Molecular Parasitology: A Decade Of Detailed Study Begins To Pay Off

Begins To Pay Off Parasites evoke a gut reaction, both literally and figuratively. The synonyms for the worms, insects, and protozoans that survive off the life force of other animals are skin-crawling and stomach-churning: bloodsuckers and leeches, to name a few. And it's not by accident that these words evoke such feelings. Once they are firmly ensconced in various viscera, internal parasites produce a range of debilitating and deadly symptoms. Such conditions are more than metaphorical for many people. In developing countries especially, parasitic diseases like malaria, schistosomiasis, leishmaniasis, sleeping sickness, and hookworm-related anemia affect hundreds of millions. For decades, the study of parasites has been the domain of specialists in tropical medicine and epidemiology. But now, the vermin that are the scourge of the Third World are the subjects of exciting new biomedical investigations. Research on the molecular biology of parasites could lead to new ways of combating classic parasitic diseases; identifying potential sources of new drugs for such nonparasitic conditions as thrombosis; and informing such other disciplines as immunology and oncology. DE-CLOAKED: Rockefellar University's George Cross studies the antigen sheaths of trypanosomes Molecular biological tools have changed parasitology "the way they've changed most other fields," according to George Cross, a professor of molecular parasitology at Rockefeller University. As can be done in a collection of other species like mice, yeast, and fruit flies, "you can manipulate, knock out, and modify parasite genes to explore their function." Cross primarily studies antigenic variation in trypanosomes, or how these protozoa cloak themselves in differing sets of antigens to outwit the human immune system (G.A.M. Cross, BioEssays, 18:283-91, 1996). Sleeping sickness, characterized by fever and physical wasting, followed by coma and death, is caused by a group of parasites called Trypanosoma, carried by the African tsetse fly. Molecular biological studies are moving researchers' understanding of persistent diseases like sleeping sickness and malaria into a new phase. "In the decade from 1980 to 1990, molecular biology contributed an enormous amount of information to help us understand what the genes of trypanosomes look like, but that was essentially descriptive," recounts Cross. "It was only in the last five years that we've been able to manipulate the genes. Now we can actually test hypotheses about how things really work." "Molecular parasitology's a new field, essentially," says Bill Trager, a professor, emeritus, in cellular parasitology at Rockefeller University. "It really started with malarial parasites. " For example, he notes, Ruth Nussenzweig, a molecular parasitologist at the New York University School of Medicine, and her colleagues "applied molecular biology to the study of sporozooytes of malaria" in the early 1980s. This budding concentration on the inner workings of parasites has spawned a need for new forums for collegial interactions (see accompanying list of resources). One of these is the Annual Molecular Parasitology Meeting. Since the first international meeting six years ago, the number of participants has more than doubled to about 440. "It was felt that there was no forum for the basic science of parasites" comparable to opportunities arising at get-togethers in tropical medicine, taxonomy, and immunology, explains parasitologist Daniel Goldberg, a Howard Hughes Medical Institute investigator at Washington University. Goldberg co-organizes the conference with parasitologists Elisabetta Ullu of Yale University and Marilyn Parsons of the Seattle Biomedical Research Institute. "We focus on molecular biology, genetics, biochemistry, and cell biology, not on epidemiology or immunology," notes Goldberg. SAME AS IT EVER WAS: Lack of funding is "still a problem," says Harvard's John David. The study of parasite genetics and cellular and molecular biology is being applied to a host of other fields, primarily biomedical topics such as immunology, oncology, and telomere biology. For example, Cross and his Rockefeller colleagues, including molecular biologist David Horn, are studying how telomere position modulates gene transcription in trypanosomes. They hope not only to illuminate the mechanisms regulating antigenic variation in trypanosomes, but also to contribute to the understanding of similar processes in higher organisms (D. Horn, G.A.M. Cross, Cell, 83:555-61, 1995). Cytokines, hormone-like substances that help orchestrate the response of human immune-system cells, are another hot area of research (see Hot Papers, page 14). "Part of molecular biology is immunology, and the latest trends in this field have to do with cytokines," observes Ken Warren, vice president of the Picower Institute for Medical Research in Manhasset, N.Y. "Parasitology is at the forefront" of understanding the role of cytokines in the human immune response, he notes. Medical researchers are beginning to take notice of the work done on basic parasite biology and infection. "I'm constantly being invited to meetings that have to do with cancer and autoimmunity, because [conference attendees] are interested in the lessons we have learned from studying parasites," says Alan Sher, a senior staff fellow in the parasitic diseases lab of the National Institute of Allergy and Infectious Diseases. "I think that parasites are superb models for studying a wide variety of principles in other disciplines." Despite the