Grasping for Clues to The Biology of Itch

Greg Miller

Chronic itch afflicts millions of people, but little is known about the underlying mechanisms

For most people, itch is an occasional, short-lived annoyance, provoked by a run-in with bloodthirsty insects or poisonous plants. But for Mary Ellen Nilsen, itchiness became a life-altering experience. In 1998, at age 38, Nilsen had a shingles outbreak, a resurgence of the chickenpox virus. Antiviral drugs cleared up the painful shingles rash on her face and scalp, but a ferocious itch took its place. "It was relentless," Nilsen says. Over a 13-month period, Nilsen scratched and scratched, despite her best efforts not to and despite her horror at the growing lesions she saw in the mirror. At the time, Nilsen says, she had no idea that the damage she was doing to herself was more than skin deep, but she ended up in a Boston emergency room with brain tissue protruding through a hole she'd scratched in her skull.

"She gave herself frontal-lobe brain damage," says Anne Louise Oaklander, a neuroscientist and neurologist at Harvard Medical School in Boston, who treated Nilsen and described her case at a recent meeting^* here. Oaklander blames the infuriating itch on severe nerve damage caused by the virus--damage that also left Nilsen unable to feel pain from her scratching-induced wounds. Although Nilsen's experience is extreme, to say the least, chronic itch is far from rare. Millions of people worldwide suffer from incessant and largely unexplained itchiness brought on by kidney or liver disease, HIV, or various other ailments. Chronic itch disrupts sleep, reduces the quality of life, and undermines the health of those who suffer from it--yet there is little doctors can do to help.

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A Knockout Award in Medicine

Gretchen Vogel
The one-two research punch that allowed the creation of designer mice has earned the 2007 Nobel Prize in Physiology or Medicine. Mario Capecchi, a Howard Hughes Medical Institute investigator at the University of Utah in Salt Lake City, Oliver Smithies of the University of North Carolina, Chapel Hill, and Martin Evans of Cardiff University, U.K., will share the prize for developing the techniques to make knockout mice, animals that lack a specific gene or genes. Such mice have allowed scientists to learn the roles of thousands of mammalian genes and provided laboratory models of human afflictions in which to test potential therapies.

Against the odds. Pursuing ideas that others said would never work, the three researchers who share this year's Nobel Prize in physiology or medicine set the stage for the creation of designer mouse strains in which specific genes are altered or disabled.

The techniques "truly provided a revolution in mammalian biology," says Raju Kucherlapati, a geneticist at Harvard University. "It is not an exaggeration to say that there is no mammalian biologist today who does not use these tools in one way or another."

Biologists have long studied mutant mice for insights into the mammalian body. But for decades, they were limited to rodents whose DNA had been disrupted in random places by natural mutations or the application of mutagenic chemicals. In fact, most of the time, biologists studying a mutant mouse strain didn't even know which gene was broken. The ability to mutate a specific gene at will seemed a distant dream.

Working independently in the 1980s, however, Capecchi and Smithies each crafted ways to slip foreign DNA into a specific place in the chromosomes of mammalian cells. A similar strategy, exploiting a natural DNA-swapping process called homologous recombination, had been used to alter genes in yeast and other organisms, but most people assumed it wouldn't work in mammals. Indeed, in the early 1980s, Capecchi's grant application was rejected by the National Institutes of Health in Bethesda, Maryland, with the advice that he should forget the idea.

He persevered, using money cobbled together from other projects. And a few years later, both he and Smithies, then working at the University of Wisconsin, Madison, showed that targeting specific genes in mammalian cells via homologous recombination was indeed possible. But the work was in cells in culture dishes, and the technique seemed far too inefficient to be used to make whole animals with genetic alterations.

Enter Martin Evans, then at the University of Cambridge, U.K. He led a group that in 1981 reported growing embryonic stem (ES) cells from mouse embryos. Evans, too, had faced skepticism. Experts had doubted whether such cells, which can become any cell in the body, could be grown in the lab. Even Evans was confused when he first saw the cells in culture, says Elizabeth Robertson of the University of Oxford, U.K., who was a postdoc in the lab. "He came to us and said, 'Someone contaminated my media!' " because there were strange-looking cells growing in it. Lab members had to convince him that the cells were ES cells, she says.

