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This image shows new beta cells that arise in adult mouse pancreas in vivo after viral delivery of a cocktail of three transcription factors, Ngn3, Pdx1, and Mafa. Viral infected cells are recognized by their expression of nuclear green fluorescent protein (GFP). Induced beta cells are revealed by insulin staining (red). Blue DAPI staining labels all cell nuclei. An endogenous islet is outlined with a white dotted line.

“What this shows is that you can go directly from one type of adult cell to another, without going back to the beginning.”

August 27, 2008 – Howard Hughes Medical Institute researchers have converted adult pancreatic cells into insulin-producing beta cells in living mice. This is a first because the researchers directly changed the functional identity of adult cells without using embryonic stem cells or relying on techniques that reverse a cell’s genetic programming to its earliest stages.

Remarkably, the investigators repurposed the adult cells quickly by using viruses to shuttle just three regulatory genes that triggered the remarkable developmental changes. It took only a brief blip of activity by the regulatory genes to imbue the cells with their new job descriptions, which they have retained for as long as nine months.

The experiments, which are reported on August 27, 2008, in an advance online publication in the journal Nature, realize a longtime goal in regenerative medicine: To produce specialized repair cells directly from a pool of adult cells that are healthy, abundant and easily obtained. Until now, repair cells have been generated from embryonic stem cells or more recently from pluripotent stem cells created by fully reprogramming adult cells.

“What this shows is that you can go directly from one type of adult cell to another, without going back to the beginning,” said Douglas A. Melton, a Howard Hughes Medical Institute (HHMI) investigator at Harvard University and co-director of the Harvard Stem Cell Institute. “You could say, for example, it’s like turning a scientist into a lawyer without sending her all the way back to kindergarten.”

In this case, the strategy was used in mice to convert exocrine cells, which compose 95 percent of the pancreas, to the relatively scarce beta cells that produce insulin. For more than a decade, Melton has studied how embryonic stem cells give rise to the pancreas and its insulin-producing beta cells, which are destroyed in patients with type 1 diabetes. Ultimately, his studies could lead to ways to generate new pancreatic beta cells that could be used as a treatment for diabetes. However, Melton cautioned that the new results are a proof of principle and do not have immediate medical applications.

Exocrine cells are specialized to churn out an array of digestive enzymes. Although they, like all cells, carry the genes that enable insulin production, those genes have been silenced. Melton’s experiments attempted to modify the genome of the exocrine cell to “awaken” certain genes and activate the insulin-producing features of beta cells.

The concept of adult cell-switching, or “lineage switching” as it is sometimes called, has been a major goal of regenerative medicine researchers. This approach has advantages because it avoids using stem cells derived from human embryos.

With the advent of newer techniques that obviate the need for human embryonic cells, researchers have been racing to incorporate those ideas into their own work. In a major breakthrough in 2006, Japanese researcher Shinya Yamanaka and his colleagues made stem cells from adult mouse skin cells (fibroblasts) by inserting four specific genes that were active in mouse embryonic stem cells. Those genes, which code for transcription factors, reprogrammed the skin cells so they became pluripotent and therefore had the capacity to develop into any type of tissue. These “induced pluripotent stem cells” or iPS cells, could in theory be guided in the laboratory to become specialized cells that might repair damaged nerves, hearts, or other organs.

Melton and postdoctoral fellow Qiao “Joe” Zhou, first author on the Nature paper, were encouraged by the revelation that a handful of transcription factor genes reactivated the embryonic program of adult skin cells. They wondered whether an equally small number of transcription factors could turn off the specialized functions of a given adult cell and turn on those needed to generate the target repair cell.

Starting from a list containing all 1,100 transcription factors in mice, the HHMI scientists selected 200 that were active in cells that form the pancreas. They later narrowed that list to just 28 transcription factors that were most active in the region of the pancreas that contains beta cells. The researchers next used retroviruses to ferry genes for nine of the 28 transcription factors into the exocrine cells of live mice.

Melton and Zhou were surprised to learn that, in fact, only three of the nine genes were necessary to turn exocrine cells into beta cells – an “extreme makeover,” as one of Melton’s colleagues termed it. Those genes were Ngn3, Pdx1, and Mafa.