advantages of the molecular biology approach, there are some who maintain it has, in some ways, hurt the progress of the field. "In terms of vaccine development, molecular biology has actually been a detriment," claims Sher. About 10 years ago, he says, "it was sold to the foundations that were supporting research on parasites-and to some extent [the National Institutes of Health]-that molecular biology would automatically provide the answer to vaccine development because it enables you to clone antigen genes. "People ignored the questions of how you would give the antigen, what the antigen did, and what its mechanism of action was. All they were concerned with was obtaining the antigen, cloning it, sequencing it, and expressing it. "What I am critical of is the scientists who preached this concept too far," says Sher. GENE-SEEKER: Only a few infectious-cycle genes have been identified, notes Harvard's Stephen Beverley. Stephen Beverley, a professor of biological chemistry and molecular pharmacology at Harvard Medical School, agrees with Sher, to a point. A decade ago, Beverley says, the idea was to clone antigen genes that would be likely vaccine candidates. "But, as Alan has pointed out, if it was that easy, these diseases wouldn't be a problem in the first place. It was a time when people were very optimistic about the powers of the technology," he comments. As Beverley sees it, the overreliance on molecular biological techniques "was a case of hubris. People thought that it would be a lot easier than it turned out to be. The problem was that these parasites were just that good at dealing with the human immune system. We still have a lot to learn. "I wouldn't say it's a total detriment because it got a lot of people interested in the problem. Parasitology was not what I would call a mainstream area 15 years ago." While critical about the previous path his area has taken, Sher is "very positive" about the "beautiful work" that's now being done in the mechanism of gene expression and on drug resistance in malaria. Support for tropical medicine-mostly in the area of parasitic diseases-has always taken a back seat to other areas of biomedical research, especially those most prominent in industrialized nations, parasitologists maintain. "I think it's still a problem," remarks John R. David, chairman of the department of tropical public health in the Harvard School of Public Health. David works on the immunology of schistosomiasis and leishmaniasis. "A lot of funding sources for parasitology have gone, one after the other," laments David. The two philanthropies that are generally agreed to have kick-started the field in the late 1970s through the 1980s-the New York-based Rockefeller Foundation and the MacArthur Foundation in Chicago-have pulled out of the field of parasitology, as well as some other areas of scientific research. One of the first programs was Rockefeller's "The Great Neglected Diseases of Mankind," a 13-year grant program with an unheard-of 0 percent overhead. Picower's Warren was director for health science at the Rockefeller Foundation from 1977 to 1988. Grant recipients, he recalls, "were working at the cutting edge of science. When we started our program at the Rockefeller Foundation in 1977, molecular biology was making inroads into medical research. Our program and that of the MacArthur Foundation brought parasitology into the forefront of modern biomedical research. PARASITOLOGY RESOURCES Professional Societies: American Society of Parasitologists c/o Daniel R. Brooks, Secretary-Treasurer Department of Zoology University of Toronto Toronto, Ontario Canada M5S 3G5 (416) 978-3509 Fax: (416) 971-2381 E-mail: parasite@zoo.toronto.edu 1,400 members President: Lillian Mayberry World Wide Web Site: http://www-museum.unl.edu/asp/ Journal: Journal of Parasitology American Society of Tropical Medicine and Hygiene 60 Revere Dr., Suite 500 Northbrook, Ill. 60062 Tel :(847) 480-9592 Fax :(847) 480-9282 E-mail: astmh@aol.com 3,000 members President: Donald Burke Executive Director: Joyce Paschell Journal: American Journal of Tropical Medicine and Hygiene Internet Sites: Home page for the journal Molecular and Biochemical Parasitology http://www.ier.nl/cas/estoc/contents/SA1/01666851.html World Health Organization Web Page Contains WHO documents on tropical health http://www/cho.ch Directory of Parasitologists Lists scientists working in the field URL ftp://magnus.acs.ohio-state.edu/pub/zoology Parasite Genome Projects Provides descriptions of projects and links to other genome projects URL http://woodland.bio.ic.ac.uk/fgn/parasite-genome/parasite-genome.html USENET groups: Newsgroups for parasitology-related areas, including bionet.parasitology, bionet.molbio, and bionet.protista Visit http://www.bio.net/ for all bionet postings Meeting: Annual Molecular Parasitology Meeting For information, contact Mary Zimmerman Washington University Department of Molecular Microbiology Box 8230 660 S. Euclid Ave. St. Louis, Mo. 63110 Fax: (314) 362-1232 E-mail: maryz@borcim.wustl.edu "Now these programs are gone," he observes. In Rockefeller's case, this is because of a decision by foundation officials to change the direction of funding to emphasize social sciences research over biomedical investigations, according to Warren. Indeed, worldwide support for basic parasitology has waned for several reasons (P. Aldous, Science, 264:1857-9, 1994). Among them, say researchers in the field, are that it is easier to convince foundation boards and policymakers to fund the development of applied products, such as antimalarial drugs; and that there has been