Health Meaning

W ASHINGTON, DC - A review by recasting program peers national Institutes of health (NIH) takes the intense fire of the AIDS community. Complaints activists patients and scientists have been accumulating for 2 weeks in the scientific review for NIH Center (CSR), which is considering the recommendations of a group led by Bruce Alberts, president of the National Academy of Sciences, to redraft grant applications rank groups ( science , 30 July, p. 666).

The Alberts committee suggested the review committees grouping peer in broad areas of science rather than specific disease categories or methods of research, as many are now grouped. For example, the panel proposed the removal of the existing category "AIDS and AIDS-related research" and moving the sections seven study under this heading in new, more general scientific categories such as immunology or behavioral processes.

One critic Mario Stevenson, a virologist at the University of Massachusetts, Worcester, said: "I am a firm believer in the old saying:" If it is not broke, do not fix it. "... And I think that criticism in the field of AIDS work very well." He and others have approved letters of protest, arguing that the elimination of the specific category dilute expertise AIDS and lower the quality of peer review. Charles Carpenter of Brown University, Chairman of the Board, which advises the NIH Office of Research on AIDS, sent a letter to CSR behalf of the warning that the proposed reform council could expose grant proposals "a review by investigators do not have appropriate AIDS research knowledge. "

CSR director Elvera Ehrenfeld said she was surprised by the angry reaction. She thinks that AIDS researchers may be confused by "an unfortunate misunderstanding" that the existing study items disappear. the AIDS panels would simply be placed into new groups, she said. However, some critics "may be valid," Ehrenfeld said, "and that's why we asked for feedback, "which are due to CSR on 15 October Alberts also wants to dispel concern.". It is clear that we must explore with AIDS researchers exactly what bothers and why "

B ETHESDA , M ARYLAND - Doctors and scientists from University of Pennsylvania defended their clinical judgment today in the case of Jesse Gelsinger, 18, who died September 17 while receiving experimental gene therapy. At a meeting here, the National Institutes of Health, a team leader and gene therapy pioneer James Wilson said he "felt comfortable" with the decision to treat the teenager with a strong dose of virus GM, though it is clear in retrospect that the viral concoction has killed Gelsinger.

Wilson and his co-researchers, Mark Batshaw and Steven Raper, presented data suggesting that unexplained anomaly is Gelsinger in metabolism, genetic makeup, or immune status triggered a toxic reaction to the therapy --a response that could not have been expected, they said, on the basis of earlier data.

Gelsinger had a rare genetic disorder, ornithine transcarbamylase (OTC) deficiency, which can cause a lethal buildup of ammonia in the body. Although he kept his symptoms under control through diet and the ammonia-drugs lowering, he volunteered to join the trial for gene therapy for risk, hoping it would lead to a cure. Gelsinger, 18 patient to be treated in the study died of respiratory failure four days after receiving a high dose of adenovirus genetically crippled (a common cause of human infections) which was equipped with the human gene little by little.

defense team came after gene therapy authorities to the Food and Drug Administration (FDA) yesterday blamed the Penn trial. Kathryn Zoon, director of FDA's Center for Biological evaluation products and research, said a preliminary investigation had found "gaps" to a protocol approved by the FDA agreed. An official at the FDA found that when Gelsinger underwent therapy, the ammonia level in the blood was more than 50% above the maximum permissible level specified in the memorandum, a deviation from the plan that the FDA n has not been notified in advance. Batshaw acknowledged that "we would have called FDA" about the change.

Other researchers say the team took a risky approach by administering high doses of the modified virus. "They pushed the edge of the envelope, "says Thomas Caskey, director of the therapy program and Merck Genome Gene West Point, Pennsylvania.

HIV may well be the most studied virus of all time, but the steps between its introduction into the body through sexual intercourse and an established infection remains mysterious . Now, researchers reported intriguing evidence that a poorly understood protein may allow the virus to sneak behind the defenses of the body. In addition to clarifying the mechanism of the sexual transmission of HIV, the findings identify new targets for vaccines against AIDS.

The new work, presented in two articles in the cell on March 3 , was born studies of dendritic cells, the sentinels that alert the immune system when the violent invading the borders of the body . The researchers reported that a protein called DC-SIGN carries HIV dendritic cells in the mucosa of the cervix or rectum to distant lymph nodes. There, the DC-SIGN hands HIV in CD4 ⁺ T cells, immune cells that the virus easily infects and destroys, eventually leading to AIDS.

The team, led by Yvette van Kooyk, a tumor immunologist at the Medical Center of the St. Radboud University in Nijmegen, the Netherlands, conducted test tube experiments to learn how HIV interacts with DC-SIGN. The protein binds tightly to the virus, they report, stabilize during the trip of the lining to lymph nodes. This stabilization makes a huge difference: No DC-SIGN, HIV has lost its infectivity in less than a day. Protected by the protein, however, the virus could infect CD4 cells after 4 days.

