FDA Science Forum

The Food & Drug Administration's annual science forum provides an opportunity for researchers from FDA and other government agencies, industry, and universities to exchange scientific information on critical health issues. This year's forum, held April 27-28, explored a wide variety of issues, including the public health significance of mad cow disease, the growing problem of antibiotic resistance, the potential allergenicity of genetically modified food, animal cloning, developments in nanotechnology, and emerging trends in health care.

In his opening speech, Health & Human Services Secretary Michael O. Leavitt said that no part of medicine is likely to change as much in the coming decade as prescription drugs. "Handwritten prescriptions will become a thing of the past, and we will see an intensification of postmarket monitoring," he said. "Personalized therapies will also expand and disrupt the prescription drug business."

Another issue the nation will have to address is the growing and highly complex problem of drug counterfeiting, Leavitt said. As an example, he described a website called Canadian Generics that was recently shut down. The site was operating from Belize with an Internet service provider based in China, checks were cleared in the Virgin Islands, and the counterfeit drugs sold by the site were sent from Texas. Canadian Generics sold pills with either far more or far less active ingredient than the label specified and injectable drugs containing only water.

A session on the public health significance of bovine spongiform encephalopathy (BSE)--mad cow disease--emphasized that there is still a lot to learn about this problem. William Hueston, director of the Center for Animal Health & Food Safety at the University of Minnesota, said, "This is an area where we will continue to see new science for years to come."

One recent finding is that after transgenic mice are exposed to BSE, the infective prions accumulate during an early stage of the illness in the liver, kidney, and pancreas--organs that formerly were considered prion-free. At a later stage, prions disappear from these organs.

Another finding, Hueston said, is that populations apparently differ greatly in their susceptibility to variant Creutzfeldt-Jakob disease (vCJD), the human form of BSE. In most species subject to prion disease, susceptibility seems to depend on the amino acids that are coded for at a particular site--codon 129--on the prion protein gene. The most susceptible humans are those with methionine-methionine encoded at the site. In the U.S., only 33% of the population has this methionine homozygosity, he said, but in Japan, 92% of the population has this characteristic.

THE AMOUNT of infected brain that can sicken cattle is now known to be very small, Hueston said. When 15 cows were each given a single 1-mg dose of infected brain, one of them came down with BSE. As of April 26, a total of 330,838 at-risk cattle had been tested in the U.S. Since the large-scale testing program began in early 2004, no cases of BSE have been detected.

A significant concern is possible transmission of BSE prions from rendered slaughter products, Burt Pritchett, a veterinarian in FDA's Center for Veterinary Medicine said. He pointed out that rendering converts huge amounts of animal waste into useful products. In the U.S. each year, he said, 15 billion lb of slaughter by-products and 0.7 to 1.2 billion lb of cattle that die on farms or on the way to market must be disposed of.

Half of the total weight of the rendered material is water, 25% is fat, and the remaining 25% ends up as meat and bone meal. Rendering kills ordinary pathogens, but 1 to 10% of the prions in the original material ends up in the meat and bone meal, Pritchett said. "Meat and bone meal is an economical and nutritious source of feed that competes with soy meal, corn, and feather meal"--made from chicken litter discarded from poultry farms.

Since 1997, the solution to possible prion transmission through meat and bone meal has been to ban it as a feed for cattle. But, Pritchett said, cattle can still be exposed to prions from infected animals in several other ways. Milk products and blood plasma from cattle are fed to calves, and plate waste from restaurants and poultry litter that contains spilled cattle-derived meat and bone meal are fed to cattle. In addition, ruminant feed contains rendered poultry and pigs. These could be silent carriers of BSE, he said.

Shortly after a BSE-infected cow was discovered in the U.S. in December 2003, FDA proposed banning plate waste, blood, milk products, and poultry litter from cattle feed, but these rules are still under agency review, he said.

Gelatin has come under fire recently as a possible source of prions, said Patrick Goossens, president of the Gelatine Manufacturers of Europe. But gelatin--which is made from pigskin, cattle hide, and bone--is in fact a very safe product used in food, capsules, and photography, he claimed.

An important level of safety is provided by the production process, Goossens explained. The sulfuric acid and lime used to treat gelatin reduce any possible infectivity to a level that could not possibly be a concern for human health, he said. "Studies done by independent labs showed that the gelatin manufacturing process reduces infectivity [by a factor of more than 10,000] even under conditions in which the raw materials contain unrealistically high levels of prions." As a result, both FDA and the European Commission have decided that the risk of prion transmission from gelatin is close to zero, he said.

Speakers in the antimicrobial resistance symposium gave an overview of the main bacteria that have been responsible for the most resistant diseases and what steps are being taken to ameliorate the problems.

