S T E M C E L L S

Therapeutic Cloning Reaches MilestoneLast week stem cell researchers finally reached a goal that has eluded them through more than a decade of setbacks and scandal. Two teams have independently derived human embryonic stem cells by cloning adult skin cells. The promise of the technique remains tantalizing: replacement tissues for treat­ing diseases from diabetes to Parkinson’s, matched to the patient whose cells gave rise to them. But the practical, ethical, and legal hurdles are as high as ever. The method will also have to prove its worth against a strong competitor: a way to make personalized stem cells that doesn’t involve embryos.

The cloning technique, called somatic cell nuclear transfer (SCNT; see diagram), gained fame with the cloning ofDolly the sheep 18 years ago. Scientists soon learned to use SCNT to clone cattle, mice, dogs, and other animals. Researchers eagerly set out to clone human cells—not to replicate humans, which most scientists strongly oppose, but to generate early human embryos from which stem cells could be harvested. Although a decade ago a South Korean scientist fraudulently claimed success, human cells proved resistant to cloning.

A year ago, Shoukhrat Mitalipov and his colleagues at the Oregon National Primate Research Center in Beaverton finally used SCNT to produce stem cell lines from the DNA of human fetal and infant cells (Science, 17 May 2013, p. 795). But it wasn’t clear whether the team ’s tricks would work with cells from human adults.

On 17 April, Dong Ryul Lee and Young Gie Chung of CHA University in Seoul and their colleagues settled that question, reporting in Cell Stem Cell the creation of embryonic stem (ES) cell lines from skin cells of two men, one 35 years old and one 75 years old. And on 28 April online in Nature, Dieter Egli of the New York Stem Cell Foundation (NYSCF) Research Institute in New York City and his colleagues describe going a step further, making ES cells from a 32-year-old woman who has type 1 diabetes. They then prompted the ES cells to become insulin-producing cells, which are missing in people with the disease.

Egli says that he and his colleagues have put the insulin-producing cells into mice, where they produced the hormone in response to blood glucose levels. (That work is still unpublished.) “We are now one step closer to being able to treat diabetic patients with their own insulin-producing cells,” he says.

Whether such personalized replacement cells would help, especially in the long run, remains uncertain, however. They would likely fall prey to the same autoimmune attack that killed a person’s original insulin makers, other scientists caution. Obtaining the human oocytes needed to treat the millions with

DNA removed from unfertilized oocyte

Long-awaited. Scientists have used somatic cell nuclear transfer to produce embryonic stem cells from a type 1 diabetes patient.

They then differentiated the stem cells into insulin-

producing cells.

Skin cells from type 1 diabetes patient

Differentiation into insulin-producing pancreatic cells Embryonic stem cell lines

Proof of principle. Human embryonic stem cells derived from a type 1 diabetes patient.

type 1 diabetes via SCNT would also pose a major obstacle. Because extracting eggs from women causes discomfort and poses health risks, both groups paid the standard rate that egg donors for in vitro fertilization procedures receive—in the United States, up to $10,000. Given fair compensation, many women are willing to donate oocytes, Egli maintains. But spurred by ethical worries about undue pressure on women, many organizations and governments prohibit paying egg donors. That includes the California Institute for Regenerative Medicine, a major funder of stem cell research, which put these cells off- limits for its many grantees. Susan Solomon, co-founder and CEO of the privately funded NYSCF that funded Egli’s work, predicts that if the technique proves useful to create

effective therapies, friends or relatives of someone sick will be willing to donate oocytes.

Although early attempts at human SCNT used hundreds of oocytes, Egli says his team’s method is now efficient enough to derive a stem cell line from a single egg donation cycle, which usually produces between 15 and 20 oocytes. All three groups found that efficiency seems to depend heavily on the quality of the eggs used, with those from younger donors superior to those from older ones.

Legal issues still constrain SCNT. Many governments forbid or otherwise restrict its use with human cells. In the United States, no federal funding can be used for research that harms or destroys a human embryo, so scientists must set up separate lab space that does not use any National Institutes of Health or other federal grant money. Several U.S. states have banned all human SCNT research.