The maneuver converted about 20 percent of the exocrine cells to beta cells that produced insulin. This was enough to reduce blood sugar levels in diabetic mice. The expression of the three transcription factor genes disappeared less than two months after they were introduced with the virus – but the converted cells remained.

While they believe that it will be possible to convert a wide range of adult cells to other cell types using a small number of regulatory genes, the scientists say a number of questions need to be explored. Among them: How closely related to the desired target cell does the donor cell need to be? What other types of cells can be converted to beta cells? And – since using viruses to ferry genes into human patients poses unacceptable risks — can the same outcome be accomplished with chemicals or other drugs?

George Daley, an HHMI investigator and stem cell researcher at Children’s Hospital Boston, commented that “Melton’s work is going to inspire an explosion of experiments in directing the fate of tissues in one way or another in ways that may be more practical than having to reprogram them back to pluripotency.” Daley and colleagues reported recently they had converted cells from individuals with 10 degenerative diseases into stem cells with the same genetic errors. These newly created stem cells will allow researchers to reproduce human tissue formation in a Petri dish as it occurs in individuals with any of the diseases,

Both Melton and Daley emphasized that the apparent success of the shortcut method in no way eliminates the need for continued research on strategies that use iPS cells or stem cells obtained from human embryos.

Image: Courtesy of Qiao Zhou, Melton Laboratory, HHMI at Harvard University

By Michelle Fay Cortez, August. 27, Bloomberg.com — A drug commonly used to prevent premature labor in pregnant women may also reduce the risk that their infants will develop cerebral palsy, researchers said.

A review of health records more than a decade ago suggested that premature newborns whose mothers were treated with magnesium sulfate were less likely to have cerebral palsy, a neurological disorder that affects muscle tone and hampers movement and posture. Still, studies that followed yielded mixed results.

The report in tomorrow’s New England Journal of Medicine shows infusions of magnesium sulfate reduced the number and severity of cerebral palsy cases diagnosed before age two, though it failed to lower death rates. There were few side effects of treatment, which now should be considered an option for women in danger of delivering their infants too soon, said researcher Deborah Hirtz, a pediatric neurologist.

“In survivors, treatment in these preterm babies did reduce the risk of cerebral palsy,” said Hirtz, from the National Institute of Child Health and Human Development. “We think it should be out there for consideration for obstetricians to use for the treatment of women who are delivering early.”

The study, the largest of its kind involving 2,241 women, was funded by the National Institute of Child Health and Human Development, or NICHD. The researchers also looked at just moderate and severe disease, since mild cerebral palsy can improve or disappear as children get older. Premature birth raises the risk of the condition.

5,000 Diagnosed

After two years, 1.5 percent of those getting in the treatment group had moderate cerebral palsy, compared with 2 percent of those whose mothers were given a placebo. Severe cases were diagnosed in 0.5 percent of magnesium sulfate group and 1.6 percent of those in the placebo group.

More than 5,000 children are diagnosed with cerebral palsy each year, and about 30 percent of them are born prematurely. The risk is greatest in children who spent the least amount of time in the womb. While doctors once speculated that the condition developed when infants were born with the umbilical cord wrapped around their necks, it now appears a lack of oxygen or brain injury earlier in development is more often to blame.

The number of children with cerebral palsy has increased as more premature children survive thanks to advances in medical care, wrote Fiona Stanley from the University of Western Australia in Perth, Australia, and Caroline Crowther from the University of Adelaide, in an editorial.

“Although promising, we would advise caution because of the differences” among the treatment approaches seen in the varying drug trials, they wrote. “Better understanding is needed of factors that might influence the likelihood that offspring will benefit from maternal magnesium sulfate treatment, such as the reason for imminent preterm birth, the dose of magnesium sulfate and the timing of administration.”

Turning Sonoma County into a laboratory to test new strategies for cooling the globe.

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It looks like any other business park construction site: mounds of dirt pushed around by graders belching diesel smoke, concrete structures in various stages of completion, surveyors adjusting the tripods of their transits while simultaneously poring over blueprints. But this complex isn’t your everyday business-as-usual business park. For one thing, it’s in Sonoma County, a region better known for superb wines and dainty artisanal foods than dreary corporate developments. Indeed, large vineyards stretch just west of the construction site, and nature intrudes in unexpected ways. Two red-tailed hawks spar overhead, and a black-tailed jackrabbit crouches under a clump of mustard near a cyclone fence. Among the cattails, oaks, and willows cloaking a nearby creek, red-winged blackbirds, Pacific-slope flycatchers, and black phoebes squabble over nesting territory.