little payoff so far in terms of translating the millions already spent on molecular parasitology into new therapies and vaccines. "Some programs do remain," David notes. He cites a grant program at the Edna McConnell Clark Foundation in New York (A. Martello, The Scientist, May 28, 1991, page 26) and the training program sponsored by the Wellcome Unit of Molecular Parasitology at the University of Glasgow, Scotland. Warren also points to the Tropical Disease Research Program of the World Health Organization, which funds training programs and provides institutional support for research centers in developing countries. Despite funding ups and downs, investigators persevered, making slow but steady progress over the last five years or so. "The goal of many-certainly our lab-has been to try to get modern methods for studying pathogenesis in these parasites up and running," says Harvard's Beverley. "But it turned out to be more difficult than we anticipated. It wasn't until 1989 to 1990 that the first successes occurred in trypanosomatids." Beverley's lab works on Leishmania, a group of protozoans transmitted by bloodsucking sandflies, thought to infect 12 million people worldwide. The goal of his lab and others is to find new genes involved in leishmaniasis, the suite of human diseases that cause painful ulcers and lesions inside and outside the body. "For us in parasitology that's really important, because we only have a small number of genes identified in the infectious cycle, and we know that there are a lot more out there," he states. University of Kentucky biochemist Salvatore Turco, Beverley, and colleagues have developed methods for making mutants that are defective in a virulence-determining surface protein. These mutants have lost their disease-causing punch. Beverley's lab transfects genes into the mutants to pinpoint the pathogenic protein in question (A. Descoteaux et al., Science, 269:1869-72, 1995). "We've also used this methodology to identify drug-resistant genes in Leishmania," he says. "For the field of parasitology, probably the work that will have the most impact will be the transfection of malarial genes, but that's still in the early stages." The goal is to design compounds that block the resistance. "The tendency in malaria has been to concentrate on vaccine targets, but that was more difficult than we'd all hoped, not because of molecular biology or genetics, but because of [a lack of a full understanding of] how the parasite deals with our immune system," explains Beverley. While some parasitologists are looking to outsmart parasites at their own game, others are joining forces with them in the constant hunt for new drugs. Their approach is based on the idea that parasites and their human hosts have a finely tuned interaction that has co-evolved over several millennia. Blood-feeding hookworms, for example, release enzymes and anticoagulants to maintain an uninterrupted flow from human intestines. These chemicals, which don't seem to inordinately bother their hosts, may one day provide potentially safer and more powerful anticoagulants to treat such conditions as thrombosis. Michael Cappello, an instructor in pediatrics at the Yale University School of Medicine, isolated and described these proteins along with Peter Hotez, an associate professor in pediatrics at Yale; George Vlasuk, an executive at Corvas International, a biotech firm in San Diego; and others (M. Cappello et al., Proceedings of the National Academy of Sciences, 92:6152-6, 1995; P. Stanssens et al., PNAS, 93:2149-54, 1996). The Yale group isolated a potent inhibitor of factor XA, a molecule important in the coagulation of human blood. "Then in collaboration with George Vlasuk, we were able to show that in addition to the XA inhibitor there was also a potent inhibitor of VIIA tissue factor, a molecule in the step in coagulation just prior to factor XA," says Cappello. He notes, however, that Yale's collaboration with Corvas "has pretty much ended," owing to a potential dispute over a patent between the university and the biotech firm over the anticoagulants (J. Friedly, Science, 271:1800-1, 1996). Researchers are interested in hookworms not for the enzymes alone. "Hookworm-related anemia is probably the leading cause of anemia in the developing world," says Cappello. "There are about a billion people infected worldwide." Yale's Medical Helminthology Lab-made up of Cappello, Hotez, and colleagues John Hawdon, Kathleen Donnelly, and Kashinath Ghosh-recently formed a partnership with Biomedisyn Corp., a biotech startup in Woodbridge, Conn. The alliance has two objectives: to develop a hookworm vaccine and to screen medically important parasites for novel bioactive molecules, relates the firm's president, Frank Volvovitz. Why parasites and not other hot sources of new drugs, such as rainforest plants or combinatorial chemistry? "The parasites, especially these, represent a very intriguing, provocative source," remarks Volvovitz. "The molecules that they make have evolved in a way that the host does not necessarily reject them. We believe these molecules will be very well tolerated by humans." Potential drugs aside, the study of parasites has a rich history, Cappello points out. He notes that in 1910, University of Pennsylvania pathologists Leo Loeb and Moyer S. Fleisher observed the anticlotting capabilities of hookworms. "It's hard not to be intrigued by an observation that's persisted for nearly 100 years," Cappello observes.

Molecular Parasitology: A Decade Of Detailed Study Begins To Pay Off

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