A few years later, Evans and his colleagues showed that they could produce live mice by injecting cultured ES cells into a developing embryo. The result is a chimera, an animal whose tissues are a mix of the ES cells and those from the host embryo. In many of those chimeras, the added ES cells by chance produce the animal's sperm or eggs, and when these chimeras mate, some of their offspring carry the stem cells' genes in all their tissues.

Capecchi and Smithies both quickly saw that ES cells offered an opportunity to generate live animals with a desired mutation in every cell. Researchers could target genes in ES cells and then sort out the cells that carried the desired modification, using them to create chimeras. Some of the chimeras' offspring would have the altered gene in all their tissues, and by breeding these animals together, biologists could create mice that completely lack the two working copies of a given gene. Although they never formally collaborated, Evans "brought the ES cells to my lab in his own pocket," Smithies says, while Capecchi spent time in Evans's lab learning the technology.

Every biologist soon wanted a favorite gene punched out, and a handful of companies quickly began competing with places such as the Jackson Laboratory in Bar Harbor, Maine, to provide knockout strains to drug companies and academic labs. To date, researchers have knocked out at least 11,000 genes in mice, observing what goes wrong in development or adulthood and thereby gaining a sense of what the gene does. By deactivating specific genes this way, for example, Capecchi and his colleagues went on to identify ones that shape limbs, organs, and the overall mammalian body plan. Both Smithies and Evans developed mice lacking the cystic fibrosis gene, one of many knockout mouse strains created to mimic a human illness. Indeed, there is now a worldwide effort to knock out every mouse gene (Science, 30 June 2006, p. 1862).

Skeptical grant reviewers were not the only hurdle Capecchi overcame on his way to scientific stardom. As a child in war-torn Italy, he survived alone--often begging and stealing on the streets--between the ages of 4 and 9 while his mother, a poet, was imprisoned in the Dachau concentration camp for her anti-Fascist writings. After the war, she tracked down a very malnourished Mario in a hospital, and a few days later they were on a boat to the United States to live with her brother in Pennsylvania. The young Mario expected the streets to be literally paved with gold, he told a press conference in Salt Lake City on the day he won the prize. What he found instead, Capecchi says, "was opportunity."

Evolutionary genetics: Making the most of redundancy

Edward J. Louis¹

Single genes, chromosomal regions and even entire genomes can undergo duplication. What good can come of these extra copies? Evolution seems to use several tricks to take advantage of the situation.

Gene mutations often result in abnormal levels or function of their protein products. Consequently, the divergence rate of DNA sequences that encode genes is generally slower than that for non-coding sequences. So how does new genetic material arise? One valuable source is sequences formed through gene and genome duplication events.

The commonest consequence of genomic duplication seems to be the loss of all or part of duplicated sequences through deletion¹ or degeneration², causing non-functionality. This can be a powerful evolutionary force — for example, gene loss in response to whole-genome duplication led to rapid speciation in yeast³. Alternatively, although it is much less-well understood, one or both of the duplicated sequences might acquire new functions, as they are under less selective pressure, and can afford to undergo mutations that would lead to new characteristics and functions. On page 677 of this issue, Hittinger and Carroll⁴ analyse one such pair of duplicated genes with divergent functions.

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Cancer: Micromanagement of metastasis

Patricia S. Steeg¹

Although they were discovered only in the early 1990s, many regulatory functions of microRNAs — naturally occurring short RNA sequences — have already been reported. The latest news is that they mediate cancer spread.

To successfully spread, or metastasize, a tumour cell must complete a complex set of processes, including invasion, survival and arrest in the circulatory system, and colonization of foreign organs¹. How are these events regulated? In a paper published in this issue (page 682), Ma et al.² propose that microRNAs (miRNAs), which regulate levels of messenger RNAs (mRNAs), coordinate some of the intricate gene-expression programmes implicated in cancer metastasis.

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Doctors not to blame over HIV infection by tainted blood

Canadian court acquits medics accused of negligence.

Meredith Wadman

A Canadian court has acquitted four doctors and a US blood products company of criminal negligence in the case of four haemophiliacs who were infected with HIV after receiving transfusions of tainted blood in the 1980s.

After a five-year police investigation and a lengthy trial that involved more than 100 witnesses and 1,000 exhibits, Judge Mary Lou Benotto of the Ontario Superior Court of Justice in Toronto effectively said that the doctors and the company were not only acquitted but fully exonerated.

