GOVERNMENT & POLICY
FDA SCIENCE FORUM Researchers describe breakthroughs, as well as difficult challenges facing the agency BETTE HILEMAN, C&EN WASHINGTON
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HE FOOD & DRUG ADMINISTRA-
tion's annual science forum provides an opportunity for re searchers from FDA and other government agencies, industry, and universities to exchange scientific in formation on critical health issues. This year's forum, held April 27-28, explored a wide variety of issues, including the pub lic health significance of mad cow disease, the growing problem of antibiotic resis tance, the potential allergenicity of ge netically modified food, animal cloning, developments in nanotechnology, and emerging trends in health care. In his opening speech, Health & Hu man 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 pre scriptions will become a thing of the past, and we will see an intensification of postmarket monitoring," he said. "Personal ized therapies will also expand and disrupt the prescription drug business." Another issue the nation will have to ad dress is the growing and highly complex problem ofdrug 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 Is lands, and the counterfeit drugs sold by the site were sent fromTexas. Canadian Gener ics 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 signifi cance of bovine spongiform encephalopa thy (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 trans genic mice are exposed to BSE, the infec
tive prions accumulate during an early stage of the illness in the liver, kidney, and pan creas—organs that formerly were consid ered prion-free. At a later stage, prions dis appear from these organs. Another finding, Hueston said, is that populations apparently differ greatly in their susceptibility to variant CreutzfeldtJakob disease (vCJD), the human form of BSE. In most species subject to prion dis ease, susceptibility seems to depend on the amino acids that are coded for at a partic ular site—codon 129 —on the prion pro tein gene. The most susceptible humans are those with metmonine-methionine en-
GOLDEN RICE The new strain (left), has 16 μg per g of β-carotene, in contrast to an older strain (right), which has only 1.6 μg per g. coded at the site. In the U.S., only 33% of the population has this methionine ho mozygosity, 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 largescale testing program began in early 2004, no cases of BSE have been detected.
A significant concern is possible trans mission of BSE prions from rendered slaughter products, Burt Pritchett, a vet erinarian in FDA's Center for Veterinary Medicine said. He pointed out that ren dering 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 re maining 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 pri on transmission through meat and bone meal has been to ban it as a feed for cattle. But, Pritchett said, cattle can still be ex posed 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 poul try litter that contains spilled cattle-de rived meat and bone meal are fed to cattle. In addition, ruminant feed contains ren dered 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 cat tle 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 Man ufacturers 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 provid ed 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. "Stud ies 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
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GOVERNMENT & POLICY the raw materials contain unrealistically them—and resistance rates continue to rise. high levels ofprions." As a result, both FDA Most staph bacteria that resist methicillin and the European Commission have de also resist several other antibiotics, he said, cided that the risk of prion transmission and some resist all seven of the antimicro from gelatin is close to zero, he said. bials commonly used for staph. What is most surprising about resistant staph is that Speakers in the antimicrobial resistance it is on the increase in both inpatient and symposium gave an overview of the main outpatient settings, he said. bacteria that have been responsible for the most resistant diseases and what steps are Real-time monitoring of resistant being taken to ameliorate the problems. strains and trends is essential, Sahm said, in order "to gain a better understanding The number one resistance problem is Staphylococcus aureus, said Daniel F. Sahm of about the environments in which they arise." For example, the second most com Focus Bio-Inova. Forty-nine percent of mon bacterial resistance problem is Strep these bacteria are resistant to methicillin— tococcus pneumoniae, where 16% of infecthe antibiotic usually prescribed to kill RESEARCH
Nanotech Meets Medicine anotechnology is a developing field that is showing promise in a number of areas. One such area discussed at the 11th annual Food & Drug Administration Science Forum last month is medicine. The size of nanoparticles is on the same order of magnitude as biological materials; thus, nanotech nology can aid in improving the efficiency and effectiveness of things like drug de livery and bioimplants. In the area of drug delivery, Jennifer L West, joint professor in chemical en gineering and in biomedical engineering at Rice University, is directing research using nanoshell systems for drug deliv ery. The nanoshells are tiny spheres with dielectric silica cores covered with a layer of gold nanoparticles. The key for using these nanoshells for drug delivery is their tunable optical wavelength properties. This tunablity is dependent on the gold nanoshell thick ness and has been varied by West and her fellow researchers to fall in the near-infrared wavelength region—a re gion where human blood and tissue are relatively transparent. West discussed a system for insulin delivery in which these tunable nano shells are embedded into thermoresponsive polymers. The polymers form a capsulelike pod in which insulin (or another drug) can be contained. When light of the proper wavelength irradiates the polymer, however, the embedded nanoshells heat up and in turn activate the polymer, which causes it to collapse and release the insulin. Nanoshells have also been used in West's lab to target and ablate cancer cells (C&EN, April 19, 2004, page 35).
