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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.

The New York Times, August 26, 2008 – Stanford University, concerned about the influence drug companies may have on medical education, is expected to announce Tuesday that it will severely restrict industry financing of doctors’ continuing education at its medical school.

Nearly all doctors in the country must take annual refresher courses that drug makers have long paid for. While the industry says its money is intended solely to keep doctors up to date, critics charge that companies agree to support only classes that promote their products.

On Tuesday, Stanford plans to announce that it will no longer let drug and device companies specify which courses they wish to finance. Instead, companies will be asked to contribute only to a schoolwide pool of money that can be used for any class, even ones that never mention a company’s products.

With its approach, Stanford becomes the sixth major medical school — including those at the universities of Massachusetts, Pittsburgh, Colorado, Kansas and California Davis — to form schoolwide pools for university contributions to medical education, according to the Prescription Project, a nonprofit organization that largely opposes industry financing of medical education. The Memorial Sloan-Kettering Cancer Center, meanwhile, has banned all industry support for its doctor classes.

Dr. David Korn, chief scientific officer of the Association of American Medical Colleges, said Stanford’s new policy was ”an extremely important step forward.” The association recommended in June that medical schools pool contributions from companies as a means of shielding teachers from commercial influences.

Ken Johnson, a spokesman for the Pharmaceutical Research and Manufacturers of America, said Monday that ”America’s pharmaceutical research companies have taken positive steps to help ensure they provide nothing but accurate and balanced information to health care providers.”

Dr. Philip A. Pizzo, dean of Stanford’s School of Medicine, said in an interview that the school wanted to take a firm stand on the issue, even if it meant that drug and device companies might no longer contribute to the educational effort if they could not specify which classes they wanted to support.

”I want to make sure we’re not marketing for industry or being influenced by their marketing,” Dr. Pizzo said.

The policy comes in the wake of growing scrutiny of industry financing of doctor education. In April 2007, Senator Charles E. Grassley, Republican of Iowa, issued a report that documented how drug makers used the classes to increase sales of their latest products.

In an e-mail statement on Monday, Senator Grassley said, ”Reforms based on transparency can foster accountability and build confidence in medical education and, in turn, the practice of medicine.”

Since Senator Grassley began his investigation, a growing number of drug makers have begun to make public their lists of educational grant recipients, and Pfizer recently announced that it would no longer directly support commercial medical education companies, which deliver many of the classes that doctors attend and may be more susceptible to industry influence than ones based at medical schools.

Doctors have grown accustomed to taking educational classes free — often with a lunch included. Separating commercial influences from doctor education might require doctors to pay their own way, which some doctors have said they would resist.

Dr. Murray Kopelow, chief executive of the Accreditation Council for Continuing Medical Education, said that Stanford’s new policy was part of a growing push in medical education to further separate crucial medical information from marketing messages.

”It’s a good plan, and it’s a big deal that a place like Stanford has adopted it,” Dr. Kopelow said. ”When this is all over, medical education will not be the same as what it’s been.”

By Judith K. Jones, MD, PhD, August 18, 2008, Medscape Pharmacists – When I was in charge of the postmarketing drug safety program at the US Food and Drug Administration (FDA) in the early 1980s, 1 particular drug report became etched in my memory.

“I think we are killing the babies,” a physician told me over the phone. The caller worked in a neonatal intensive care unit that housed very early neonates, babies who previously might not have survived but were now being saved with intensive care treatment.

Nevertheless, this physician worried that some of the interventions might be doing more harm than good. He wondered if the neonates’ tiny size might increase their risk for toxicity to benzyl alcohol, an antibacterial preservative found in flushing solution for arterial lines. When he calculated the daily dose of this additive relative to neonatal weight, he found that it exceeded toxic levels. He even cited several deaths that might have been related to benzyl alcohol toxicity.

I asked the physician to send the case details to the FDA. He also presented his findings at a scientific meeting the following week to see if others had noted the same potential problem. Neonatologists from at least 1 other center returned to their unit and concluded that this adverse event might be occurring there as well. In the meantime, the FDA examined the extent and distribution of those multidose vials of heparinized bacteriostatic sodium chloride and water within a relatively short time, promulgated warnings about the risk, and finally withdrew them from the market. As the topic was later examined in more detail, it was apparent that a number of neonates may have experienced the toxic effects of this preservative in this very unique overdose
situation.[1,2]

That case study clearly shows the importance of reporting adverse drug events (ADEs), and it demonstrates how 1 alert healthcare provider can and did make a difference.

In fact, individual ADE reports to the FDA and to the manufacturer can make a significant difference in the safety of a drug after it has been approved for use by a diverse population. These reports represent the most expedient method of identifying possible new and serious ADEs. They can be readily evaluated by officers at the FDA and may be acted on to update the product’s safety status through various actions described below.

In contrast to some other countries, most notably Sweden,[3] clinicians in the United States are not required to report ADEs. As a result, the reporting rate is relatively low, partly due to a lack of information on what and how to report. Previous articles in this Medscape series have outlined methods for recognizing ADEs and tools for reporting ADEs, in an effort to improve reporting. This article addresses another reason that may contribute to low reporting: lack of understanding about the importance of individual reports.