On a practical level, the results can inform vaccine design. To date, many HIV vaccine designers aim to elicit antibodies that disrupt HIV fusion with CD4 its targets. Now, one might seek to induce antibodies that block the binding of DC-SIGN to HIV. "It is a very elegant work," said AIDS researcher Douglas Richman of the University of California, San Diego.

T UCSON , A RIZONA - If the pharmaceutical companies are good at thing, there are tons of new molecules. In recent years they have embraced a technical producer of high-speed drugs known as combinatorial chemistry to multiply the new compounds by the millions. The problem is that few ever work against diseases. But at a meeting on the future of combinatorial chemistry here yesterday, a chemist proposed a new way to increase the chances :. Pair the most promising building blocks to produce compounds whose activity is much greater than the sum of their parts

a popular technique in combinatorial chemistry is to start with a handful of molecular building blocks then connecting in all possible combinations. As expected, the number of compounds quickly becomes unwieldy. Using all currently available building blocks, the researchers could produce a staggering 10 ⁶⁰ small combinations druglike molecules.

To make things more manageable, Jonathan Ellman of the University of California, Berkeley, and his colleagues have focused on the components with the best chance of success. They are turned toward a class of molecular building blocks called oximes which are common components of pharmaceuticals. The researchers screened a library of just over 300 oximes for their ability to bind to a cell-signaling protein called Src, which is considered too active in cancer and osteoporosis. When tested alone oximes, about 10% showed moderate ability to inhibit Src in the test tube. However, when these have been linked to poor binding, the story changed dramatically. The team synthesized Ellman about 4000 pairs of oxime and found a handful of potent inhibitors of Src, a success rate that usually requires much more compounds.

The new approach is powerful because it has the potential to produce drugs that bind to more than one part of a target molecule, said Sheila DeWitt, a combinatorial chemist Arqule, a company Woburn, Massachusetts. This could lead to a new way to make ultra powerful drugs. "If it works, it will have enormous value," she said.

B ETHESDA , M ARYLAND - It is time for bold action to stimulate the development of vaccines for major killers in the world - AIDS, malaria and tuberculosis - according to a panel of experts convened here May 22 to 23 Technically, these vaccines are feasible, the group concluded, but the funding will go up considerably

Scientists believe that new vaccines are the only way to get the great plagues of the world under control. Economists believe that healthy populations could also be a shot in the arm for development, particularly in Africa. But with the exception of AIDS, the pharmaceutical industry has not taken much interest in the development of vaccines against common diseases because they do not expect to make a profit. And there was little political support on Capitol Hill to pass on diseases that afflict some US citizens.

But it seems to change. Recently, the industry leaders have expressed a desire to help, and in January, President Clinton announced his Millennium Vaccine Initiative, in which he proposed a series of measures to boost research on vaccines. Bills introduced in the House and Senate would do the same. The meeting this week was held at the request of Clinton and hosted by the National Institute of Allergy and Infectious Diseases (NIAID), was set up to propose new ways to propel the development of vaccines. With the peaking political interest, "now is your chance, people," said NIAID Director Anthony Fauci them together researchers, experts in public health, and executives from the pharmaceutical and biotechnology industry

In three sessions -. For tuberculosis, malaria and AIDS - participants identified the main obstacles on the road to a vaccine and came with a plethora of ideas to make them disappear. The malaria researchers want the president to launch a "vaccination against malaria aggressive" and increase federal funding of the current $ 25 million to $ 500 million per year; Moreover, the US should commit to buying $ 500 million a year the value of vaccines once they have been developed to ensure the industry with a market. AIDS group called for a funding increase of 10 times, while TB researchers suggested the establishment of a new agency, flexible funding that rewards good scientific ideas quickly. The suggestions will be compiled into a report and sent to the White House.

Get scientists and industry to map out a common strategy "is a very important step," said Malegapuru Makgoba, Chairman of the South Africa Medical Research. And with the current political momentum, the results are handy, Makgoba said: ". I am confident, for example, that we will see a vaccine against AIDS in the next 5 or 6 years "

D URBAN , S OUTH A AFRICA - When the south African president Thabo Mbeki has risen to meet the opening ceremony of the international AIDS Conference XIII yesterday, thousands of researchers in packed Kingsmead Stadium hoped he was going to say three simple words: the causes of HIV AIDS. He did not do it. "He waffled while Rome burns," said Glenda Gray, a pediatrician who co-directs an HIV perinatal clinic in huge Chris Hani Baragwanath Hospital in Soweto.