The park reflects local concern for this arcadian environment by incorporating an energy system that will slash power consumption, saving approximately 30 percent of heating and 60 percent of cooling costs. But this project is more than the latest permutation of “green” development. It’s an experiment as big as the county itself, largely conceived by UC scientists collaborating with other researchers and county staffers. And it’s an experiment that resonates far beyond the leafy frontiers of Sonoma County.

Under the plan, which has the working title of the Sonoma County Sustainability Initiative, the county will be transformed into a landscape-scale laboratory to test and refine technologies to combat global warming. Contemplated separately, some of the initiative’s goals, such as delivering water to farms and cities without any net release of carbon to the atmosphere, seem wonky to the point of brain death. But consider: Water delivery can account for up to one-fifth of the electrical power consumed in the western United States. Much of that electricity is derived from fossil fuel–burning power plants, which release copious amounts of carbon dioxide into the air. If a practical system can be devised to offset the carbon produced by water transport, it could be a big step toward cooling the planet.

Researchers from around the world have been invited to come to the Wine Country, reach into their black boxes, and subject their pet notions to grueling road tests. Already on the drawing boards are commercial and residential geothermal heating systems, the widespread use of photovoltaic panels, wind and wave energy complexes, fleets of plug-in hybrid cars, and “carbon reservoirs”—large tree plantations that draw carbon from the air and store it in the woody tissues of growing redwoods and firs. “We’ll be able to see what works and what doesn’t under field conditions,” says Randy Poole, the general manager of the Sonoma County Water Agency and a prime mover in the initiative. “Things that look promising under controlled laboratory conditions don’t necessarily pan out in the real world. Sonoma County has an incredibly varied topography and multiple microclimates—large plains and steep mountains, cool coastal regions and hot inland interiors. We can provide the scale needed to identify the truly practical systems and winnow out the inferior ones.”

Cordel Stillman, deputy chief engineer of the water agency, leads me up a grassy berm to reveal the technology behind the nascent business park’s energy-saving secrets. Long and lanky as an NBA star, Stillman has a career engineer’s unsentimental point of view and laconic, somewhat didactic conversational style, mitigated by large, dark eyes that seem to vibrate when he’s making a point. At the top of the mound, he gestures to a sizable reservoir of greenish water. Several mallards are paddling around the middle of it, quacking idly and grooming their plumage. “This holds, oh, about 100 million gallons,” Stillman says. He nods to another levee, across a small, marshy creek. “We have another reservoir over there, holding about the same amount. That should provide all the capacity we need.” By capacity, he means latent energy. The reservoirs hold treated wastewater, provided, conveniently, by a nearby sewage treatment plant operated by the water agency. In the most basic terms, these reservoirs will replace the standard heating and cooling units employed in typical commercial buildings. When the business park is completed, Stillman explains, the reservoirs will serve as heat sinks, with temperatures hovering between 55° and 60°F, regardless of season.

A heat sink is a substance or environment that can both store heat and transfer it rapidly to another object. In the case of the reservoirs and the business park, the water maintains heat from the ambient atmosphere. The reservoirs are big enough and Sonoma County’s climate sufficiently moderate so that the water stays within a narrow temperature range. To heat or cool the business park, water is drawn from the reservoirs to the complex’s buildings. Each has a heat exchanger to obtain heat from or transfer heat to the water. A compressor then uses this energy to warm or cool air. Because the water hovers close to the temperatures required for human comfort, around 60°F, much less energy is required to bring the buildings up or down to the desired temperature range. And once its heat energy is harvested, the water can be used to irrigate landscaping and nearby vineyards, or flush toilets.

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Mound zero: Sonoma County Water Agency engineer Cordel Stillman (left) is working on a geothermal heating and cooling system. Randy Poole (right) is the agency’s general manager and a major force behind the initiative.

