to be tested because I want to know.’ ”

No one routinely collects demographic information about who gets tested for Huntington’s. At the Huntington’s Disease Center at Columbia, staff members say they have seen few young people taking the test.

Ms. Moser is still part of a distinct minority. But some researchers say her attitude is increasingly common among young people who know they may develop Huntington’s.

More informed about the genetics of the disease than any previous generation, they are convinced that they would rather know how many healthy years they have left than wake up one day to find the illness upon them. They are confident that new reproductive technologies can allow them to have children without transmitting the disease and are eager to be first in line should a treatment become available.

“We’re seeing a shift,” said Dr. Michael Hayden, a professor of human genetics at the University of British Columbia in Vancouver who has been providing various tests for Huntington’s for 20 years. “Younger people are coming for testing now, people in their 20s and early 30s; before, that was very rare. I’ve counseled some of them. They feel it is part of their heritage and that it is possible to lead a life that’s not defined by this gene.”

Before the test, Ms. Moser made two lists of life goals. Under “if negative,” she wrote married, children and Ireland. Under “if positive” was exercise, vitamins and ballroom dancing. Balance, in that case, would be important. Opening a bed-and-breakfast, a goal since childhood, made both lists.

In the weeks before getting the test results, Ms. Moser gave Ms. Elio explicit instructions about acceptable responses. If she was negative, flowers were O.K. If positive, they were not. In either case, drinking was acceptable. Crying was not.

But it was Ms. Elio’s husband, Chris Elio, who first broached the subject of taking care of Ms. Moser, whom their young children called “my Katie,” as in “this is my mom, this is my dad, this is my Katie.” They should address it before the results were in, Mr. Elio told his wife, so that she would not feel, later, that they had done it out of a sense of obligation.

The next day, in an e-mail note that was unusually formal for friends who sent text messages constantly and watched “Desperate Housewives” while on the phone together, Ms. Elio told Ms. Moser that she and her husband wanted her to move in with them if she got sick. Ms. Moser set the note aside. She did not expect to need it.

‘It’s Too Hard to Look’

The results had come a week early, and Ms. Moser assured her friends that the “Sex and the City” trivia party she had planned for that night was still on. After all, she was not sick, not dying. And she had already made the dips.

“I’m the same person I’ve always been,” she insisted that night as her guests gamely dipped strawberries in her chocolate fountain. “It’s been in me from the beginning.”

But when she went to work the next day, she lingered outside the door of the occupational therapy gym, not wanting to face her colleagues. She avoided the Huntington’s floor entirely, choosing to attend to patients ailing of just about anything else. “It’s too hard to look at them,” she told her friends.

In those first months, Ms. Moser summoned all her strength to pretend that nothing cataclysmic had happened. At times, it seemed easy enough. In the mirror, the same green eyes looked back at her. She was still tall, a devoted Julia Roberts fan, a prolific baker.

She dropped the news of her genetic status into some conversations like small talk, but kept it from her family. She made light of her newfound fate, though often friends were not sure how to take the jokes.

“That’s my Huntington’s kicking in,” she told Rachel Markan, a co-worker, after knocking a patient’s folder on the floor.

Other times, Ms. Moser abruptly dropped any pretense of routine banter. On a trip to Florida, she and Ms. Elio saw a man in a wheelchair being tube-fed, a method often used to keep Huntington’s patients alive for years after they can no longer swallow.

“I don’t want a feeding tube,” she announced flatly.

In those early days, she calculated that she had at least until 50 before symptoms set in. That was enough time to open a bed-and-breakfast, if she acted fast. Enough time to repay $70,000 in student loans under her 30-year term.

Doing the math on the loans, though, could send her into a tailspin.

“I’ll be repaying them and then I’ll start getting sick,” she said. “I mean, there’s no time in there.”

Finding New Purpose

At the end of the summer, as the weather grew colder, Ms. Moser forced herself to return to the Huntington’s unit.

In each patient, she saw her future: the biophysicist slumped in his wheelchair, the refrigerator repairman inert in his bed, the onetime professional tennis player who floated through the common room, arms undulating in the startlingly graceful movements that had earned the disease its original name, “Huntington’s chorea,” from the Greek “to dance.”

Then there was her cousin Jimmy, who had wrapped papers for The New York Post for 19 years until suddenly he could no longer tie the knots. When she greeted him, his bright blue eyes darted to her face, then away. If he knew her, it was impossible to tell.

She did what she could for them. She customized their wheelchairs with padding to fit each one’s unique tics. She doled out special silverware, oversized or bent in just the right angles to prolong their ability to feed themselves.

Fending off despair, Ms. Moser was also filled with new purpose. Someone, somewhere, she told friends, had to find a cure.

It has been over a century since the disease was identified by George Huntington, a doctor in Amagansett, N.Y., and over a decade since researchers first found the gene responsible for it.

