Politics makes for strange bug-fellows

Rather than “royally” waste money funding infectious disease research for geopolitical reasons, developed nations must instead establish well-funded, well – connected consortia to help countries with the greatest chance of success, world health experts said today.

The recommendation comes exactly one week before the Bush-sponsored Global Fund to Fight AIDS, Tuberculosis and Malaria doles out its first set of grants.

“We must move away from dispensing aid for geopolitical reasons, because such aid is usually royally wasted,” said Olusoj Adeyi, a senior health specialist at the World Bank. Speaking at a forum on emerging infections sponsored by the US National Academies of Sciences (NAS), the goal, he added, is to transform national entities “to a unified epidemiological system.”

Resources should instead be channeled into “countries that have the best ability to make progress, or make policies,” said William Steiger, of the US Department of Health and Human Services.

The Global Fund has thus far collected $2 billion in pledges from both public and private sectors. But combating infectious diseases is estimated to require tens of billions of dollars annually, according to the World Health Organization.

Because much of the money required will come from the private sector and philanthropic organizations ultimately, Steiger says, making the fund, and its operation, credible to the private sector is critical to its success.

At the same time, organizations cannot simply use corporate strategies in addressing emerging infections, cautioned Roy Widdus, of the Initiative for Public -Private Partnerships for Health. “We cannot adopt approach of business everywhere in international public health.”

While funding must be performance-based, Widdus added, “we need to make sure that it doesn’t divert our attention in thinking about how to help people who have been failed by their governments.”

As a consequence of globalization, disease burdens in the developing world are affecting the developed world, notes Adeyi. To combat infectious diseases around the world, developed nations must deploy their advanced disease-control capabilities and resources in should be deployed in developing ones.

Ensuring the effectiveness of these partnerships is going to require a lot of money, a long -term commitment, and the right reasons for helping developing countries, he added.

Several speakers also emphasized the importance of developing long-term programs in countries of need, rather than dumping enormous sums of money for the short term.

“Soft funding leads to squishy results,” said the Fogarty International Center’s Eric Mintz. Funding human resources does just as much “global good” as funding the development of products like vaccine, medicines, and new diagnostic technology, Mintz said, referring to his agency’s newly established program on funding US-trained foreign scholars to establish labs in their home countries.

Funding product development in the absence of personnel who can appreciate and properly utilize it, he added, is only taking care of half the job.

Unmet need in infectious disease research: social science

Despite nearly a decade’s consensus that numerous social factors contribute to the global spread of infectious diseases, the field still suffers from a dearth of important social-science information, according to a researcher speaking at a meeting of the US National Academies of Sciences (NAS) today.

“We need to look at population movements, organization, behaviors, and culture,” said Jonathan Mayer, a geographer at the University of Washington. At the NAS Institute of Medicine’s forum on emerging infections, Mayer spoke on how the dynamics of vector-borne diseases are changing with increased globalization. Understanding these dynamics means we must unify vector and human ecology, he said.

In 1992, an IOM workshop in which Mayer participated identified numerous social factors, such as land use, civil unrest, and demographics, as contributing to microbial threats to health. Since then, little has been done to show how these factors influence emerging infectious diseases, he contends.

“Social and behavioral sciences are just starting to pay attention to this suite of issues,” agreed Deborah Balk, a researcher at Columbia University’s Center for International Earth Science Information Network whose work focuses on how climate change affects public health in developing countries. (Balk was not present at the meeting.) “Much of the dialogue has been too narrowly focused on how a particular climate anomaly may affect a particular disease vector, without sufficient regard paid to climate variation and intervening factors like migration or land use adaptations,” she told BioMedNet News.

Population movement was a recurring theme among many forum participants today. Between the mid-1970s and 1990s, considering migrant workers, refugees, and internally displaced populations, the volume of human movement in the world has increased fourfold, said speaker Martin Cetron of the US Centers for Disease Control and Prevention. Because it now takes less than 36 hours to circumnavigate the globe, Cetron added, the incubation periods of many diseases are now shorter than the time it takes to move from one place to another.

Therefore, he said, “disease is going to emerge in the clinics and communities of the points of destination, not during travel.” However, he suggested, it may become necessary to reintroduce “vector spraying” on international flights.