ADE reports can signal important safety issues. Assessing these reports can lead to changes in how a drug is used or advertised, and it can even lead to removal from the market. Another example involves the acne medication isotretinoin (Accutane). After it was approved in the early 1980s, this drug was found to be associated with birth defects of the central nervous system (microcephaly or hydrocephalus) and cardiovascular system (anomalies of the great vessels). Microtia or absence of external ears was also noted in a majority of cases.[4,5]

The question of drug-related birth defects is a particularly difficult one, and clinicians must be especially observant and report suspected ADEs to help determine possible signals of new adverse effects. Of all near- or full-term births, 3% to 5% are associated with a major birth defect; however, extremely low frequencies of any particular defect make epidemiologic studies in large populations a challenge. For example, less than 1 in 1000 live births is associated with gastroschisis, tetralogy of Fallot, or transposition of the great vessels. Thus, reports by alert clinicians often are the most efficient method of identifying potential defects at an early stage. In the case of isotretinoin, spontaneous reports early in its marketing served as the basis for rapid introduction of specific exposure registries. In addition, risk management programs were implemented to prevent the use of the drug in pregnancy.[6]

How is a clinical observation translated into useful new information on a drug? The Figure below shows the flow of information that may ultimately result in changes to a drug’s label information. This, in turn, may affect how it is advertised, packaged, and in some cases, formulated or marketed. It is important to emphasize that manufacturers are required by law to report all events associated with their product to the FDA, regardless of whether or not they consider them causally related. If the events are new (ie, not in the product label) and are serious (defined as resulting in death, hospitalization, prolongation of hospitalization or illness, or birth defects), they must be reported within 15 days from the time the company becomes aware of the event. This also applies to literature reports — when the manufacturer identifies ADEs through routine literature searches, they must report them in the same manner. Reports that are neither new nor serious are provided to FDA in periodic reports (every 6 months in the first 3 years after marketing, then yearly).

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Figure 1.
The flow of information and actions on a suspected adverse drug reaction report (SADR)

The FDA’s regulatory requirements were set up with the specific understanding that a drug is approved on the basis of at least 2 randomized controlled clinical trials that show it to be effective. The safety of an approved drug is examined extensively in preclinical studies (in vitro and in animals to determine the potential risk of cancer and birth defects, in particular) and in all the human clinical trials up to the time of approval. However, the FDA recognizes that even when large clinical trials (ie, > 10,000 patients) are conducted for approval, not every safety issue will be identified. This occurs for several reasons: (1) the subjects who were evaluated in the trials are relatively healthier and take fewer other drugs than patients who will ultimately use the drug; (2) the drugs were not tested in special populations who may need to use the drug, such as pregnant women, children, or the frail elderly; and (3) many adverse reactions of serious public health concern occur very infrequently. For example, hepatic failure is found in 1 in 5000 to 20,000 people. However, when a product is used by millions of persons, this rare occurrence can translate to a sizable number of cases. There is simply insufficient statistical power in the clinical trial data to expect that these rare effects will be detected.

Researchers use the “rule of 3” to derive a rough estimate of the power to detect events.[7,8] If an ADE occurs at a rate of 1/5000, then it will be necessary to evaluate the drug in 15,000 patients to have a 95% chance to detect just 1 case. Therefore, many thousands more patients would need to be studied to identify sufficient cases for analysis.

Federal food and drug laws and resulting regulations are based on the knowledge that there will almost surely be new cases of ADEs occurring in special populations who were not exposed in the clinical trials and/or are quite rare and only detected when sufficient individuals are exposed. This important fact underlines the importance of the individual clinician who stands at the frontier of understanding a new product’s spectrum of effects.

If the clinician includes “possible ADE” in the differential diagnosis for any new event, he or she increases the likelihood of early discovery of these new and rare events once they are reported. In some cases, only a few events can serve to signal a problem and may result in action to update the information on the drug — actions that potentially can save lives.

This activity is supported by an independent educational grant from PhRMA.

References

1. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning., N Engl J Med. 1982;307):1384-1388. Abstract
2. Hiller JL, Benda GI, Rahatzad M, et al. Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics. 1986;77:500-506. Abstract
3. Wiholm BE, Westerholm B. Drug utilization and morbidity statistics for the evaluation of drug safety in Sweden. Acta Med Scand Suppl. 1984;683:107-117. Abstract
4. Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol. 1984;10:851-854. Abstract
5. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313:837-841. Abstract
6. Goldberg JD, Golbus MS. The value of case reports in human teratology. Am J Obstet Gynecol. 1986;154:479-482. Abstract
7. Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA. 1983:249;1743-1745. Abstract
8. Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ. 1995:311;619-620. Abstract

Judith K. Jones, MD, PhD, Adjunct Professor of Public Health, University of Michigan Summer Health Program in Public Health, Ann Arbor, Michigan

Disclosure: Judith K. Jones, MD, PhD, has disclosed that she has received research grants for epidemiology research from Abbott Laboratories; Allergan; C.B. Fleet Co. Inc.; Cephalon; Genetech, Inc.; Hoffman-LaRoche; and Oxford Pharmaceuticals. Dr. Jones has also disclosed that she has received a research grant for risk management from Bayer Healthcare, and received consulting fees from Bristol-Myers Squibb, Hoffman-LaRoche, Otsuka Pharmaceutical, Quintiles, and sanofi-aventis.