Mbeki recently convened a panel to help his government develop policies against the growing AIDS crisis, but it has included so-called "dissidents", who insist that HIV does not cause the disease and whether AIDS is a new disease or old diseases collectively given a new name. scientists around the world have rebuked Mbeki to give new vitality to the dissidents, whose community arguments had it a few years ago to licensees background. Many hoped that the President would finally distance themselves from eccentric views.

But Mbeki addressed the issue indirectly. much of his speech quoted a report by the World Health Organization 1995 that fingered "poverty extreme "as" the biggest cause of ill health and suffering across the world. " Mbeki noted, however, that his government would continue to intensify its anti-AIDS campaign promoting condom use, support for research on vaccines against AIDS and HIV medications, and respond humanely "to people with AIDS and HIV. "But he made no mention of its decision not to provide relatively cheap course of anti-HIV drugs to infected, pregnant women, which studies have shown can reduce 50% HIV transmission to their babies.

failure of Mbeki to acknowledge directly that HIV causes AIDS researchers angered against AIDS in South Africa and elsewhere. "it was a good opportunity for him put a closure on the whole, and he did not, "complained virologist Lynn Morris, who works at the Johannesburg National Institute of virology and sat on the panel that Mbeki convened. Indeed, many researchers and activists have left during the speech by Mbeki.

Yet some South African researchers have seen up the speech as a step forward. "Considering all that we experienced in the past months, it is an excellent speech," said Malegapuru William Makgoba, Medical Research Council of the leader of the country and another member of the Mbeki panel. "He had the ability to just about AIDS. But he always talked about HIV-AIDS. Then he connects HIV to AIDS. "What some saw as the exact wording, Makgoba concluded was a" clever way "for Mbeki to disengage from the debate. Those who criticized the speech, Makgoba said, were" surly. "

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pig cells released an ancient virus when transplanted into mice lacking an immune system, according to results published in the August 17 issue of Nature . This transmission is a potential concern for xenotransplantation research, but there is still no evidence that the virus overnight guests or it could trigger an outbreak. "This virus is not very scary," says transplant biologist David Solomon of The Scripps Research Institute in La Jolla, California, who led the study.

All pig cells contain the so- called porcine endogenous retrovirus (PERV), which usually hibernates as a DNA fragment into the genome of the pig But when retroviral genes are activated. - we do not know how it happens - the cell begins churning out viral particles theoretically. these particles could spread to other species. Some scientists fear the virus could sicken transplant patients, or even spread to other people. Solomon and his colleagues decided to study the PERV activity in cells pancreatic islets, which have already been transplanted in pigs in some human diabetics.

the team injected cells of pig islets in mouse kidneys that lack immune system function. These so-called NOD / SCID accept pig tissues as their own (as do the transplant patients receiving immunosuppressive drugs). When the team tested the activity of PERV islands over the next seven weeks, they found signs of an active infection. Because the mouse lived in a sterile environment, the transplant procedure must be "awakened" the pig retroviruses. In addition, they found that the pig cells were scattered throughout the body in 17 of 25 mice, and some of these wandering cells had infected cells near the mouse.

This is not necessarily the cause of the alarm. Nobody has found no evidence that PERV is spreading in people or non-human primates used in research of xenotransplantation notes Khazal Paradis, a doctor of transplantation with Novartis in the UK. "The bottom line," Solomon adds, "is that we do not have sick animals, and we do not have sick patients."

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full text of Nature

a study in this week's issue of science showed that a new AIDS vaccine can protect monkeys from getting sick, providing new avenues for AIDS vaccine human. But experts warn that many barriers remain high, and there are currently no plans to move the experimental vaccine in human trials.

The study, led by Norman Letvin and Dan Barouch of Beth Israel Deaconess Medical Center in Boston, in collaboration with Merck Research Laboratories in West Point, Pennsylvania, combines several high-tech concepts. The heart of the vaccine is a bacterial DNA fragment, called a plasmid, which can carry genes from other organisms. genes contained a plasmid encoding SHIV proteins, a combination of HIV and simian cousin, SIV concocted laboratory. In addition, the researchers created another plasmid encoded a messenger of the immune system, interleukin-2 (IL-2), attached to a piece of an antibody, or immunoglobulin (Ig). This protein, the researchers hoped, would rev the immune response of the vaccine.

When challenged with a relatively high dose of SHIV which rapidly destroys the immune system in apes, animals that received the vaccine developed a fictitious disease or died within 140 days. The monkeys that received the DNA vaccine and IL-2 / Ig plasmid, however, fared better. All had an intact immune system and low levels of SHIV in their blood after 140 days

The researchers also added new fuel to a long-standing debate on the power of antibodies against another warrior, immunological killer T cells. In the early days of vaccine research against AIDS, almost everyone in favor of vaccines aimed to stimulate antibody. More recently, the killer T cells have become the preferred goal. This experiment showed that the killer T cells played the main role in the control of SHIV infection in monkeys.