Increasing population movements, coupled with the rapid increase in the urbanization of the developing world, will yield conditions ripe for outbreaks, warned Harvard professor of population and international health Mary Wilson. “These areas are typically poor, warm, and surrounded by large slums and shanty towns that lack infrastructure and resources,” Wilson said.

Urbanization is also a factor that needs to be considered, she added. Outbreaks in cities of the developing world may be globalized more readily because, unlike their counterparts in the developed world, these cities tend to be linked both to rural areas (from poor people seeking work) and to the larger world community, via international airports, she said.

Migrational activity is much more continuous in developing urban areas, said Balk, and this may lead to people moving around with various disease “burdens.” But while there are studies that show migration indeed has an impact on disease, it’s much harder to show the more complex picture of how seasonal migration affects the sending and receiving communities, she said.

“People know that migration matters, it’s just hard to quantify,” she said.

Alzheimer’s amyloid proponents pinpoint precursors

After years of arguing that monstrous clumps of misfolded proteins, known as senile amyloid plaques, cause neurodegenerative diseases such as Alzheimer’s (AD), proponents of the hypothesis now think that smaller, maverick precursors of these proteins may in fact be responsible, according to two papers published today.

“There have been a lot of ideas bouncing around about small clumps being the toxic entity, and these papers provide some of the first compelling evidence along those lines,” said Nancy Bonini, a geneticist at the University of Pennsylvania.

Bonini, who was not involved in either study, has worked extensively on the role of protein misfolding. Her research has shown that increasing the levels of “chaperone” proteins, which help other proteins fold properly, reduces misfolding and will suppress the onset of certain human neurodegenerative diseases in transgenic fruit flies.

The papers deal with two studies of misfolding, one in vitro and the other in vivo.

In the in vitro study, an anglo-italian team chemically unfolded normally harmless bacterial and bovine proteins, and allowed them to refold. In the process of refolding, the proteins almost immediately began forming various, misfolded aggregates. After a few days, these aggregates started to develop “protofibrils,” and after about 20 days, the protofibrils were replaced by mature amyloid fibrils.

The team, led by Christopher Dobson of the University of Cambridge, found that while the mature amyloids were harmless to cells, the earlier aggregates – the protofibrils – were highly toxic.

In the in vivo study, a Harvard team injected dimers and trimers of the human amyloid -beta protein into the brains of rats, and found that these much smaller aggregates “markedly” inhibited long -term potentiation (LTP), a measure of memory and learning.

Dennis Selkoe, who led the Harvard team, is a longstanding proponent of the amyloid theory; this latest report represents a significant modification of his traditional stance.

These papers, published in Nature, suggest that fibrillar amyloid is now not ‘it,’ or at least certainly not the only culprit, says Bonini. “It’s a big step forward to have identified specific forms that are clearly showing toxicity,” she told BioMedNet News.

But the work fails to convince Mark Smith of Case Western Reserve University, who believes that amyloids are a consequence, not a cause of Alzheimer’s.

“In all neurodegenerative diseases characterized by accumulation of insoluble proteins – whether prion proteins in Creutzfeldt -Jacob disease or amyloids in AD – I would propose that they’re there to protect the brain,” he told BioMedNet News.

Smith says the studies are “interesting from a purely scientific perspective” and give insight into the importance of protein folding and cell death. He remains circumspect about their importance in the etiology of neurodegenerative disease, however. The authors show a correlation, but a correlation does not mean they have proven causality, he notes.

“First, I’m not convinced we’ve shown that these oligomers or protofibrils exist normally in the human brain, or are just artifacts from the process of chemical isolation,” he said.

Even if they did occur in vivo, no one knows the general function of amyloid proteins, he adds, highlighting the public failure earlier this year of an AD vaccine after 15 patients developed brain inflammation and their Alzheimer’s symptoms worsened. The vaccine inhibited beta-amyloid production.

Before anyone gets too excited about this latest round of findings, Smith says, amyloid proponents should first analyze the data from the patients who participated in the clinical trial.

If their oligomer levels went up and their symptoms worsened, he says, then this supports the hypothesis that oligomers may play a role in causing the disease.