By Andrew J. Vickers, PhD, August 18, 2008, Medscape, From WebMD – Tommy John, the renowned pitcher, once made 3 errors on a single play: He fumbled a grounder, threw wildly past first base, then bobbled the relay throw from right field and threw past the catcher. I was reminded of that story when peer-reviewing a paper describing a randomized trial. Near the start of the results section, the authors wrote something like, “Although there was no difference in baseline age between groups (P = .458), controls were significantly more likely to be male (P = .000).”

This goes one better than Tommy John, because there are actually 4 errors in this single sentence (or perhaps even 4.5).* The first error has been discussed in a previous article (please see Related Links): You cannot conclude “no difference” between groups on the basis of a high P value because failing to prove a difference is not the same as proving no difference.

Here are the other 3 errors:

  1. P values for baseline differences between randomized groups. P values are used to test a hypothesis — in this case, a null hypothesis that can be informally stated as: “There is no real difference between groups; any differences we see are due to chance alone.” But this is a randomized trial, so any differences between groups must be due to chance alone. In short, we are testing a null hypothesis that we know to be true. Nonetheless, reporting P values for baseline differences in randomized trials remains routine: When I recently refused a clinician’s request to calculate these P values for baseline differences, he sent me references to several recent papers published in high-profile journals to show that what I thought was wrong was actually quite common. Given that copying others is not necessarily the best path to statistical truth, I politely declined a second time.
  2. Inappropriate levels of precision. The first p value in our multierror sentence is reported to 3 significant figures (P = .458). What do the 5 and 8 tell us here? We are already way above statistical significance; a little bit more or less isn’t going to change our conclusions, so reporting the P value to a single significant figure (ie, P = .5) is fine. Inappropriate levels of precision are pretty ubiquitous in the scientific literature, perhaps because a very precise number sounds more “scientific.” One of my favorite examples is a paper that reported a mean length of pregnancy of 32.833 weeks, suggesting that we want to know the time of conception to the nearest 10 minutes. This would require some rather close questioning of the pregnant couple.
  3. Reporting a P value of zero. No experimental result has a zero probability; even if I throw a billion unbiased coins I have a small, but definitely non-zero, chance of getting all heads. I once pointed this out in a peer review, only to have the authors reply that the statistical software had given them P = .000, so the value must be right.

This gets to the heart of why I care about these errors even though they don’t make much difference to anything (why don’t I just ignore those unnecessary decimal places?). Many people seem to think that we statisticians spend most of our time doing calculations, but that is perhaps the least interesting thing that we do. Far more important is that we spend time looking at numbers and thinking through what they mean. If I see any number in a scientific report that is meaningless — a P value for baseline differences in a randomized trial, say, or a sixth significant figure –I know that the authors are not being careful about what they are doing; they are just pulling numbers from a computer print-out. And that doesn’t sound like science to me.

*Note: About that “half an error”: the authors tell us that “baseline” age was no different between groups. This was a trial on pain in which all patients were on study for the same period of time, so unless patients in different treatment groups grew old at different rates, there is no reason to tell us that it is “baseline” age that is being compared.

Andrew J. Vickers, PhD, Assistant Attending Research Methodologist, Memorial Sloan-Kettering Cancer Center, New York, NY

Disclosure: Andrew J. Vickers, PhD, has disclosed no relevant financial relationships.

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The New York Times

The OvaSure Cancer Test debut raises questions about whether greater regulation is needed to assure the validity of a trove of sophisticated new diagnostic tests that are entering the market and are being used as the basis for important treatment decisions.

By Andrew Pollack, August 26, 2008, The New York Times – A new blood test aimed at detecting ovarian cancer at an early, still treatable stage is stirring hopes among women and their physicians. But the Food and Drug Administration and some experts say the test has not been proved to work.

The test, called OvaSure, was developed at Yale and has been offered since late June by LabCorp, one of the nation’s largest clinical laboratory companies.

The need for such a test is immense. When ovarian cancer is detected at its earliest stage, when it is still confined to the ovaries, more than 90 percent of women will live at least five years, according to the American Cancer Society. But only about 20 percent of cases are detected that early. If the cancer is detected in its latest stages, after it has spread, only about 30 percent of women survive five years.

But far from greeting the new test with elation, many experts are saying it might do more harm than good, leading women to unnecessary surgeries. The Society of Gynecologic Oncologists almost immediately issued a statement saying it did not believe the test had been validated enough for routine use.

“You’ve got industry trying to capitalize on fear,” said Dr. Andrew Berchuck, director of gynecologic oncology at Duke University and the immediate past president of the society. “We’d all love to see a screening test for ovarian cancer,” he added, “but OvaSure is very premature.”

OvaSure’s debut also raises questions about whether greater regulation is needed to assure the validity of a trove of sophisticated new diagnostic tests that are entering the market and are being used as the basis for important treatment decisions. OvaSure did not go through review by the Food and Drug Administration because the agency generally has not regulated tests developed and performed by a single laboratory, as opposed to test kits that are sold to laboratories, hospitals and doctors. (All OvaSure blood samples are sent to LabCorp for analysis.)

But the F.D.A. has now summoned LabCorp to discuss OvaSure, saying the data appear insufficient to back the company’s claims about the test. “We believe you are offering a high-risk test that has not received adequate clinical validation and may harm the public health,” the agency said in an Aug. 7 letter sent to LabCorp that was posted on the F.D.A. Web site. A spokesman for LabCorp, which is short for Laboratory Corporation of America Holdings, said the company looked forward to reviewing the data with the agency but would continue offering the test in the meantime.