“The allegations of criminal conduct on the part of these men and this corporation were not only unsupported by the evidence, they were disproved,” Benotto wrote in her 1 October decision. “The events here were tragic. However, to assign blame where none exists is to compound the tragedy.”

The case is the latest of numerous global investigations into the circumstances in which thousands of patients were given infected blood even after it became known, in autumn 1984, that heat treatment killed HIV in blood products. More than 1,000 Canadians, about 700 of them with haemophilia, were infected by HIV from transfusions, almost all of them before mid-1985.

The Canadian court case addressed the infection of 4 people in British Columbia and Alberta in 1986 and 1987. They received an HIV-infected blood-clotting product made by Armour Pharmaceutical, then a maker of blood products based in New Jersey.

The now-elderly doctors charged were Roger Perrault, then the national director of the Canadian Red Cross blood transfusion service; John Furesz, then director of Health Canada's Bureau of Biologics (BDB); Wark Boucher, who headed the BDB's blood product division; and Michael Rodell, then a vice-president of Armour Pharmaceutical.

The Canadian Hemophilia Society said it was “surprised and disappointed” by the outcome. “This verdict sends the wrong message to those responsible for the health of the public,” Pam Wilton, its president, said in statement.

But David Scott, an Ottawa lawyer who defended Furesz, said: “These charges were undoubtedly politically motivated. If those in charge of the criminal process succumb to political pressure to lay criminal charges in inappropriate cases, they will unwittingly undermine the public confidence in the administration of justice.”

Lawyers for the Crown didn't say whether they plan to appeal within the 30-day time frame allowed. “I cannot imagine them doing so,” says Edward Greenspan, the Toronto lawyer who represented Perrault. “But then again I couldn't imagine them spending 17 months in a court of law proving nothing.”

Kill king corn

Biofuels need new technology, new agronomy and new politics if they are not to do more harm than good.

Zea mays has become the very emblem of plenty, with rich golden cobs of corn (maize) overspilling from some of the most effectively farmed arable lands on the planet. Jatropha curcas, on the other hand, is an unprepossessing and indeed toxic plant, better suited to scrubland and hedges. Yet in the world of biofuels, ugly-duckling jatropha has the potential to be, if not a hero, then at least one of the good guys, and a harbinger of better things to come. The golden-headed siren corn, on the other hand, is inspiring a wrong-headed gold-rush — to a dead-end of development that is polluting the modest aspirations the world might have for biofuels in general.

The common complaints about biofuels — and they seem to become more common by the day — are that they are expensive and ineffective at reducing fossil-fuel consumption, that they intensify farming needlessly, that they dress up discredited farm subsidies in new green clothes, and that they push up the price of food. All these things are true to some extent of corn-based ethanol, America's biofuel of choice, and many are also true of Europe's favoured biodiesel plans.

As far as the greenhouse goes, figures from the International Institute for Sustainable Development's Global Subsidies Initiative put the cost of averting carbon dioxide emissions by using corn-based ethanol at more than $500 a tonne of carbon dioxide. What's more, the heavy use of nitrogen fertilizer in growing corn leads to significant emissions of nitrous oxide, an even more potent greenhouse gas.

Despite this, the generous tax allowance of 51 cents a gallon given to ethanol blenders in the United States has made corn peculiarly profitable (provided that tariffs continue to keep out far more efficiently produced ethanol from the sugar plantations of Brazil). In a recent article in Foreign Affairs, C. Ford Runge and Benjamin Senauer of the University of Minnesota in Minneapolis point to estimates that this artificial price-hike will drive world corn prices up by 20% by 2010. This has a knock-on effect on other staple crops — more land for corn means less for wheat, for example. Higher prices are good news for farmers, including some of those in developed countries. But they can be bad news for the very poor, who spend a disproportionate amount of their income on food. According to World Bank studies, for the poorest people in the world a 1% increase in the price of staple food leads to a 0.5% drop in caloric consumption.

This sorry state of affairs has the small benefit of providing a stark, contrasting background against which to sketch out what a successful and sustainable biofuels industry might look like. It will be based not on digestible starch from staple crops such as corn or cassava, but for the most part on indigestible cellulose, with some room for biodiesels that, because they grow on marginal land, do not compete with food production. In the medium to long term, it will not seek to produce ethanol — a poor fuel — but a range of more complex fuels delivered by carefully designed microbes.

A successful biofuels industry will not be based on digestible starch from staple crops such as corn.

