Avian influenza—it’s strictly for the birds

A Yale alumnus who investigates animal diseases for the UN believes a human pandemic is unlikely.

Sitting in his Rome office, gazing at cypress trees and terra cotta rooftops, Juan Lubroth, D.V.M., M.Phil. ’92, Ph.D. ’95, sighs when he hears the words “avian influenza pandemic”—not because he foresees the demise of the human race in a terrifying display of sickness and death, but because he believes that such concerns currently have little merit.

“After over two years of looking at avian influenza, I do not see an imminent pandemic occurring in humans. Yes, we have had a little over 100 deaths in humans attributed to this virus, but this pales in comparison with deaths from other pathogens in humans, such as HIV, tuberculosis and childhood diarrhea,” Lubroth said during an interview last spring. And he should know. As the senior officer and head of the Emergency Prevention System (EMPRES) livestock component at the Food and Agriculture Organization of the United Nations since 2002, Lubroth and his team have contained numerous avian influenza outbreaks. From their analysis of the viral sequence, they don’t believe we are any closer to a human pandemic.

“Avian influenza needs to be put into perspective. Today, I have an epidemic in poultry, and people’s livelihoods and source of protein are at stake. That is my battle right now—in poultry,” Lubroth said. To shore up this form of food security, he and his team are trying to teach poultry handlers how to improve their hygienic practices in order to reduce the spread of avian influenza among chickens and, in turn, among humans. These responsibilities fall under Lubroth’s mandate to track the international animal trade and ensure that food products are safe and free from such infectious agents as those that cause foot-and-mouth disease, swine fever, Rift Valley fever and avian influenza, among others. Lubroth jokes that he lives in Alitalia—Italy’s national airline—given his frequent travels to Thailand, Egypt, Turkey, Vietnam and China.

As a veterinarian, Lubroth is the self-described “black sheep” in a family of architects—his father, grandfather, one of his two brothers, his sister, an uncle and a cousin are all architects. Even his only child, 28-year-old Gregorio, is in his third year at the Yale School of Architecture master’s program. Yet during his childhood in Madrid, Lubroth found himself drawn to a different calling. His family’s large verdant garden, full of animals, formed a pastoral oasis amidst the high-rises of the bustling city. Born the youngest of four children in 1957, it fell to him to clean up after the family’s dogs, cats, chickens and ducks. Lubroth demonstrated an aptitude for caring for animals, and when he was 12 he began volunteering at a local veterinary clinic. As he matured, Lubroth increasingly appreciated the relationship between human health and animal health, and he felt that investigating that link represented an ideal strategy for improving the lives of individuals in developing countries.

To further his education and escape the political unrest in Spain during the transition from the dictatorship of Francisco Franco to democratic rule, Lubroth accepted a scholarship at Whitman College in Walla Walla, Wash., where he studied biology and played on the college’s soccer team. At the University of Georgia he earned a master’s degree in medical microbiology and worked as a wildlife biologist. While there he met his wife of 24 years, Adriana, a native of Colombia, at a concert by the B-52’s. As he puts it, Lubroth married both Adriana and her young son, Gregorio. Lubroth stayed on at the university to earn his veterinary degree, fulfilling a longtime dream.

Since then, Lubroth’s professional pursuits have led him far and wide: to New York to study foreign animal diseases, to Mexico City to prevent foot-and-mouth disease and to Brazil for more studies of foot-and-mouth. Before his appointment to EMPRES, which is based in Rome, Lubroth headed the Reagents and Vaccine Section and Diagnostic Services Section at the Plum Island Animal Disease Center of the U.S. Department of Agriculture in New York. During his travels and many jobs, Lubroth picked up a second master’s degree along with a Ph.D. from Yale’s Department of Epidemiology and Public Health, where he focused his interests in infectious diseases, specifically foot-and-mouth disease.

Through it all, Lubroth’s mission has remained the same: “It is my passion to work with developing countries to help with their strife by providing better health, both in animals and in humans.” Although his nonstop travel limits his time with his wife and prevents him from weeding through the stacks of articles and files cluttering his office, Lubroth is delighted with his position. “I feel that there is only one medicine, there is only one health. Whether it is environmental or wildlife or livestock, we are dealing with the same world,” he said.

—Kara A. Nyberg

A road trip in Latin America and a lifelong interest in a debilitating endemic disease

In 1966 a young Harvard graduate with a B.A. in Romance languages and literature set out on a three-month drive through Mexico and Central America. The part-time interpreter for the U.S. Department of State never imagined that his road trip would lead to a career in medical science.