Dr. Myla Lai-Goldman, chief medical officer of LabCorp, said that OvaSure had been validated in several studies and that additional data were expected by the end of this year. Diagnostic tests typically are studied further after they have reached the market, she said. Dr. Goldman said there was “tremendous interest” from physicians in learning more about OvaSure.

Patients and advocacy groups seem divided on OvaSure, which costs about $220 to $240.

“We are hearing from people that they are very excited about it,” said Cara Tenenbaum, policy director for the Ovarian Cancer National Alliance. But the alliance urges women to wait for more data before relying on the test.

More than 21,000 new cases of ovarian cancer will be diagnosed in the United States this year and more than 15,000 people are expected to die from the disease, according to the American Cancer Society.

OvaSure measures the level of six proteins in a sample of blood, some produced by a tumor and some produced by the body in reaction to a tumor. It then calculates a probability that the woman has ovarian cancer. One of the six proteins is CA-125, which is used by itself as a test to monitor disease progression in women who already have ovarian cancer but is not good at picking up early disease.

In a study published in the journal Clinical Cancer Research in February, the test correctly classified 221 of 224 blood samples taken from women with ovarian cancer or from controls. It identified 95 percent of the cancers, and its false positive rate — detecting a cancer that was not there — was 0.6 percent.

But Dr. Beth Y. Karlan, director of the Women’s Cancer Research Institute at Cedars-Sinai Medical Center in Los Angeles, said the samples tested were not representative of what might be encountered in routine screening. There were very few blood samples from women with early stages of the most deadly type of ovarian cancer. “That’s really what we want to find,” she said.

The biggest concern is not that the test will miss cancers but that it will say a cancer is there when it is not. That would then subject women to needless surgery to have their ovaries removed.

Dr. Berchuck of Duke said only 1 of 3,000 women has ovarian cancer. So even if a screening test had a 1 percent rate of false positives, it would mean that 30 out of 3,000 women tested might be subject to unnecessary surgery for every one real case of cancer.

Teresa Hills, who had a visible mass on her left ovary, got a positive result from OvaSure. But when the ovary was removed, the mass turned out to be benign.

The false positive did not prompt unnecessary surgery because Ms. Hills was going to have the mass removed in any case. But it did cause needless anxiety.

“You can’t sleep, you can’t eat, you’re paralyzed with fear,” said Ms. Hills, a 44-year-old mother of three from Rockford, Ill. She said she lost 10 pounds in two weeks after the false diagnosis.

Dr. Lai-Goldman at LabCorp said that OvaSure should be restricted to women at high risk of ovarian cancer and that the test should be repeated if the result is positive. Those measures would limit the number of false positives.

LabCorp estimates that there are 10 million women at high risk. These include carriers of mutations in genes called BRCA1 or BRCA2, as well as women with histories of ovarian or breast cancer.

Dr. Gil Mor, the lead developer of the test at Yale, said the use of OvaSure might reduce ovarian surgeries, not increase them. That is because women with BRCA mutations often have their ovaries removed to prevent cancer. A negative result on the OvaSure test might allow such women to put off the surgery.

“They are removing the ovaries without the test,” said Dr. Mor, an associate professor of obstetrics and gynecology. “So what are we talking about here? We are trying to do the opposite and say don’t remove the ovaries.”

That logic appeals to some. Dr. Elizabeth Poyner, a gynecologic oncologist in Manhattan with a lot of high-risk patients, said she was thinking about how to incorporate OvaSure into her practice. One of her patients, a Manhattan woman with a BRCA2 mutation, said she was planning to take the test in hopes of postponing ovary removal.

“I’d really like a couple of more years to have the heart health and the bone health and all the benefits that come from having estrogen naturally,” said the woman, who is in her early 40s and spoke on the condition she not be identified because she had not told some relatives that she has the mutation.

But Dr. Julian C. Schink, director of gynecologic oncology at Northwestern University, said it would be “playing Russian roulette” to put off ovary surgery unless OvaSure detected cancer. “We just don’t have any data to show this test will turn positive before the disease turns metastatic,” he said.

The test is also not intended to detect the recurrence of cancer. Jean McKibben, a retired schoolteacher from Centennial, Colo., said her test result suggested zero probability that her cancer had returned. But scans then found a tumor. Only later did Ms. McKibben learn that the test does not work for women whose ovaries have been removed.

The ovarian cancer detection field has had disappointments before. Four years ago, the F.D.A. intervened to effectively stop the marketing of another complex ovarian cancer screening test developed by a company called Correlogic Systems. The test, called OvaCheck, had also spurred great hope, but never made it to market as experts questioned its validity.

With the number of genetic and other tests proliferating, the agency has been under pressure to assure that the tests are accurate. Two years ago, the agency said it intended to regulate complex tests, like OvaSure, that measure multiple proteins or genes and use a mathematical formula to compute a result. But it has not finalized the policy.

Peter J. Levine, president of Correlogic, said the company was developing a new ovarian screening test and would apply by the end of the year for F.D.A. approval. He said it would be unfair if LabCorp did not need approval.

Another company, Vermillion, applied to the F.D.A. in June for approval of a test, called OVA1, aimed at determining whether ovarian masses are cancerous.

Dr. Daniel Schultz, who oversees diagnostic tests for the F.D.A., said the agency was trying to balance demands for greater oversight of tests against concerns that regulation could impede development of needed diagnostics.