She noted that nanoshells can be de signed to target cancerous cells through addition of antibodies and peptides to the shell. Once targeted, the nanoshells bind to the tumors and, by applying the proper wavelength of light, heat up and destroy the tumor. West said damage done by this heating process is limited to 100 μηη
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GOLD P L A T E D West used nanoshells that are made by layering gold around a silicone core. from the tumor surface. In related work, she is now developing a metastatic dis ease model to treat cancerous tumors. Another area where nanotechnology is showing promise is in biomimics, namely biological implants such as joint replacements and artificial blood ves sels. Thomas J. Webster, associate pro fessor of biomedical engineering at Pur due University, explained that many of the current implants used today fail be cause of adverse tissue response. One problem, he noted, is that tissues have nanostructures, whereas implants are smooth at the nanoscale. The goal of Webster's work is to de velop surfaces that are similar to the tis sue itself so that cells will adhere to them; that is, to develop implants that have structure at the nanoscale that is recognizable to cells. His work includes the use of nanofiber ceramics and car bon nanofibers.—SUSAN MORRISSEY
tions 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 FDAs Center for Biologies Evaluation & Research. They provide immunity against infectious agents that resist antimicrobial therapy and can prevent diseases that are frequently treat ed with antibiotics, she explained. For example, Bash said, because of im munizations that began in about 1997, haemophillus influenzae type Β 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 immu nizations. "Subsequent follow-up has shown a rapid decline in invasive pneu mococcal disease in young children, and this has led to a decline in the disease across all ages," she said. At the same time, be ginning in 2000, pneumoccocal bacteria became less resistant to penicillin, proba bly because its use declined as pneumococcol disease became less prevalent. Another approach to preventing com mon infections may be genetic engineer ing. Kurt A. Zuelke, a research leader in the Department ofAgriculture's Biotech nology & Germplasm Lab, described re search 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 5. aureus bacteria. About one-third ofdairy cows become in fected with mastitis each year, costing the industry about $2 billion annually Zuelke said. Vaccines and antibiotics are only min imally 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 commer cially grown genetically engineered crops have been evaluated for potential increas es in allergenic properties, using methods consistent with current understanding of food allergens, he said. The amino acid sequence of the encoded protein is comWWW.CEN-0NLINE.ORG
pared with all known allergens to deter mine whether the protein is an allergen or similar to a known allergen. Stability of the encoded protein in stomach pepsin,
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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 sug gested 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 Trans genic "golden rice" —socalled because of its yellow color—that has been engi neered to contain a precur sor to vitamin A could pre vent many cases ofblindness, he said. The newest strain of golden rice has 23 times the β-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 βcarotene 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,
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and other entities to develop and market the rice. Under the agreement, farmers can replant golden rice and trade it locally May er 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 ofgolden rice have been con ducted 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 goldenriceva rieties 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 out side the agency Although advanced tech nologies have solved some problems, such as haemophilus influenza in young chil dren, they are exacerbating others. For ex ample, sophisticated computer networks now allow drug counterfeiters to pose ex treme dangers for millions of people. •
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Invitation to Tender Technical Advisors for New WRAP Material Programmes - Tyres, Plasterboard, Batteries WRAP (the Waste & Resources Action Programme) is a major Government programme established to accelerate resource efficiency by creating stable and efficient markets for recycled materials and products and removing barriers to waste minimisation, re-use and recycling. WRAP has recently started new programmes in Tyres, Plasterboard and Batteries recycling and as these areas of responsibility grow there will be an increasing need for external professional technical advice to help assist WRAP in achieving its aims. Technical advice and relevant experience is essential to help support the development of these new WRAP material streams and WRAP is therefore seeking to appoint technical advisors onto a framework agreement to provide WRAP, The Old Academy, 21 Horse Fair, Banbury, Oxon, 0X16 OAH. Tel: 01295 819900 Fax: 01295 819911 E-mail:
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