“The culture was fascinating, the poverty oppressive, and I got hooked on Latin America,” recalled Louis V. Kirchhoff, M.D. ’77, M.P.H. ’77. In 1967, determined to use his fluency in Spanish and Portuguese to improve lives, Kirchhoff, the son of a Chicago insurance agent, became the lone Peace Corps volunteer in drought-prone Apodi, a Brazilian town without running water, electricity or paved streets.

Kirchhoff set out to demonstrate that vegetables could be grown out of season—a project that would require irrigation. He rented 2.5 acres of land, then organized sharecropper families to build an irrigation system. That led to year-round crops—and income. By the early 1970s, Apodi, in the northeastern state of Rio Grande do Norte, was nicknamed the “Tomato Capital” of the westernmost region.

Despite the agricultural improvements, Kirchhoff recognized that the sharecroppers of Apodi had few options. “They had no access to education, better jobs or even birth control information,” he said. Health care consisted of two pharmacists dispensing informal diagnoses and prescription drugs.

“Everyone had parasites, so I got a book on them,” recalled Kirchhoff. That’s when he learned about Chagas disease, a major cause of morbidity and death in Latin America that is associated with poverty and a semi-arid climate. The Chagas parasite (Trypanosoma cruzi) is transmitted when infected reduviid bugs (also known as triatomine or kissing bugs for their habit of attacking the face) gorge themselves on blood drawn from sleeping people and deposit parasite-laden feces near the site of the bite wound. The parasites enter the wound when the victim scratches the bite. Chagas causes debilitating, sometimes fatal, cardiac and gastrointestinal manifestations in 10 to 30 percent of those who have it, even decades after transmission.

Convinced that infectious diseases were the biggest health problem in poor tropical regions, Kirchhoff left Brazil with a reawakened childhood career goal. His Russian-born mother had always urged him to become a doctor, one of her own criteria for success in America. He returned to school and took undergraduate as well as graduate science and epidemiology courses only to discover—at 26—rampant age discrimination at most medical schools. Fortunately, Yale admitted Kirchhoff to its M.D./M.P.H. program.

In 1976 he found himself back in Brazil because his thesis advisor, Alfred Evans, M.D., was studying links between Epstein-Barr virus (EBV) and tumors in Brazil. After a lengthy initial interview, Evans asked, “You don’t happen to speak Portuguese, do you?”

Kirchhoff spent four months in São Paulo studying a possible Hodgkin lymphoma-EBV link. Collecting and organizing data solidified Kirchhoff’s love of research and earned him Yale’s Harold Lamport Biomedical Research Prize at graduation.

After a residency in internal medicine at Michigan and a four-year fellowship at the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, in 1985 he became an assistant professor at the University of Iowa College of Medicine and began studying Chagas genetics and diagnostics. Between 12 and 14 million people (including about 100,000 residents of the United States) harbor the Chagas parasite; about 25,000 die annually, typically of premature heart disease. Asymptomatic in 70 to 90 percent of cases, Chagas is easily transmitted by blood transfusion. Kirchhoff wanted to develop an accurate seriodiagnostic tool to avoid transmission of the parasite by transfusion.

His appointment in 1990 as associate professor of internal medicine, infectious diseases and epidemiology at the University of Iowa brought him nearer to his goal. “Getting tenure brought more freedom to explore less traditional avenues of academic research, in technology transfer and commercialization,” said Kirchhoff. He had already developed a radioimmune precipitation assay, still the gold standard for confirmatory testing, yet slow and complicated to use. With co-inventor Keiko Otsu, he employed recombinant DNA technology to develop chimeric antigens as the basis of a test that is accurate and easy to use.

Last year the company he founded in 1998, Goldfinch Diagnostics, signed a licensing agreement with Abbott Laboratories to use the chimeric antigens as the basis of an automated assay for screening the United States blood supply for Chagas. The assay may eventually be marketed in Latin America as well. And in September Kirchhoff received a national Tibbetts Award for the development of the chimeric antigens.

Settled in Iowa City, Kirchhoff, who is divorced, continues to attend on internal medicine and infectious disease services. His children, Alicia, 29, and Aaron, 26, are both artists. Kirchhoff’s favorite pursuits include foreign films, National Public Radio and jogging. (In June, he ran his sixth marathon—in Argentina.)

“I get an enormous sense of accomplishment thinking about what my technology may do,” Kirchhoff reflected. “When the automated assay comes to market, it will be very satisfying that I could have an original idea, bang away at it in my lab for 10 years and finally be able to more effectively protect transfusion recipients. I will be delighted.”