“We understand that concerns have been raised regarding the impact that F.D.A. regulation would have on this whole field,” he said.

Even if OvaSure is validated, or a better test is developed, questions will remain on whether screening is useful, similar to controversies that have arisen about prostate cancer screening.

Dr. Berchuck of Duke said it had not been proved that a test that detects cancer early would cut deaths from the disease. It could be that cancers detected early were the less aggressive ones that would not have killed the woman anyway.

Some experts say women should pay more attention to symptoms, like pain and bloating. But these symptoms can also be caused by other conditions.

The Canary Foundation, which finances research on early cancer detection, is focusing on developing better imaging techniques. Transvaginal ultrasound, which is sometimes used now, is not that good at detecting early disease.

“Too much of the dialogue has been on how good is the blood test,” said Don Listwin, a Silicon Valley executive who started the foundation after his mother died from ovarian cancer that was diagnosed late. “They thought it was a bladder infection.”

Mr. Listwin said mammograms and the P.S.A. test were fairly unreliable in detecting breast and prostate cancer, respectively. Yet they can be used for screening because a positive test result can be followed by a needle biopsy to confirm whether cancer is present.

But it is difficult to do a biopsy of the ovary because of its location, so a positive blood test result might lead directly to surgery. If imaging could be used for confirmation, he said, then even a somewhat inaccurate blood test might suffice for screening.

July 2, 2008

The Society of Gynecologic Oncologists (SGO) recognizes the need for accurate early detection biomarkers for ovarian cancer. For this reason, SGO reviewed the literature regarding OvaSure, a serum-based diagnostic test for ovarian cancer.

After reviewing OvaSure’s materials, it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.

SGO is committed to actively following and contributing to this vitally important research. As physicians who care only for women with gynecologic cancers, our hope is that these cancers can either be prevented or detected early. Because no currently available test has been shown to reliably detect ovarian cancer in its earliest and most curable stages, we will await the results of further clinical validation of OvaSure with
great interest.

By Nicholas Bakalar, August 26, 2008, The New York Times – Chewing gum after abdominal surgery may help in recovery, British researchers found in a review of several small studies.

The scientists looked at results from five randomized trials involving 158 patients who had undergone colectomy, the complete or partial removal of the colon. In each study, the postsurgical treatment of patients was the same except that roughly half were randomly assigned to chew gum after their operations.

The researchers found that chewing gum reduced the time for the gut to become active, and lowered the incidence of obstruction of the bowel that sometimes follows surgery. Four studies found the length of postoperative stay in the hospital to be a little more than one day shorter for gum chewers, but that result was not statistically significant and may have been due to chance.

The authors, writing in the August issue of The Archives of Surgery, suggest that chewing gum stimulates the release of gastrointestinal hormones while avoiding the nausea and vomiting often caused by eating too soon after an operation.

“No one knows what the mechanism is,” said Dr. Sanjay Purkayastha, the lead author and a surgical resident at St. Mary’s Hospital, Imperial College London. “But chewing has some effect on kick-starting the gut. We suggest that patients chew gum three times a day post-surgery.”

The social-networking strategy that took an obscure senator Obama, to the doors of the White House.

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Web Jockey: Jascha Franklin-Hodge, the 29-year-old cofounder and chief technology officer of Blue State Digital, the company behind Obama’s social technologies, says that “on every metric, this campaign has operated on a scale that has exceeded what was done before.” Beyond fund-raising, the Web tools enabled event planning, phone banks, and targeted e-mailing.
Credit: Porter Gifford

By David Talbot, September/October 2008, MIT Technology Review – Joe Trippi, Howard Dean’s 2004 presidential campaign manager and Internet impresario, describes Super Tuesday II–the March 4 primaries in Texas, Ohio, Vermont, and Rhode Island–as the moment Barack Obama used social technology to decisive effect. The day’s largest hoard of delegates would be contested in Texas, where a strong showing would require exceptional discipline and voter-education efforts. In Texas, Democrats vote first at the polls and then, if they choose, again at caucuses after the polls close. The caucuses award one-third of the Democratic delegates.

Hillary Clinton’s camp had about 20,000 volunteers at work in Texas. But in an e-mail, Trippi learned that 104,000 Texans had joined Obama’s social-networking site, www.my.barackobama.com, known as MyBO. MyBO and the main Obama site had already logged their share of achievements, particularly in helping rake in cash. The month before, the freshman senator from Illinois had set a record in American politics by garnering $55 million in donations in a single month. In Texas, MyBO also gave the Obama team the instant capacity to wage fully networked campaign warfare. After seeing the volunteer numbers, Trippi says, “I remember saying, ‘Game, match–it’s over.'”

The Obama campaign could get marching orders to the Texans registered with MyBO with minimal effort. The MyBO databases could slice and dice lists of volunteers by geographic microregion and pair people with appropriate tasks, including prepping nearby voters on caucus procedure. “You could go online and download the names, addresses, and phone numbers of 100 people in your neighborhood to get out and vote–or the 40 people on your block who were undecided,” Trippi says. “‘Here is the leaflet: print it out and get it to them.’ It was you, at your computer, in your house, printing and downloading. They did it all very well.” Clinton won the Texas primary vote 51 to 47 percent. But Obama’s people, following their MyBO playbook, so overwhelmed the chaotic, crowded caucuses that he scored an overall victory in the Texas delegate count, 99 to 94. His showing nearly canceled out Clinton’s win that day in Ohio. Clinton lost her last major opportunity to stop the Obama juggernaut. “In 1992, Carville said, ‘It’s the economy, stupid,'” Trippi says, recalling the exhortation of Bill Clinton’s campaign manager, James Carville. “This year, it was the network, stupid!”