“But if levels went down because of vaccination therapy, and this would be expected [since the vaccine should have decreased amyloid production], then they should abandon this theory,” he said.

Blocking kinase shown to limit heart attack damage

The key to repairing heart tissue damage after a heart attack or cardiac surgery may be to inhibit an enzyme known to play a role in congestive heart failure, says a Duke University researcher. His latest studies, reported this week at the New York Academy of Sciences, show that blocking the enzyme beta-adrenergic receptor kinase (bARK) reduces damage to left ventricular function after heart attack.
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This bolsters work published a year ago, which suggested the same protective effect in hearts that stop and then resume beating. The Duke team hopes that the findings may ultimately lead to new enzyme-blocking drugs that could be given either after heart attack or heart surgery, or prophylactically in people at high risk for heart attacks.

Walter Koch and his team used gene therapy on rabbits to inhibit bARK, which is present in failing hearts typically at three to five times normal levels. Using a modified adenovirus as a vector, Koch introduced the gene for bARKct, which blocks bARK, into the rabbits’ heart cells. At the same time, the investigators also placed a loop around one of the arteries before closing the chest and allowing the animals to recover. Later, they triggered a heart attack by pulling on the loop, and then measured heart functions for 45 minutes.

The bARK-inhibited hearts showed “significantly attenuated” ventricular function compared to that usually observed under such conditions, said Koch. The results are as yet unpublished.

The experiment builds upon the team’s previous work, which showed first that gene therapy with bARKct could heal damaged tissue even three weeks after a heart attack, and then showed that bARKct hearts were better able to withstand the damage associated with cold cardioplegic arrest, the customary method of stopping hearts during bypass operations and harvesting and transport before heart transplant.

Koch and his collaborators “have now amassed a convincing body of evidence” to support the therapeutic strategy of targeting bARK in naturally occurring heart failure, says Gerald Dorn, who is director of cardiology at the University of Cincinnati.

At the New York meeting, Koch also presented unpublished results from his lab’s microarray research on DNA from mice that had been genetically engineered to have heart failure, which bolster the rabbit experiments. “We were able to blindly predict the difference between the normal and heart failure mouse based solely on their gene expression,” says Burns Blaxall, who conducted the experiment.

Earlier experiments showed that cross-breeding mice prone to heart failure with mice that expressed bARKct “rescued” the offspring; the heart-failure phenotype was prevented. In microarray experiment, Blaxall was able to discern genetic differences between heart failure mice and “rescued” mice.

Dorn says this suggests “bARKct is somehow directly addressing the causative factor” and “acting at the genetic level to prevent some of the critical molecular perturbations of heart failure, not just generally enhancing myocardial function.”

The Duke experiments show potential for either gene therapy with bARKct, Dorn told BioMedNet News, or for creating an analagous drug.

“The precise mechanisms of how bARKct prevents heart failure and enhances post-ischemic myocardial function will no doubt be worked out in the coming months and years,” Dorn predicted. Whether the work is relevant to humans remains to be seen; Koch is planning clinical trials of the gene-therapy approach, starting with end -stage heart failure patients.

The Duke team feels the gene therapy approach is not the most practical for humans. They are hoping to encourage drug companies to search for small-molecule bARK inhibitors. Koch says a number of biotech firms are already looking into receptor kinases.

Smoking gun in nicotine addiction

The discovery, released today, of a new mechanism by which nicotine increases dopamine levels in the brain even hours after exposure may lead to a clearer picture of addiction and “better medications, with less side effects,” according to some addiction experts.

Neurobiologist Daniel S. McGehee and his colleagues at the University of Chicago have found that nicotine inhibits the release of the neurotransmitter GABA, which normally serves to turn off brain dopamine production. “This depression is due to the desensitization of the nicotinic receptors on the GABA cells,” McGehee told BioMedNet News.

Scientists have long known that nicotine, like most other addictive drugs, increases the production of dopamine in the reward system of the brain, which acts to reinforce behaviors critical to survival, such as drinking when thirsty or eating when hungry. Nicotine increases dopamine levels by mimicking the neurotransmitter acetylcholine (ACh), and binding to its receptor sites on dopaminergic neurons in the brain’s ventral tegmental area (VTA).