A rosy biofuels future will enjoy the benefits of free trade, allowing the countries and peoples of the tropics to ship some of their abundant sunlight north in the form of fuel. It will also require serious amounts of agronomic research — as we report on page 652, one of the most significant problems with jatropha is that, as yet, remarkably little is known about how best to grow and improve it. One focus of such research must be in the development of plants, such as jatropha, that make do on little water, and those that require low inputs of nitrogen. This is inherently more feasible in the case of fuels, where all that needs to be taken out of the system are carbon and hydrogen, than in the case of food, where there is a need to export nitrogen in the form of protein as well. Another focus will be on systems that actively store carbon in the soil, improving it for future agricultural use and at the same time doing a little bit more to take the edge off the carbon/climate crisis.

Biofuels are unlikely ever to be more than bit-players in the great task of weaning civilization from Earth's coal-mine and oil-well teats. But they may yet have valuable niches — including some that allow them to serve some of the world's poor, both as fuels for their own use and as exports. Provided, that is, that someone kills king corn.

Of Attraction and Rejection — Asthma and the Microbial World

n the first half of the past century, it was thought that asthma was precipitated or prolonged by infection and that infection with several bacteria, including Streptococcus pneumoniae and Haemophilus influenzae, had a role in asthma.¹ Some investigators had suggested that bacterial allergy or chronic focal infection could be a cause of asthma.² More recently, population-based studies relating infections with Chlamydia pneumoniae and Mycoplasma pneumoniae to asthma severity encouraged a resurgent debate, but clinical trials involving various antibiotics failed to demonstrate sustained clinical benefit.¹

In this issue of the Journal, Bisgaard and colleagues⁷ propose an alternative explanation; that is, that bacterial colonization of the airways may induce neutrophilic inflammation in the airways and thereby cause asthma. In their prospective study, in which they followed children at risk of asthma from birth to age 5 years, detection of S. pneumoniae, H. influenzae, Moraxella catarrhalis, or a combination of these organisms in aspirates of the hypopharyngeal region at 4 weeks of age was a significant predictor of asthma, reversible airway obstruction, blood eosinophil concentration, and total IgE at age 5 years.

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Pluripotency Redux — Advances in Stem-Cell Research

A cell's ability to give to rise to all the cell types of the embryo and the adult organism is called pluripotency. Pluripotent cells are found within mammalian blastocysts and persist briefly in embryos after implantation. Embryonic stem cells, derived from the inner cell mass of blastocysts, are a renewable source of pluripotent stem cells that are proving valuable in basic science studies and may eventually become a source of cells for safe, effective cell-based therapies. Much embryonic stem-cell research has focused on determining the molecular signature of pluripotency, and a picture is emerging of a complex interaction among transcription factor networks, signaling pathways, and epigenetic processes involving modifications in the structure of DNA, histones, and chromatin.

Deciphering the molecular basis of pluripotency will facilitate the development of procedures for efficiently deriving patient-specific stem cells. In somatic-cell nuclear transfer, which has held the greatest promise for generating such cell lines, the nucleus of a somatic cell is introduced into an enucleated oocyte or mitotic zygote and is "reprogrammed" to an embryonic state, resulting in the formation of a blastocyst from which embryonic stem cells can be derived. Although this procedure has been demonstrated in animals, it has yet to be accomplished with human oocytes or zygotes. An alternative approach to reprogramming a somatic cell is to fuse it with an embryonic stem cell, but the resulting hybrid pluripotent cell is tetraploid and of limited practical application.

Against this background, a study published last year by Takahashi and Yamanaka¹ surprised and excited stem-cell biologists. Using a novel strategy, the investigators showed that fibroblasts derived from tissues of adult and fetal mice could be induced to become embryonic-stem-cell–like cells with the introduction of four genes expressing transcription factors. Twenty-four genes were initially chosen as candidates on the basis of their preferential expression in embryonic stem cells or their known roles in the maintenance of such cells or in cell-cycle regulation. These genes were introduced into fibroblasts isolated from mouse embryos and adult tail tips in a combinatorial manner through retroviral transduction.