Similar “geothermal” heat pump systems already are in use in individual homes in the Midwest and at a military housing tract at Ft. Polk in Louisiana. But those systems rely on capturing temperature differentials in subterranean pipes. Sonoma’s plan, which will incorporate two business parks and a large winery complex as pilot projects, is the first to address large commercial complexes, and the first to rely on wastewater as a heat sink. “Until now, this was something of an alternative technology that an ambitious handyman in the Midwest might use to reduce the heating and cooling costs in his home,” Stillman says. “But by scaling up the process and turning to water as a heat sink, we’re showing you can use these systems for large commercial, industrial and residential developments. And as you scale up, your savings in energy and reductions in carbon emissions become dramatic.”

Sonoma’s goals will seem hyper-ambitious to many energy pundits. What chance, after all, does a small county best known for exceedingly complex pinot noirs and bucolic lifestyles have of affecting national and international policies? Conventional wisdom dictates: none. A group of UC professors thinks otherwise. The county, they say, could be the fulcrum for a global tipping point. These days, says Dan Kammen, the director of UC’s Renewable and Appropriate Energy Laboratory, the only significant response to global warming is coming from the grassroots. The feds have whiffed. And while some states—most notably, California—have set lofty and laudable goals for greenhouse gas reduction, little has been implemented. It’s in the nation’s small to mid-sized communities that things are happening. Sonoma is at the vanguard with projects that are already breaking ground, but cities such as Santa Fe and Boulder also are proposing broad-based, technologically sophisticated responses to carbon emissions. These programs are so promising, Kammen says, they ultimately could serve as a template for a national initiative.

“The Sonoma plan is looking very, very attractive to me,” says Kammen, who looks preternaturally youthful for someone who took his Ph.D. 20 years ago. “Geothermal heat pumps are not a new technology, but the proposal to utilize them on this scale is new. It points to a ramping up of the technology that ultimately could make a huge difference.”

The Sonoma plan incorporates many of the elements promoted by Kammen’s lab, including the extensive use of plug-in hybrid cars, methane captured from landfills, liquid biofuels derived from waste products, and widespread employment of photovoltaic panels. Other academics, including Michael Hanemann, the director of Berkeley’s California Climate Change Center, and Margaret Taylor, an assistant professor at the Richard and Rhoda Goldman School of Public Policy, are also advising the county on its initiative.

Poole says the expertise and prestige provided by UC faculty members were essential in garnering $1 million in pilot project funding from the county board of supervisors. “Ultimately, their advice allowed us to go from a general idea to on-the-ground projects that could change the global economy.”

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The water agency has its own greenhouse gas reduction goals—specifically, the delivery of “carbon neutral” water. That means all water served to the six cities, three special districts, and two counties by the agency will be obtained, treated, and delivered with no net release of carbon dioxide or other greenhouse gases. “Water essentially is publicly owned, and as a result there is no regulatory agency pushing energy efficiency,” Hanemann observes. “Water has been insulated from the pressures that the utilities and developers have felt. In California, the public debate over water has centered on the impact water development has had on fisheries, particularly in the Sacramento-San Joaquin Delta. But the other great environmental impact of water—the energy required to move it around, and the atmospheric carbon that energy consumption releases—isn’t addressed.” In Sonoma County, water transportation and treatment accounts for about 20 percent of the county’s energy consumption; that ratio holds true for the state as a whole, Hanemann says.

“That’s why the water agency’s target of ‘zero net carbon’ water delivery is so compelling,” Hanemann says. “First, it speaks to a major element of the greenhouse gas problem that hasn’t ever been addressed. Second, it can really work. It doesn’t necessarily require technology we don’t have. If the steps they’re proposing are fully implemented, they should be able to achieve their goal.”

For a nation stressed by unrelenting bad news about global warming, Sonoma’s initiative is heartening. But, says Kammen, it’s important to get the landscape-sized laboratory up and running. “The main framing point here is that we have a lot of approaches that individually are promising, but we have to determine their collective efficacy,” he says. “Personally, I think they’ll make a big impact—but we need to start scaling up now. We need to get moving.”

Glen Martin is a former environmental reporter for the San Francisco Chronicle. His freelance credits include Audubon, Sierra, Discover, Outside, National Wildlife, Gourmet, and Bay Nature. He currently is working on a project with Laurence Frank, of UC’s Museum of Vertebrate Biology, on the decline of lions and hyenas in East Africa.