To raise money for research, Ms. Moser volunteered for walks and dinners and golf outings sponsored by the Huntington’s Disease Society of America. She organized a Hula-Hoop-a-thon on the roof of Cardinal Cooke, then a bowl-a-thon at the Port Authority. But at many of the events, attendance was sparse.

It is hard to get people to turn out for Huntington’s benefits, she learned from the society’s professional fund-raisers. Even families affected by the disease, the most obvious constituents, often will not help publicize events.

“They don’t want people to know they’re connected to Huntington’s,” Ms. Moser said, with a mix of anger and recognition. “It’s like in my family — it’s not a good thing.”

Her first session with a therapist brought a chilling glimpse of how the disorder is viewed even by some who know plenty about it. “She told me it was my moral and ethical obligation not to have children,” Ms. Moser told Ms. Elio by cellphone as soon as she left the office, her voice breaking.

In lulls between fund-raisers, Ms. Moser raced to educate her own world about Huntington’s. She added links about the disease to her MySpace page. She plastered her desk at work with “Cure HD” stickers and starred in a video about the Huntington’s unit for her union’s Web site.

Ms. Moser gave blood for one study and spoke into a microphone for researchers trying to detect subtle speech differences in people who have extra CAG repeats before more noticeable disease symptoms emerge.

When researchers found a way to cure mice bred to replicate features of the disease in humans, Ms. Moser sent the news to friends and acquaintances.

But it was hard to celebrate. “Thank God,” the joke went around on the Huntington’s National Youth Alliance e-mail list Ms. Moser subscribed to, “at least there won’t be any more poor mice wandering around with Huntington’s disease.”

In October, one of Ms. Moser’s aunts lost her balance while walking and broke her nose. It was the latest in a series of falls. “The cure needs to be soon for me,” Ms. Moser said. “Sooner for everybody else.”

A Confrontation in Court

In the waiting room of the Dutchess County family courthouse on a crisp morning in the fall of 2005, Ms. Moser approached her mother, who turned away.

“I need to tell her something important,” Ms. Moser told a family member who had accompanied her mother to the hearing.

He conveyed the message and brought one in return: Unless she was dying, her mother did not have anything to say to her.

That Ms. Moser had tested positive meant that her mother would develop Huntington’s, if she had not already. A year earlier, Ms. Moser’s mother had convinced a judge that her sister, Nora Maldonado, was neglecting her daughter. She was given guardianship of the daughter, 4-year-old Jillian.

Ms. Moser had been skeptical of her mother’s accusations that Ms. Maldonado was not feeding or bathing Jillian properly, and she wondered whether her effort to claim Jillian had been induced by the psychological symptoms of the disease.

Her testimony about her mother’s genetic status, Ms. Moser knew, could help persuade the judge to return Jillian. Ms. Maldonado had found out years earlier that she did not have the Huntington’s gene.

Ms. Moser did not believe that someone in the early stages of Huntington’s should automatically be disqualified from taking care of a child. But her own rocky childhood had convinced her that Jillian would be better off with Ms. Maldonado.

She told her aunt’s lawyer about her test results and agreed to testify.

In the courtroom, Ms. Moser took the witness stand. Her mother’s lawyer jumped up as soon as the topic of Huntington’s arose. It was irrelevant, he said. But by the time the judge had sustained his objections, Ms. Moser’s mother, stricken, had understood.

The next day, in the bathroom, Ms. Maldonado approached Ms. Moser’s mother.

“I’m sorry,” she said. Ms. Moser’s mother said nothing.

The court has continued to let Ms. Moser’s mother retain guardianship of Jillian. But she has not spoken to her daughter again.

“It’s a horrible illness,” Ms. Moser’s mother said, months later, gesturing to her husband. “Now he has a wife who has it. Did she think of him? Did she think of me? Who’s going to marry her?”

Facing the Future

Before the test, it was as if Ms. Moser had been balanced between parallel universes, one in which she would never get the disease and one in which she would. The test had made her whole.

She began to prepare the Elio children and Jillian for her illness, determined that they would not be scared, as she had been with her grandfather. When Jillian wanted to know how people got Huntington’s disease “in their pants,” Ms. Moser wrote the text of a children’s book that explained what these other kinds of “genes” were and why they would make her sick.

But over the winter, Ms. Elio complained gently that her friend had become “Ms. H.D.” And an impromptu note that arrived for the children in the early spring convinced her that Ms. Moser was dwelling too much on her own death.

“You all make me so happy, and I am so proud of who you are and who you will be,” read the note, on rainbow scratch-and-write paper. “I will always remember the fun things we do together.”

Taking matters into her own hands, Ms. Elio created a profile for Ms. Moser on an online dating service. Ms. Moser was skeptical but supplied a picture. Dating, she said, was the worst thing about knowing she had the Huntington’s gene. It was hard to imagine someone falling enough in love with her to take on Huntington’s knowingly, or asking it of someone she loved. At the same time, she said, knowing her status could help her find the right person, if he was out there.