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Governo limita tratamento de hepatite na rede pública

Pela nova regra, a fibrose deve ter nível acima de 2

ANGELA PINHO
DA SUCURSAL DE BRASÍLIA

O Ministério da Saúde publicou ontem no "Diário Oficial" da União uma resolução que restringe a abrangência do tratamento para a hepatite C crônica na rede pública.
Pela nova regra, terão direito a tratamento pacientes com fibrose a partir do nível dois, em uma escala de degeneração do fígado de um a cinco, sendo cinco a mais grave. A resolução de 2002, que estava em vigor antes, previa que teriam acesso a tratamento pacientes com fibrose a partir do grau um.
No entanto a restrição não vale para as pessoas que, além de hepatite C, são portadoras do vírus HIV. "O governo quer esperar as pessoas piorarem para dar tratamento", disse Carlos Varaldo, coordenador do Grupo Otimismo de Apoio ao Portador de Hepatite, que reúne portadores da doença. Ele disse ver motivos econômicos na decisão.
A coordenadora do Programa Nacional de Hepatites Virais do Ministério da Saúde, Gerusa Figueiredo, negou. Segundo ela, a restrição, que já seria feita na Europa e nos EUA, é motivada pela quantidade de efeitos colaterais dos medicamentos e pelo índice de eficácia deles ser menor do que 80%.
Ela afirma que, como há novas drogas sendo testadas, pessoas com grau um poderiam utilizá-las dentro de três anos com menos efeitos colaterais. De acordo com a coordenadora, havia um erro de redação na regra de 2002. O texto mencionava que teriam direito a tratamento pessoas com grau de fibrose de moderada a grave, o que, segundo ela, corresponde à faixa do grau dois em diante.
Para Juvêncio Furtado, da diretoria da Sociedade Brasileira de Infectologia, a passagem do grau um para o grau dois leva, em média, cinco anos. Por isso, ele diz que há casos em que é melhor adiar os efeitos colaterais. Mas ressalta: "Aos 60, 65, talvez seja melhor tratar, pois pode ser a única chance".

Ceará intensifica combate à leishmaniose após 15 mortes

Doença contaminou 254 pessoas desde janeiro; meta era erradicar os casos no Estado ainda em 2007

Lauriberto Braga, FORTALEZA

Quinze pessoas morreram e outras 254 contraíram leishmaniose visceral - popularmente conhecida como calazar - neste ano no Ceará. Os números preocupam as autoridades de saúde do Estado porque a meta para este ano era erradicar a doença. Por isso, o combate à leishmaniose será intensificado a partir de hoje. Duzentos médicos, enfermeiros, veterinários, mobilizadores sociais e agentes de endemias de dez municípios serão preparados para fazer o diagnóstico e tratamento.

No ano passado, 32 pessoas morreram com a doença. De 1986 a 2006 - período de grande incidência da doença, considerada como uma das principais endemias do mundo -, foram registrados 137 óbitos no Ceará.

Segundo orientação do Ministério da Saúde, os municípios cearenses foram divididos em três níveis de risco de transmissão: intensa, moderada ou esporádica sem transmissão. A separação baseou-se na média de casos de 2002 a 2006. As cidades com transmissão intensa são Caucaia, Barbalha, Bela Cruz, Canindé, Crateús, Crato, Fortaleza, Granja, Ipu, Juazeiro do Norte, Maracanaú, Mauriti, Novas Russas, Sobral e Viçosa do Ceará.

Em Caucaia, situada na região metropolitana de Fortaleza, o combate a esse tipo de leishmaniose utiliza as campanhas de vacinação anti-rábica pdetectar a quantidade de animais doentes. Na cidade são feitos também exames de sorologia. Em duas campanhas, foram examinados 40 mil animais, sendo que 767 deles tiveram de ser sacrificados.

O foco da doença é o mosquito Lutzomyia longipalpis, o único responsável pela transmissão do protozoário leishmânia tanto do cão para o homem como do homem para o cão. Outros animais também podem ser contaminados pela doença, como raposas, gambás e roedores.

O aumento do número de mortes no Ceará está relacionado à dificuldade de se estabelecer o diagnóstico precoce, imprescindível para o início do tratamento. Sintomas como febre, inchaço no baço e no fígado, emagrecimento e apatia são semelhantes aos da dengue.

Ao picar um animal ou homem com leishmaniose visceral, o mosquito transmissor - também conhecido como mosquito-palha, birigüi, barigüi, bererê e tatuquira - contribui para o ciclo de proliferação da leishmânia, passando a doença por meio de outras picadas. Entre as medidas indicadas para o combate do mosquito estão: manter os quintais, estábulos e galinheiros limpos, livres de fezes, folhas e frutas em decomposição; recolher o lixo e garantir sua adequada coleta; e manter os cães bem tratados, vacinados e dentro de casa.