The number one resistance problem is Staphylococcus aureus, said Daniel F. Sahm of Focus Bio-Inova. Forty-nine percent of these bacteria are resistant to methicillin--the antibiotic usually prescribed to kill them--and resistance rates continue to rise. Most staph bacteria that resist methicillin also resist several other antibiotics, he said, and some resist all seven of the antimicrobials commonly used for staph. What is most surprising about resistant staph is that it is on the increase in both inpatient and outpatient settings, he said.

Real-time monitoring of resistant strains and trends is essential, Sahm said, in order "to gain a better understanding about the environments in which they arise." For example, the second most common bacterial resistance problem is Streptococcus pneumoniae, where 16% of infections are now resistant to penicillin, but multidrug resistance has declined, he said. For Escherichia coli, however, the multidrug resistance rate in hospital settings is about 15% and rising.

VACCINES are now helping to control some bacterial diseases, said Margaret C. Bash, a medical officer at FDA's Center for Biologics Evaluation & Research. They provide immunity against infectious agents that resist antimicrobial therapy and can prevent diseases that are frequently treated with antibiotics, she explained.

For example, Bash said, because of immunizations that began in about 1997, haemophillus influenzae type B infections are not an issue anymore for U.S. infants and young children. Another example is invasive pneumococcal disease. In 2000, a highly effective pneumococcal vaccine began to be used for routine infant immunizations. "Subsequent follow-up has shown a rapid decline in invasive pneumococcal disease in young children, and this has led to a decline in the disease across all ages," she said. At the same time, beginning in 2000, pneumoccocal bacteria became less resistant to penicillin, probably because its use declined as pneumococcol disease became less prevalent.

Another approach to preventing common infections may be genetic engineering. Kurt A. Zuelke, a research leader in the Department of Agriculture's Biotechnology & Germplasm Lab, described research that led to a genetically engineered cow named GEM. GEM is a clone whose cells were modified to resist mastitis. Her cells create a peptide called lysostaphin that kills S. aureus bacteria.

About one-third of dairy cows become infected with mastitis each year, costing the industry about $2 billion annually, Zuelke said. Vaccines and antibiotics are only minimally effective against this infection. When GEM was challenged with staph bacteria, she showed no signs of the disease. "We are very excited about this data," he said.

While bioengineered cows may have some promising traits, genetically altered foods continue to cause worry. Richard E. Goodman, professor of food science and technology at the University of Nebraska, Lincoln, provided the forum with an overview of the potential allergenicity of genetically engineered food. All commercially grown genetically engineered crops have been evaluated for potential increases in allergenic properties, using methods consistent with current understanding of food allergens, he said. The amino acid sequence of the encoded protein is compared with all known allergens to determine whether the protein is an allergen or similar to a known allergen. Stability of the encoded protein in stomach pepsin, a risk factor for allergenicity, is also tested.

These assessment methods have worked to prevent the unintended introduction of allergens in commercial engineered crops, Goodman said. Some scientists have suggested using animal models for allergen tests, "but there are no predictive animal models for food allergens" in humans, he said.

Vitamin-enhanced rice is the focus of an important modified-food project. Each year about 500,000 children go blind from vitamin A deficiency, said Jorge E. Mayer, golden rice project manager at Campus Technologies Freiburg at the University of Freiburg, in Germany. Transgenic "golden rice"--so-called because of its yellow color--that has been engineered to contain a precursor to vitamin A could prevent many cases of blindness, he said. The newest strain of golden rice has 23 times the ß-carotene content of the original version, an amount sufficient to cover vitamin A requirements of deficient children in rice-based societies. Because it is not yet certain that the form of ß-carotene in golden rice is bioavailable to humans, trials of bioavailability will begin in August.

A public-private partnership has been created between Syngenta, the Rockefeller Foundation, the University of Freiburg, and other entities to develop and market the rice. Under the agreement, farmers can replant golden rice and trade it locally, Mayer said. Transgenic-organism-based " 'biofortification' could reduce malnutrition in a cost-effective and sustainable manner if we adopted a rational deregulation process based on benefit/risk analysis," he said.

Field trials of golden rice have been conducted in Louisiana because regulatory red tape has delayed trials in India, Vietnam, the Philippines, and Bangladesh, Mayer said. With a streamlined regulatory framework in target countries, breeding golden rice varieties for these countries could proceed and eliminate unnecessary deaths and blindness from vitamin A deficiency, he explained.

It was obvious at this well-attended meeting that FDA faces a broad range of technical problems that pose challenges for researchers from both inside and outside the agency. Although advanced technologies have solved some problems, such as haemophilus influenza in young children, they are exacerbating others. For example, sophisticated computer networks now allow drug counterfeiters to pose extreme dangers for millions of people.