Throughout the political season, the Obama campaign has dominated new media, capitalizing on a confluence of trends. Americans are more able to access media-rich content online; 55 percent have broadband Internet connections at home, double the figure for spring 2004. Social-networking technologies have matured, and more Americans are comfortable with them. Although the 2004 Dean campaign broke ground with its online meeting technologies and blogging, “people didn’t quite have the facility,” says Lawrence Lessig, a Stanford law professor who has given the Obama campaign Internet policy advice (Lessig wrote The People Own Ideas! in our May/June 2005 issue). “The world has now caught up with the technology.” The Obama campaign, he adds, recognized this early: “The key networking advance in the Obama field operation was really deploying community-building tools in a smart way from the very beginning.”

Of course, many of the 2008 candidates had websites, click-to-donate tools, and social-networking features–even John McCain, who does not personally use e-mail. But the Obama team put such technologies at the center of its campaign–among other things, recruiting 24-year-old Chris Hughes, cofounder of Facebook, to help develop them. And it managed those tools well. Supporters had considerable discretion to use MyBO to organize on their own; the campaign did not micromanage but struck a balance between top-down control and anarchy. In short, Obama, the former Chicago community organizer, created the ultimate online political machine.

The Obama campaign did not provide access or interviews for this story; it only confirmed some details of our reporting and offered written comments. This story is based on interviews with third parties involved in developing Obama’s social-networking strategy or who were familiar with it, and on public records.

An Online Nervous System

A row of elegant, renovated 19th-century industrial buildings lines Boston’s Congress Street east of Fort Point Channel. On any given day, behind a plain wooden door on the third floor of 374 Congress, 15 to 20 casually clad programmers tap away at computers. On the day I visited, the strains of Creedence Clearwater Revival filled the room; a Ping-Pong table dominated the small kitchen. This is the technology center for Blue State Digital, which means that it is also the nervous system for its two largest clients, the Barack Obama campaign and the Democratic National Committee. Founded by alumni of the Dean campaign, Blue State Digital added interactive elements to Obama’s website–including MyBO–and now tends to its daily care and feeding. The site’s servers hum away in a Boston suburb and are backed up in the Chicago area.

Jascha Franklin-Hodge, 29, greeted me with a friendly handshake and a gap-toothed grin. He has a deep voice and a hearty laugh; his face is ringed by a narrow beard. Franklin-Hodge dropped out of MIT after his freshman year and spent a few years in online music startups before running the Internet infrastructure for the Dean campaign, which received a then-unprecedented $27 million in online donations. “When the campaign ended, we thought, ‘Howard Dean was not destined to be president, but what we are doing online–this is too big to let go away,'” he says. He and three others cofounded Blue State Digital, where he is chief technology officer. (Another cofounder, Joe Rospars, is now on leave with the Obama campaign as its new-media director.)

The MyBO tools are, in essence, rebuilt and consolidated versions of those created for the Dean campaign. Dean’s website allowed supporters to donate money, organize meetings, and distribute media, says Zephyr Teachout, who was Dean’s Internet director and is now a visiting law professor at Duke University. “We developed all the tools the Obama campaign is using: SMS [text messaging], phone tools, Web capacity,” Teachout recalls. “They [Blue State Digital] did a lot of nice work in taking this crude set of unrelated applications and making a complete suite.”

Blue State Digital had nine days to add its tools to Obama’s site before the senator announced his candidacy on February 10, 2007, in Springfield, IL. Among other preparations, the team braced for heavy traffic. “We made some projections of traffic levels, contribution amounts, and e-mail levels based on estimates from folks who worked with [John] Kerry and Dean in 2004,” recalls Franklin-Hodge. As Obama’s Springfield speech progressed, “we were watching the traffic go up and up, surpassing all our previous records.” (He would not provide specific numbers.) It was clear that early assumptions were low. “We blew through all of those [estimates] in February,” he says. “So we had to do a lot of work to make sure we kept up with the demand his online success had placed on the system.” By July 2008, the campaign had raised more than $200 million from more than a million online donors (Obama had raised $340 million from all sources by the end of June), and MyBO had logged more than a million user accounts and facilitated 75,000 local events, according to Blue State Digital.

MyBO and the main campaign site made it easy to give money–the fuel for any campaign, because it pays for advertising and staff. Visitors could use credit cards to make one-time donations or to sign up for recurring monthly contributions. MyBO also made giving money a social event: supporters could set personal targets, run their own fund-raising efforts, and watch personal fund-raising thermometers rise. To bring people to the site in the first place, the campaign sought to make Obama a ubiquitous presence on as many new-media platforms as possible.

