Prions found outside nervous system

Finding suggests more stringent monitoring of farm animals may be needed to protect the public.

Nancy H. Ruddle, Ph.D. ’68, the John Rodman Paul Professor of Epidemiology and Public Health and professor of immunobiology, is the first to admit that she’s no expert on mad cows. Her laboratory studies the human lymphoid system and how it mediates chronic infection and autoimmune diseases such as diabetes and multiple sclerosis. But Ruddle’s recent collaboration with pathologist Adriano Aguzzi, M.D., Ph.D., in Switzerland has overturned one of the major tenets of public health efforts to curb mad cow disease.

More formally known as bovine spongiform encephalopathy (BSE), mad cow disease is caused by prions—misfolded protein fragments that clump together and destroy the brain. Other animals, such as sheep, goats and mink, are also susceptible to prion diseases. In fact, researchers believe that the mad cow epidemic started because animal feed was contaminated with the brains of sheep infected with the prion disease scrapie. In humans, contraction of the variant Creutzfeldt-Jakob Disease has been attributed to eating BSE-infected beef—specifically, the animals’ brain, spinal cord and immune system tissues such as the spleen and lymph nodes. Experts have assumed that other parts of the animal were safe to eat.

Aguzzi, a professor of neuropathology and molecular biology at the University of Zurich, has long been on the trail of prion diseases. In 1997 his team showed that the immune system’s B cells, or B lymphocytes, which are activated when the body mounts an immune response against common infections, may cause prions to replicate and spread. But no one knew how far.

Ruddle’s team was working with mouse models of inflammation in the kidneys, pancreas and liver. Her work had shown that in chronic immune diseases, T and B cells can form outposts outside of the immune system that are very similar to lymph nodes. Since prion levels are known to be high in lymph nodes, the international team hypothesized that the organized outposts may allow spread of prions to other organs of the body beyond the nervous and immune systems. Sure enough, the researchers reported in January in the journal Science that when Ruddle’s mice were infected with prions, their inflamed kidneys, pancreases and livers carried enormous prion levels—as high as those found in diseased spleens.

“It was thought that even if a cow was infected (with BSE), what was most important was that the brain didn’t get into the feed. But if you have a chronic infection in that animal, you need to think about that, too,” Ruddle said. The work may have far-reaching implications, such as the need for increased monitoring of farm animals, says Ruddle. Although cattle are routinely checked for fever, some inflammatory conditions such as early forms of diabetes, she notes, would not necessarily have visible symptoms.

—Alla Katsnelson

Yale scientists find a genetic connection to age-related macular degeneration

Biomedical research into the genetic basis of disease has progressed at a rapid clip since the sequence of the human genome was announced in 2000, but this past March 10 saw the scientific equivalent of a triple play.

Three research teams, including one led by Josephine J. Hoh, Ph.D., an assistant professor in Yale’s Department of Epidemiology and Public Health, simultaneously announced that they had identified a gene variant associated with a greatly increased risk of age-related macular degeneration (AMD), a progressive disease leading to blindness that affects more than 10 million elderly Americans.

The human genome can be thought of as a vast string of 3 billion letters in which each letter represents one of the four nucleotides that provide instructions to the body’s protein-building machinery. The genome is 99.8 percent identical among humans, but after every 100- to 300-letter stretch on average are single nucleotide polymorphisms, or SNPs (pronounced “snips”), sites where one letter is substituted for another. Scientists believe that SNPs may help explain why some people are predisposed to certain diseases or respond differently to drug therapies.

Remarkably, all three of the teams who published their findings in March independently zeroed in on precisely the same SNP, a spot on chromosome 1 that is home to a gene that codes for an immune system protein known as complement factor H (CFH). In its usual form, CFH acts as a brake on the complement system, a component of the body’s innate immune response.

According to Hoh, whose group scanned the full genomes of 96 individuals with AMD and those of 50 controls, those who carry two copies of the newly identified variant in the CFH gene are nearly 7.5 times more likely than the rest of the population to develop AMD. “This is only an association,” Hoh emphasized. “It doesn’t really tell you that this is the cause of the disease.”

Nonetheless, a faulty version of CFH may indeed be a culprit in AMD. For example, yellowish deposits at the back of the eye known as drusen, the clinical hallmark of AMD, contain complement proteins.

Hoh credits the Raymond and Beverly Sackler Fund for the Arts and Sciences for making the study possible. “This particular kind of study is expensive, not the normal thing a junior faculty member can perform,” she said. “I am extremely grateful for the support from the Sackler Family.”

Michael B. Bracken, M.P.H. ’70, Ph.D. ’74, the Susan Dwight Bliss Professor of Epidemiology and Hoh’s collaborator, adds that the work represents an entirely new way of doing epidemiology. “For the past 100 years, we’ve used a hypothesis-testing approach, where hypotheses were generated from animal studies or small human studies and then we did large epidemiology studies.”

By contrast, whole-genome searches for SNPs are “hypothesis-free”: “The association between a gene and disease is established first, and the biology is done after,” Bracken said. “This takes all that we’ve thought about doing science and turns it on its head, and it’s likely to have major payoffs in the future.”

—Peter Farley

et cetera

MicroRNA linked to oncogene

A Yale scientist has identified a microRNA, let-7, that controls an oncogene implicated in about 20 percent of cancers, including lung cancer. The finding, reported in March in the journals Cell and Developmental Cell, presents new possibilities for diagnosis and treatment, according to Frank J. Slack, Ph.D., assistant professor of molecular, cellular and developmental biology.

Oncogenes are segments of DNA that can induce uncontrolled cell growth and, ultimately, the formation of cancerous tumors. MicroRNAs regulate gene expression. Let-7, said Slack, stops the oncogene known as Ras from producing the Ras protein. In the absence of let-7 RNA, cells in the nematode C. elegans continued to divide instead of differentiating normally. Let-7 in humans, Slack said, is almost identical to the worm sequence.

Lung cancer has a poor prognosis, said Slack, “but gene therapy with let-7 may be a way to alleviate it or slow it down.”

—John Curtis

Smoking turns receptor on and off

Cigarette smoking turns on and then inactivates brain receptors that are critical to the effectiveness of antidepressants, according to a study published by Yale scientists in Biological Psychiatry last fall.

Finding a way to manipulate those receptors could make antidepressants work more quickly—most now take up to three weeks to bring emotional relief. “This finding has implications for those patients who are depressed to the point of being suicidal and for the 30 percent of people who are not responsive to antidepressants that are now available,” said Marina R. Picciotto, Ph.D., associate professor of psychiatry, pharmacology and neurobiology, and senior author of the study.

The next step, Picciotto said, will be to study the role of these nicotine receptors, nAChRs, in regulating behavioral and cellular responses to antidepressants. The receptors may have a direct effect in mediating responses or they may act indirectly, by modulating neurotransmission in other cell types.

—J.C.


			Originally published in Yale Medicine, Summer 2005. Copyright © 2005 Yale University School of Medicine. All rights reserved.