A single cigarette has enough nicotine to exhaust all the ACh receptors in the VTA within a few seconds, which left researchers puzzling to figure out why the levels of brain dopamine still continue to increase hours after a smoke. McGehee’s findings, which appear today in Neuron, may provide the explanation.

“They finally take us beyond common knowledge,” said Stephen Dewey, a neuroscientist at the Brookhaven National Laboratory. The new findings “clearly supports” research at BNL, where researchers have effectively treated the biochemical effects of all drugs of abuse by increasing the “outflow” of dopamine rather than just by inhibiting dopamine production.

Dewey is hopeful the next generation of drugs to treat nicotine addiction may include glutamergic and GABA compounds. The new knowledge should also be applied to behavior studies, because “addiction to nicotine is not just biochemical,” Dewey said.

McGehee’s findings build upon previous work that nicotinic receptors can increase the release of glutamate, another neurotransmitter that, like ACh, enhances dopamine production. The inhibition of GABA, however, is mediated by a different nicotinic receptor than the one responsible for enhanced glutamate release.

“The receptors on GABA neurons undergo desensitization more easily [with lower nicotine concentrations] than the ones that enhance glutamate release,” McGehee said. “We’re starting to get a clearer picture of how the profile of nicotine that a smoker experiences ultimately promotes dopamine release, which leads to the pleasurable or reinforcing effects.”

The new findings are “extremely important,” said John Dani, a neuroscientist at the Baylor College of Medicine. The next step, Dani said, would be to use intact animal models to understand the association between altering the circuitry and the consequent effects on behavior and decision-making.

Due to technical reasons, the researchers were forced to carry out experiments in young rats. “We know that nicotinic receptor expression varies over development, and very little drug abuse research has been carried out on rats at these young ages,” McGehee said. Continuing their GABA work on adult animals “will allow us to characterize the behavior of an animal and then test the
effects of nicotine.”

Safety assessments at a snail’s pace

After six years of deliberations, the US Environmental Protection Agency (EPA) today ended the public comment period on a longawaited cumulative risk assessment methodology for the organophosphate class of pesticides. But six years is far too long, and the whole process highlights inadequacies in the way the agency seeks and utilizes scientific counsel, contend some experts.

“The input sought and received from the scientific community has been far too narrow,” pesticide risk expert Charles Benbrook told BioMedNet News. “Only a handful of scientists have paid attention to this risk assessment.”

Benbrook, who submitted comments on Friday, directed a National Academy of Sciences committee to review stronger pesticide tolerances for food, in the late 1980s. Based partly on work by Benbrook’s committee, the 1996 Food Quality Protection Act (FPQA) requires the EPA to calculate the combined, or “cumulative,” effects of exposure to chemicals that have a common mechanism of toxicity, before it can set regulatory tolerances for those chemicals.

To assess risk, the EPA forms scientific advisory committees and invites a broad spectrum of experts from the academic, public interest, and industry communities to join them. All committee members are subject to federal laws regarding conflict of interest. The agency also tries to avoid people who have taken any public positions on an issue, says William Jordan, of the EPA’s Office of Pesticide Programs.

In the case of the widely-used organophosphates, known to interfere with the neurotransmitter acetylcholine, the methodology took six years to compile, totals nearly 3,000 pages, and is only the first of many the EPA will have to develop.

For most academic scientists, the “return on investment” on the work required by committees is simply inadequate, notes Routt Reigart, who has chaired the EPA’s Children’s Health Advisory Protection Committee for the last four years.

Being on a committee is time -intensive, says Reigart, a pediatrics professor at the Medical University of South Carolina. “If you take the time to advise EPA, you’re not doing what you are paid to do by your institution, which is to teach, write grants, conduct research.” A staff scientist for an industry group, in contrast, is “paid to sit on these panels and advise and lobby.”

The most frustrating aspect of the experience, Reigart told BioMedNet News, is that participants are often not informed of the outcomes, if any, of their advice. Being an advisory member is generally not highly valued in academic circles, he says, and many scientists feel they could spend their time in more rewarding ways.