The viral Internet offered myriad ways to propagate unfiltered Obama messages. The campaign posted the candidate’s speeches and linked to multimedia material generated by supporters. A music video set to an Obama speech–“Yes We Can,” by the hip-hop artist Will.i.am–has been posted repeatedly on YouTube, but the top two postings alone have been viewed 10 million times. A single YouTube posting of Obama’s March 18 speech on race has been viewed more than four million times. Similarly, the campaign regularly sent out text messages (at Obama rallies, speakers frequently asked attendees to text their contact information to his campaign) and made sure that Obama was prominent on other social-networking sites, such as Facebook and MySpace (see “New-Media King” chart above). The campaign even used the microblogging service Twitter, garnering about 50,000 Obama “followers” who track his short posts. “The campaign, consciously or unconsciously, became much more of a media operation than simply a presidential campaign, because they recognized that by putting their message out onto these various platforms, their supporters would spread it for them,” says Andrew Rasiej, founder of the Personal Democracy Forum, a website covering the intersection of politics and technology (and another Dean alumnus). “We are going from the era of the sound bite to the sound blast.”

Money flowed in, augmenting the haul from big-ticket fund-raisers. By the time of the Iowa caucuses on January 3, 2008, the Obama campaign had more than $35 million on hand and was able to use MyBO to organize and instruct caucus-goers. “They have done a great job in being precise in the use of the tools,” Teachout says. “In Iowa it was house parties, looking for a highly committed local network. In South Carolina, it was a massive get-out-the-vote effort.” MyBO was critical both in the early caucus states, where campaign staff was in place, and in later-voting states like Texas, Colorado, and Wisconsin, where “we provided the tools, remote training, and opportunity for supporters to build the campaign on their own,” the Obama campaign told Technology Review in a written statement. “When the campaign eventually did deploy staff to these states, they supplemented an already-built infrastructure and volunteer network.”

Using the Web, the Obama camp turbocharged age-old campaign tools. Take phone banks: through MyBO, the campaign chopped up the task of making calls into thousands of chunks small enough for a supporter to handle in an hour or two. “Millions of phone calls were made to early primary states by people who used the website to reach out and connect with them,” Franklin-Hodge says. “On every metric, this campaign has operated on a scale that has exceeded what has been done before. We facilitate actions of every sort: sending e-mails out to millions and millions of people, organizing tens of thousands of events.” The key, he says, is tightly integrating online activity with tasks people can perform in the real world. “Yes, there are blogs and Listservs,” Franklin-Hodge says. “But the point of the campaign is to get someone to donate money, make calls, write letters, organize a house party. The core of the software is having those links to taking action–to doing something.”

Pork Invaders

If the other major candidates had many of the same Web tools, their experiences show that having them isn’t enough: you must make them central to the campaign and properly manage the networks of supporters they help organize. Observers say that Clinton’s campaign deployed good tools but that online social networks and new media weren’t as big a part of its strategy; at least in its early months, it relied more on conventional tactics like big fund-raisers. After all, Clinton was at the top of the party establishment. “They [the Obama supporters] are chanting ‘Yes we can,’ and she’s saying ‘I don’t need you,'” Trippi says. “That is what the top of that campaign said by celebrating Terry McAuliffe [the veteran political operative and former Democratic National Committee chairman] and how many millions he could put together with big, big checks. She doesn’t need my $25!” The two campaigns’ fund-raising statistics support Trippi’s argument: 48 percent of Obama’s funds came from donations of less than $200, compared with 33 percent of Clinton’s, according to the Center for Responsive Politics.

Clinton’s Internet director, Peter Daou, credits the Obama campaign with doing an “amazing job” with its online social network. “If there is a difference in how the two campaigns approached [a Web strategy], a lot of those differences were based on our constituencies,” Daou says. “We were reaching a different demographic of supporters and used our tools accordingly.” For example, he says, the Clinton campaign established a presence on the baby-boomer social-networking site Eons.com, and Clinton herself often urged listeners to visit www.hillaryclinton.com. But Andrew Rasiej says that the conventional political wisdom questioned the value of the Internet. “As far as major political circles were concerned,” he says, “Howard Dean failed, and therefore the Internet didn’t work.”

While it’s hard to tease out how much Clinton’s loss was due to her Web strategy–and how much to factors such as her Iraq War vote and the half-generation difference between her and Obama’s ages–it seems clear that her campaign deëmphasized Web strategy early on, Trippi says. Even if you “have all the smartest bottom-up, tech-savvy people working for you,” he says, “if the candidate and the top of the campaign want to run a top-down campaign, there is nothing you can do. It will sit there and nothing will happen. That’s kind of what happened with the Clinton campaign.”

Republican Ron Paul had a different problem: Internet anarchy. Where the Obama campaign built one central network and managed it effectively, the Paul campaign decided early on that it would essentially be a hub for whatever networks the organizers were setting up. The results were mixed. On the one hand, volunteers organized successful “money bombs”–one-day online fund-raising frenzies (the one on November 5, 2007, netted Paul $4.3 million). But sometimes the volunteers’ energy–and money–was wasted, says Justine Lam, the Paul campaign’s Internet director, who is now the online marketing director at Politicker.com. Consider the supporter-driven effort to hire a blimp emblazoned with “Who is Ron Paul? Google Ron Paul” to cruise up and down the East Coast last winter. “We saw all this money funding a blimp, and thought, ‘We really need this money for commercials,'” Lam says.

Then there is McCain, who–somewhat ironically–was the big Internet story of 2000. That year, after his New Hampshire primary victory over George W. Bush, he quickly raised $1 million online. And at times last year, he made effective use of the Internet. His staff made videos–such as “Man in the Arena,” celebrating his wartime service–that gained popularity on YouTube. But the McCain site is ineffectual for social networking. In late June, when I tried to sign up on McCainSpace–the analogue to MyBO–I got error messages. When I tried again, I was informed that I would soon get a new password in my in-box. It never arrived. “His social-networking site was poorly done, and people found there was nothing to do on it,” says Lam. “It was very insular, a walled garden. You don’t want to keep people inside your walled garden; you want them to spread the message to new people.”