3 Win Nobel in Medicine for Gene Manipulation

NEW YORK (AP) -- As a child in Italy during World War II, he lived for years on the streets and in orphanages. Six decades later, as a scientist in the United States, Mario Capecchi joined two other researchers in winning the Nobel Prize in medicine.

Their work led to a powerful and widely used technique to manipulate genes in mice, which has helped scientists study heart disease, diabetes, cancer, cystic fibrosis and other diseases.

The $1.54 million prize was awarded Monday to Capecchi, 70, of the University of Utah in Salt Lake City; Oliver Smithies, 82, a native of Britain now at University of North Carolina in Chapel Hill, and Sir Martin J. Evans, 66, of Cardiff University in Wales.

Their ''gene-targeting'' technique lets scientists deactivate or modifying individual genes in mice and observe how those changes affect the animals. That in turn gives clues about what those genes do in human health and disease.

The work has had ''a revolutionary effect on the ability to understand how genes work,'' said Richard Woychik, director of The Jackson Laboratory in Bar Harbor, Maine, a center for mouse genetics.

The prize is a particularly striking accomplishment for Capecchi (pronounced kuh-PEK'-ee). A native of Italy, he was separated from his mother, a poet, at age 3 when the Gestapo took her to the Dachau concentration camp as a political prisoner in 1941. He spent a year with a peasant family, until the money she'd left for his care ran out.

At age 4, ''I started wandering the streets,'' he recalled Monday. For about four years, he lived on the streets or in orphanages, and he ended up in a hospital with malnutrition.

Dachau was liberated in 1945 and his mother survived.

''Then she set out to find me,'' searching through hospital records. ''I was in a hospital and when they keep you in a hospital, they didn't want you to run around. They took your clothes away. She came and bought me an outfit.''

She showed up on Capecchi's 9th birthday. Soon thereafter, ''we were on a boat to America ... I literally expected roads to be paved with gold. What I found was, it was a land of opportunity,'' he said.

In the United States, he went to school for the first time, starting in third grade despite not knowing English.

The three prize-winning scientists mostly worked separately, although they exchanged information about their research. Evans identified embryonic stem cells in mice, while the gene-targeting technique used on those cells came from work by Capecchi and Smithies.

Capecchi's work has uncovered the roles of genes involved in organ development in mammals, the committee said. Evans developed strains of gene-altered mice to study cystic fibrosis, and Smithies created strains to study such conditions as high blood pressure and heart disease.

To create gene-altered mice, researchers introduce a genetic change into mouse embryonic stem cells. These cells are then injected into mouse embryos. The mice born from these embryos are bred to produce offspring with the changed genes.

In 1989, the first mice born with genes manipulated through the technique was announced. More than 10,000 different genes in mice have since been studied this way, the Nobel committee said. That's about half the genes the rodents have.

Apart from making mice with altered DNA, the work has also shown how to manipulate genes in human embryonic stem cells for lab research. Such basic studies can help scientists learn how to turn the cells into specialized cells that might prove useful in therapy, said Doug Melton, director of the Harvard Stem Cell Institute.

And scientists hope that by putting disease-related genes into human embryonic cells for lab studies, they can learn how the diseases develop and screen potential therapies, said John Gearhart, a stem cell expert at the Johns Hopkins School of Medicine.

The prize-winning work has ''formed the foundation for much of what we do'' in human embryonic stem cell research, Melton said.

Evans, asked Monday about the prize while visiting his daughter in Cambridge, England, said, ''I haven't come to terms with it yet. In many ways it is the boyhood aspiration of science, isn't it? And here I am unexpectedly with it. It's amazing.''

Moments after a 5 a.m. call from Sweden, Smithies called the Nobel ''very gratifying.''

''My work was never toward getting the Nobel Prize,'' Smithies told The Associated Press over a cup of tea at his lab a few hours after the Nobel committee called with the news. ''It was solving a problem, and enjoying the solution.''

Smithies said he hopes winning the prize will make it easier to secure funding for other work.

The medicine prize was the first of the six prestigious awards to be announced this year. The others are chemistry, physics, literature, peace and economics.

The prizes are handed out every year on Dec. 10, the anniversary of award founder Alfred Nobel's death in 1896.

Since the medicine prize was first awarded in 1901, 90 Americans and 29 Britons have received it.