"The study is very carefully done, and the results are as good or better than anything tried in experimental settings," said Ronald Desrosiers Central New England Regional Primate Research in Southborough, Massachusetts. But no should get their hopes up too high, he added. Desrosiers, whose laboratory first protected monkeys clean with a vaccine against AIDS 11 years ago, said that "we need to be careful to remember that these are optimized laboratory parameters. "

There are other obstacles, too. Interleukin-2 may have serious side effects and if used in the wrong dose, could hinder an effective immune response, says Emilio Emini, head of vaccine against AIDS researcher at Merck. Merck currently has a single DNA vaccine in a small human study and does not intend to test this more complex vaccine in humans.

Furthermore, notes Letvin, experience "challenged" the monkeys with a strain of SHIV that is identical to the DNA vaccine - a very artificial scenario. In the real world, vaccinated people would face a wide range of HIVs. Letvin but stressed that the point of the study is to demonstrate that a vaccine can accomplish if it powerfully stimulates killer T cells. "It is way short of our ultimate goal, but until we reach that, this is a good place to be," says Letvin.

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NIH vaccine against AIDS

the International AIDS vaccine Initiative

a vaccine to protect children against polio have instigated a recent outbreak of the disease in the Dominican Republic and Haiti - the first outbreak of polio in the Western Hemisphere in over 9 years. This is the first reliable report that a polio-strength vaccine strain can be returned to a virulent and contagious spread. A mass vaccination campaign already in the works is expected to contain the epidemic.

The oral polio vaccine is very effective and easy to administer. But because it uses live strains, but weakened virus, it causes associated paralytic polio vaccine in about 1 of every 750 000 people receiving, usually those whose immune system is weakened. There was no evidence that this form of the disease induced by the vaccine is contagious.

Now an epidemic on the island of Hispaniola demonstrates that the vaccine can mutate to a virulent form and spread. Three children in a rural area of ​​the Dominican Republic and another child in a remote area of ​​Haiti came down with paralytic poliomyelitis in July and August. None of the children had been vaccinated against the disease. Laboratory analysis, first by a local laboratory and then by the US Centers for Disease Control and Prevention in Atlanta, found that the children had been infected with a vaccine derived virus that had become virulent. The Pan American Health Organization (PAHO), which announced the results of the December 1, convened a group of scientists to study the data and recommend action.

The World Health Organization, PAHO is a division strives to eradicate polio worldwide by 05. That incident will delay the schedule remains to be seen, said Donald Henderson, an epidemiologist at Johns Hopkins University in Baltimore, Maryland, who led wHO's global eradication of smallpox successful. "We really want to focus on that and check in detail," says Henderson. "This comes as a big surprise for everyone."

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Johns Hopkins University in Baltimore is placing a big bet that the hot field of cell therapies will pay off. The university announced Tuesday it would use a $ 58.5 million gift from an anonymous donor to launch an ambitious cell Engineering Institute. Its researchers will try to reprogram human cells in treatments for a range of diseases, including amyotrophic lateral sclerosis (ALS), diabetes, and spinal cord.

One objective of the work will be on the stem so-called pluripotent cells. At the end of 1998, researchers at Johns Hopkins and John Gearhart Michael Shamblott and colleagues reported that they had isolated the so-called fetal germ cells taken from immature reproductive organs of aborted fetuses, which could become any type of cell in the body. Since then, the team tried to discover how to program the cells to become specific cell types such as neurons. Initial results were promising enough that the team has begun testing the cells in several animal models of the disease

But Gearhart said the fetal cells derived -. the use of which is disputed by some antiabortion groups-- is one area, the new institute will explore. The teams will work on stem cells derived from adults and from basic research into the molecular signals that govern the ability of a cell to make a new destiny. "We are not putting all our eggs in one basket," said Gearhart. The institute will also include immunologists who will try to find ways to make stem cell therapies compatible with the immune systems of patients. Private financing institute researchers will "not invulnerable" to the heated debate on the use of public funds for research on stem cells ( Science NOW, January 30, 01), says Evan Snyder stem cell researcher of children's Hospital Boston.

university has not yet appointed a director of the institute, which will employ 27 full-time researchers and involved 50 "associate researchers' other departments or institutions, Hopkins said Executive Vice Dean Elias Zerhouni. Finally, it will take two floors of a new basic research building, which should be completed in 03.

related site

Johns Hopkins press release about the new institute with information on some of the key researchers involved