“Either way, I was going to get sick,” she said. “And I’d want someone who could handle it. If, by some twist of fate, I do get married and have children, at least we know what we’re getting into.”

After much debate, the friends settled on the third date as the right time to mention Huntington’s. But when the first date came, Ms. Moser wished she could just blurt it out.

“It kind of just lingers there,” she said. “I really just want to be able to tell people, ‘Someday, I’m going to have Huntington’s disease.’ ”

‘A Part of My Life’

Last May 6, a year to the day after she had received her test results, the subject line “CAG Count” caught Ms. Moser’s attention as she was scrolling through the online discussion forums of the Huntington’s Disease Advocacy Center. She knew she had 45 CAG repeats, but she had never investigated it further.

She clicked on the message.

“My mother’s CAG was 43,” it read. “She started forgetting the punch line to jokes at 39/40.” Another woman whose husband’s CAG count was 47 had just sold his car. “He’s 39 years old,” she wrote. “It was time for him to quit driving.”

Quickly, Ms. Moser scanned a chart that accompanied the messages for her number, 45. The median age of onset to which it corresponded was 37.

Ms. Elio got drunk with her husband the night Ms. Moser finally told her.

“That’s 12 years away,” Ms. Moser said.

The statistic, they knew, meant that half of those with her CAG number started showing symptoms after age 37. But it also meant that the other half started showing symptoms earlier.

Ms. Moser, meanwhile, flew to the annual convention of the Huntington’s Disease Society, which she had decided at the last minute to attend.

“Mother or father?” one woman, 23, from Chicago, asked a few minutes after meeting Ms. Moser in the elevator of the Milwaukee Hilton. “Have you tested? What’s your CAG?”

She was close to getting herself tested, the woman confided. How did it feel to know?

“It’s hard to think the other way anymore of not knowing,” Ms. Moser replied. “It’s become a part of my life.”

After years of trying to wring conversation from her family about Huntington’s, Ms. Moser suddenly found herself bathing in it. But for the first time in a long time, her mind was on other things. At a youth support group meeting in the hotel hallway, she took her place in the misshapen circle. Later, on the dance floor, the spasms of the symptomatic seemed as natural as the gyrations of the normal.

“I’m not alone in this,” Ms. Moser remembers thinking. “This affects other people, too, and we all just have to live our lives.”

Seizing the Day

July 15, the day of Ms. Moser’s 25th birthday party, was sunny, with a hint of moisture in the air. At her aunt’s house in Long Beach, N.Y., Ms. Moser wore a dress with pictures of cocktails on it. It was, she and Ms. Elio told anyone who would listen, her “cocktail dress.” They drew the quotation marks in the air.

A bowl of “Cure HD” pins sat on the table. Over burgers from the barbecue, Ms. Moser mentioned to family members from her father’s side that she had tested positive for the Huntington’s gene.

“What’s that?” one cousin asked.

“It will affect my ability to walk, talk and think,” Ms. Moser said. “Sometime before I’m 50.”

“That’s soon,” an uncle said matter-of-factly.

“So do you have to take medication?” her cousin asked.

“There’s nothing really to take,” Ms. Moser said.

She and the Elios put on bathing suits, loaded the children in a wagon and walked to the beach.

More than anything now, Ms. Moser said, she is filled with a sense of urgency.

“I have a lot to do,” she said. “And I don’t have a lot of time.”

Over the next months, Ms. Moser took tennis lessons every Sunday morning and went to church in the evening.

When a planned vacation with the Elio family fell through at the last minute, she went anyway, packing Disney World, Universal Studios, Wet ’n Wild and Sea World into 36 hours with a high school friend who lives in Orlando. She was honored at a dinner by the New York chapter of the Huntington’s society for her outreach efforts and managed a brief thank-you speech despite her discomfort with public speaking.

Having made a New Year’s resolution to learn to ride a unicycle, she bought a used one. “My legs are tired, my arms are tired, and I definitely need protection,” she reported to Ms. Elio. On Super Bowl Sunday, she waded into the freezing Atlantic Ocean for a Polar Bear swim to raise money for the Make-a-Wish Foundation.

Ms. Elio complained that she hardly got to see her friend. But one recent weekend, they packed up the Elio children and drove to the house the Elios were renovating in eastern Pennsylvania. The kitchen floor needed grouting, and, rejecting the home improvement gospel that calls for a special tool designed for the purpose, Ms. Moser and Ms. Elio had decided to use pastry bags.

As they turned into the driveway, Ms. Moser studied the semi-attached house next door. Maybe she would move in one day, as the Elios had proposed. Then, when she could no longer care for herself, they could put in a door.

First, though, she wanted to travel. She had heard of a job that would place her in different occupational therapy positions across the country every few months and was planning to apply.

“I’m thinking Hawaii first,” she said.

Then they donned gloves, mixed grout in a large bucket of water and began the job.

    Facing Life With a Lethal Gene, NYT, 18.3.2007, http://www.nytimes.com/2007/03/18/health/18huntington.html

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