The process is also “highly contentious and highly politicized,” said Benbrook, and it turns off many well-meaning scientists. “This is the wild, wild west of scientific dialogue,” he said. As a result, he adds, many advisory groups tend to be dominated by industry participants, because they have the most time to study the issues and prepare their expert commentary.

At the same time, the regulatory system must be based on sound science, points out Angelina Duggan of the American Crop Protection Association, an industry group that also submitted comments on the organophosphate risk assessment. If scientists “really believe that something is worth saying, or feel the need to set the record straight, then you owe it to the scientific community to participate,” just as if they would in an annual scientific meeting, she said.

“I wouldn’t disagree that the process can be political,” Duggan said. But while the process is not perfect, it’s “the best we have and need to work within it.”

APOE4 may also detect brain aging

A Duke University researcher has found signs of accelerated aging in the brains of healthy people who have a well-known genetic marker for Alzheimer’s disease (AD). Are they on their way to Alzheimer’s, or is this something different?

His unpublished results will help to resolve the question – but at the moment another researcher in the field is dubious that he has truly found a new phenomenon.

P. Murali Doraiswamy reported the newfound link between brain aging and the APOE4 allele, which is well known to be associated with Alzheimer’s disease, this week at the American Association of Geriatric Psychiatry. His team has used a novel application of an established technique, magnetic resonance spectroscopy (MRS), to measure a surrogate marker for brain aging, N-acetylspartate (NAA), in the frontal lobes of 165 healthy people aged 55 to 85, and then related these levels to whether or not they carry APOE4.

Doraiswamy and his colleagues used MRS, an adaptation of magnetic resonance imaging (MRI) “because it’s non-invasive, and because we can get metabolic information, just as if I had cut out a piece of tissue, and we can do this serially [over time],” said Cecil Charles from Duke’s Images Analyses Laboratories.

NAA levels in the frontal cortex declined “mildly” with age among all the participants in the study (R=-0.28, p<0.05); according to Doraiswamy many prior findings in the field suggest that everyone suffers from some age-related decline in frontal lobe nerve cell function. However, “the average loss of NAA across the age span was nearly threefold higher in people with the APOE4 gene than in those who were not carriers,” he said. (R=-0.45, p<0.001). Further, the APOE4 group was younger. If anything, he said, if the phenomenon could be explained by age alone, that group should have shown it to a lesser degree.

Previous studies have reported exaggerated changes in NAA levels in patients with full-blown Alzheimer’s disease who carry APOE4.

“To the best of my knowledge, this is the first report in which this technique has been employed to study a cognitively intact elderly population,” said New York University geriatric psychiatrist Nunzio Pomara, who chaired the session in which Doraiswamy presented his findings.

But Rob Friedland is not convinced that the study participants were all healthy. “The researchers found changes in the brains of those carrying APOE4, but this is probably because some of these individuals had very early stages of Alzheimer’s disease, and not as a result of brain aging,” the Case Western Reserve University researcher said in an interview, adding that Alzheimer’s and brain aging are not necessarily the same.

Friedland also disagreed with Doraiswamy’s premise that the frontal cortex is “the place where the earliest and most consistent effects of aging occur in the brain.” Aging effects occur in the temporal lobe as well, particularly in the hippocampus, he said. “They are testing part of the changes, but not all of them.”

But Doraiswamy has noted that his study looked at the frontal lobe intentionally, because preclinical AD-related changes “are more likely to occur in the temporal lobe,” he told BioMedNet News. “It’s still possible that our findings represent not just accelerated normal aging in this group, but also an increased rate of preclinical Alzheimer’s-type changes,” he said.

Doraiswamy adds that he intends to look at how different agerelated changes are between those patients who have both the APOE4 allele and a family history of AD, to those who have neither. He will also follow his subjects to see if those with the lowest NAA levels go on to develop Alzheimer’s.

Much DNA really is junk, say drug developers

Only a minimal number of useful drug targets have emerged since human genome information exploded with new data into the pharmaceutical field, speakers agreed at the BioSilico 2002 conference in New York this week.

From the drug development perspective, they agreed, much of the genome appears to be “garbage.”
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