—Carol Milano

Bonnie Gould-Rothberg and Jonathan Rothberg

Sharing a home, a family and science—two alumni try to make a difference

Jonathan and Bonnie Rothberg share not only a home and family but also a passion for probing the mysteries of the human genome. Together and separately, they attempt both to untangle genetic differences among individuals that can affect disease and to develop novel treatments that target disease at the genetic and molecular levels.

In 1993, when many scientists were trying to decipher the human genome, Jonathan Rothberg, Ph.D. ’91, had a vision: to mine the genome for drug targets. He founded CuraGen, a company that uses information systems, automation and robotics to develop drugs that target specific genes. In the company’s early years, Jonathan would bring home sets of newly generated differential gene expression (DGE) profiling data sets and ask his wife, Bonnie Gould Rothberg, M.D. ’94, M.P.H. ’05, to apply her medical background to make sense of the data. By January 1997, midway through her internal medicine residency at Yale-New Haven Hospital and with Jordana, the first of their three children, still an infant, she decided to place her clinical training on hold and assume a full-time position designing and analyzing DGE data. So she joined Jonathan at CuraGen, where she developed a pharmacogenomics program to understand the mechanisms that underlie differing responses to drugs. CuraGen developed five drugs (all in preclinical and clinical development) for treating cancer, the adverse effects of chemotherapy, kidney inflammation and type 2 diabetes.

As CuraGen grew, so did the Rothberg family. The birth of their second child, Noah, in 1999, led Jonathan to start another company. Noah turned blue the night he was born and the doctors had no idea what was wrong. “I wished I could just read off his genome,” said Jonathan. “I had a computer magazine with me and I thought that since the computer guys have been able to make things a million times faster and a million times cheaper by putting them on a chip, why not the genome?” Noah quickly turned a healthy pink, but nonetheless Jonathan created a new company, 454 Life Sciences, to pursue his vision of sequencing genomes.

454 Life Sciences is also attempting to reconstruct the genome of Neanderthals, an evolutionary predecessor and possibly a subspecies of modern Homo sapiens. “The wonderful thing about the Neanderthal project is that we may uncover the molecular basis for the mind,” Jonathan said. Since the genetic difference between modern humans and Neanderthals is only one-twentieth of 1 percent and the main distinction between the two species is largely cognitive, it’s possible that just a handful of genes are involved in human brain function.

But that’s not the Rothbergs’ only project. In 2002, Jonathan formed The Rothberg Institute for Childhood Diseases, a nonprofit organization dedicated to finding a cure for tuberous sclerosis, a genetic disorder that causes benign tumors to grow in the brain and other vital organs throughout the body, as well as cures for other orphan diseases of childhood. With three children under the age of five, Bonnie joined the institute as director of clinical development. Although her medical degree served her well, she felt that she needed formal training in clinical research design and analysis to conduct large-scale clinical research. While earning an M.P.H. at Yale, she rediscovered genomics as a subdiscipline of molecular epidemiology and is now pursuing a doctorate in chronic disease epidemiology. She is working with David L. Rimm, M.D., HS ’91, Ph.D., associate professor of pathology, using tissue microarrays to find proteins that could serve as prognostic markers for the speed of growth in melanoma tumors. Her work has also come full circle: at CuraGen she participated in the discovery of a drug for melanoma, a disease that she is now studying at Yale, where the drug is currently being tested.

With 25 U.S. patents, work featured on the covers of Cell, Science and Nature and election to the National Academy of Engineering in 2004, Jonathan has moved on to his next project, which he calls the culmination of his life observations. “If you walk into a lab, it’s very inefficient,” he said. “So I decided that instead of just miniaturizing gene sequencing, why not create a general-purpose machine very much like a computer but that would move chemicals or lab components around?” In 2004, he founded RainDance Technologies to develop a system for testing, profiling or sorting samples used in chemistry, molecular biology and biochemistry on disposable chips. The company expects to ship its first machine, which it calls the Personal Laboratory System, or PLS, in 2007.

Although Jonathan and Bonnie are both fascinated by science, it wasn’t their shared academic interests that brought them together. The two met at a party in 1993, but only began dating three months later when Bonnie found an opening in her on-call schedule. They were married in 1995. Jonathan acknowledges that hundreds of dedicated people have helped him turn his groundbreaking ideas into commercial successes. But he recognizes that his most important partnership, in life and in work, is with Bonnie.

—Jill Max


			Originally published in Yale Medicine, Winter 2007. Copyright © 2007 Yale University School of Medicine. All rights reserved.