McCain’s organization is playing to an older base of supporters. But it seems not to have grasped the breadth of recent shifts in communications technology, says David All, a Republican new-media consultant. “You have an entire generation of folks under age 25 no longer using e-mails, not even using Facebook; a majority are using text messaging,” All says. “I get Obama’s text messages, and every one is exactly what it should be. It is never pointless, it is always worth reading, and it has an action for you to take. You can have hundreds of recipients on a text message. You have hundreds of people trying to change the world in 160 characters or less. What’s the SMS strategy for John McCain? None.”

The generational differences between the Obama and McCain campaigns may be best symbolized by the distinctly retro “Pork Invaders,” a game on the McCain site (it’s also a Facebook application) styled after Space Invaders, the arcade game of the late 1970s. Pork Invaders allows you to fire bullets that say “veto” at slow-moving flying pigs and barrels.

But it’s not that the campaign isn’t trying to speak to the youth of today, as opposed to the youth of decades ago. Lately McCain has been having his daughter Meghan and two friends write a “bloggette” from the campaign trail. The bloggette site features a silhouette of a fetching woman in red high-heeled shoes. “It gives a hipper, younger perspective on the campaign and makes both of her parents seem hipper and younger,” says Julie Germany, director of the nonpartisan Institute for Politics, Democracy, and the Internet at George Washington University. The McCain campaign did not reply to several interview requests, but Germany predicts that the campaign will exploit social networking in time to make a difference in November. “What we will see is that the McCain online campaign is using the Internet just as effectively to meet its goals as the Obama campaign,” she says. Over the summer, the McCain campaign refreshed its website. But Rasiej, for one, doubts that McCain has enough time to make up lost ground.

A Networked White House?

The obvious next step for MyBO is to serve as a get-out-the-vote engine in November. All campaigns scrutinize public records showing who is registered to vote and whether they have voted in past elections. The Obama campaign will be able to merge this data with MyBO data. All MyBO members’ activity will have been chronicled: every house party they attended, each online connection, the date and amount of each donation. Rasiej sees how it might play out: the reliable voters who signed up on MyBO but did little else may be left alone. The most active ones will be deployed to get the unreliable voters–whether MyBO members or not–to the polls. And personalized pitches can be dished up, thanks to the MyBO database. “The more contextual information they can provide the field operation, the better turnout they will have,” he says.

If Obama is elected, his Web-oriented campaign strategy could carry over into his presidency. He could encourage his supporters to deluge members of Congress with calls and e-mails, or use the Web to organize collective research on policy questions. The campaign said in one of its prepared statements that “it’s certain that the relationships that have been built between Barack Obama and his supporters, and between supporters themselves, will not end on Election Day.” But whether or not a President Obama takes MyBO into the West Wing, it’s clear that the phenomenon will forever transform campaigning. “We’re scratching the surface,” Trippi says. “We’re all excited because he’s got one million people signed up–but we are 300 million people in this country. We are still at the infancy stages of what social-networking technologies are going to do, not just in our politics but in everything. There won’t be any campaign in 2012 that doesn’t try to build a social network around it.”

Lessig warns that if Obama wins but doesn’t govern according to principles of openness and change, as promised, supporters may not be so interested in serving as MyBO foot soldiers in 2012. “The thing they [the Obama camp] don’t quite recognize is how much of their enormous support comes from the perception that this is someone different,” Lessig says. “If they behave like everyone else, how much will that stanch the passion of his support?”

But for now, it’s party time. At the end of June, after Clinton suspended her campaign, MyBO put out a call for the faithful to organize house parties under a “Unite for Change” theme. More than 4,000 parties were organized nationwide on June 28; I logged in and picked three parties from about a dozen in the Boston area.

My first stop was a house party in the tony suburb of Winchester, where several couples dutifully watched an Obama-supplied campaign video. Host Mary Hart, an art professor in her 50s, said that Obama and his website made her “open my house to strangers and really get something going.” She added, “I’m e-mailing people I haven’t seen in 20 years. We have this tremendous ability to use this technology to network with people. Why don’t we use it?”

Next stop was a lawn party in the Boston neighborhood of Roxbury, whose organizer, Sachielle Samedi, 34, wore a button that said “Hot Chicks Dig Obama.” She said that support for the Obama candidacy drew neighbors together. At the party, Wayne Dudley, a retired history professor, met a kindred spirit: Brian Murdoch, a 54-year-old Episcopal priest. The two men buttonholed me for several minutes; Dudley predicted that Obama would bring about “a new world order centered on people of integrity.” Murdoch nodded vigorously. It was a fine MyBO moment.

My evening ended at a packed post-collegiate party in a Somerville walk-up apartment. Host Rebecca Herst, a 23-year-old program assistant with the Jewish Organizing Initiative, said that MyBO–unlike Facebook–allowed her to quickly upload her entire Gmail address book, grafting her network onto Obama’s. “It will be interesting to see what develops after this party, because now I’m connected to all these people,” she shouted over the growing din. Two beery young men, heading for the exits, handed her two checks for $20. Herst tucked the checks into her back pocket.

David Talbot is Technology Review’s chief correspondent.

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