The political energy needed to overturn those laws might be hard to generate given that there’s now an embryo-free alternative to producing patient-specific stem cells. By ramping up the production of a handful of genes, researchers can reprogram mature cells into embryolike ones. These induced pluripotent stem (iPS) cells are already widely used to study disease, and the first clinical trial with them to treat macular degeneration is under way in Japan. But some scientists worry that iPS cells have flaws of their own. Several studies have found that the reprogramming process is often incomplete, leaving iPS cells with molecular traces of

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the mature cell they came from. (In mouse experiments, SCNT-derived ES cells seem to have fewer traces of their original cells than iPS cells do.) Researchers are not yet sure if the subtle differences are important to the cells’ later behavior.

Complicating the comparisons, sig­nificant differences exist among iPS cell

lines—and perhaps among SCNT-produced ES cells as well. “An open question is, which iPS cells should be the ones to compare to?” says Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Studies in San Diego, California. Careful comparisons could help scientists find more effective ways to make patient-specific cells, whether

with oocytes or with other approaches, says Ian Wilmut of the University of Edinburgh in the United Kingdom.

The ability to compare the approaches in human cells is key, says Doug Melton of the Harvard Stem Cell Institute. “The only way to find out is to do these experiments.”

-GRETCHEN VOGEL

E C O N O M I C G E O L O G Y

Seafloor Mining Plan Advances, Worrying CriticsIf all goes as planned, the world’s first commercial deep-sea mine will open for business in 2016, with engineers deploying a trio of robots to claw high-grade copper and gold ore from the sea floor 1500 meters down off Papua New Guinea (PNG). Last week, after years of dickering, PNG’s govern­ment and Canada-based Nautilus Minerals signed an agreement to move forward with the ambitious project. “We were very happy” to get the deal done, says Nautilus CEO Mike Johnston.

Critics aren’t so pleased.Some marine biologists worry the mining will start before researchers can assess how it will affect deep-sea ecosystems.Others argue that national and international regulators aren’t ready to ensure that underwater miners protect the environment.“The environmental impacts are unknown [and] the mining system is completely untested,” said Effrey Dademo of ACT NOW!, a PNG group opposing the mine, in a statement.

For decades, such debates were largely academ ic, because m ining at depths greater than 1000 meters was considered eco n o m ica lly unw orkab le . B ut as technology advanced, Nautilus and other companies began prospecting. In some locations, the sea floor is littered with polymetallic nodules—hard, round masses of rock slowly precipitated from seawater and bearing iron, manganese, nickel, and other metals—that miners could scoop up with relative ease. In others, mineral-laden water gushing from hydrothermal vents has created rich outcrops. Although the vents are harder to mine, the payoff can be greater, because the deposits can include both precious metals and rare earth elements

critical for computers, cellphones, and other modern technologies.

For its project, Nautilus has targeted a vent site known as Solwara 1, located near seafloor cracks created as two tectonic plates pull apart. Superhot fluids spew from deep in the crust, mixing with the cold seawater to form towers of ore-laden sediment known as “black smokers.” Company surveyors say the area, covering about 11 hectares, is particularly rich in copper and gold.

It is also home to many kinds of sea creatures, including tubeworms and bivalves, according to environmental impact studies sponsored by Nautilus. But the company says it can mine without doing much long- lasting damage, in part by taking steps to control sediment plumes and relocate animal communities. The “overall effects [will be]

reversible and moderate,” says a 2008 company study, which predicts that seafloor populations would rebound within a few years after mining ended.

Opponents are skeptical, with some saying they doubt that the PNG government—which has a 15% stake in the project—has the technical expertise to conduct adequate and independent

oversight. O ceanographer Cindy Van Dover of Duke

University in Durham, North Carolina, who helped Nautilus conduct some of its preliminary studies, concedes that

“there’s no way to know what the impact” will be.

Doing the studies that some scientists would like to see completed before mining begins would be expensive, she notes, with sustained seafloor research costing $80,000 a day or more. There are no concrete plans for major new environmental impact

studies. “I don’t know how to get to that happy place where the scientific community will let the mining go on and be confident that we will get the right amount of science,” she says.

In the meantime, Nautilus says it plans to move ahead with outfitting a vessel to deploy its mining robots, including a 300- ton behemoth that will chew through the sea floor, and another that will pump a slurry of mineral-rich ore to the surface. It hopes to be operating within 30 months, Johnston says.

Nautilus may soon have company. Other nations, including Fiji, are negotiating seafloor mining rights. And the United Nation’s little-known International Seabed Authority, based in Kingston, has already issued 19 perm its for prospecting in international waters.

-CAROLYN GRAMLING

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