The secret may lie in the "junk"
	Peanut allergy could recede
	How aspirin works
	First in funding...again
	Rat model could yield clues in autism
	A new center for "bold" discoveries

The secret may lie in the "junk"

If you always suspected some of your relatives were more ape than human, the genome findings that we share around 99 percent of our genes with chimpanzees bear that out. Now explaining why we remain so different is sending geneticists down new avenues of research involving humans and mice. Surely environment is important. But a key factor, they believe, lies in how the body regulates the very genes we have in common, and for that, says geneticist Andrew Feinberg, we should probably look outside the genes.

A recent study in Feinberg's lab that compared massive stretches of human DNA and mouse showed many similar genes: "We expected that," says Feinberg. What was surprising, however, was how little humans and mice hold in common in the DNA outside of genes--the so-called "junk" DNA whose role, so far, remains one of science's mysteries. Feinberg likens "junk" DNA--or intergenic DNA in more genteel circles--to the vast expanse of the South Pacific, dotted only by tiny reefs and islands ... the genes.

To their delight, the scientists found most of the shared "junk" DNA clustered about genes is said to be imprinted. Imprinting, Feinberg explains, is a silencing of genes from one particular parent. Not all of a person's genes are imprinted, but those that are influence embryonic growth and suppression of certain types of cancer.

A world expert on imprinting, Feinberg was the first to show that a human disease, a set of birth defects called Beckwith Wiedemann syndrome, stems from bad imprinting, and he suspects there are others. "But we don't understand what regulates imprinting," says Feinberg, "or where it takes place. That's why we turned to the mouse/human comparison."

Not only do the newly found DNA sequences lie within "striking range" of imprinted genes, but their makeup is characteristically regulatory, he says. "We can't say outright that one role of junk DNA is to regulate imprinting of genes; it's just that we can't think of any other reason those conserved sequences would be there." --Marjorie Centofanti

Peanut allergy could recede

For the nearly one in 200 children and adults with peanut allergy, avoiding peanut products becomes a life-long mission. Among the most severely allergic, even the slightest peanut trace left in a cooking pan or on a plate can cause the tongue to swell so much that suffocation can quickly ensue.

But now a recent Hopkins study suggests that 20 percent of children with peanut allergy could outgrow it. The results of the study, led by Hopkins pediatrician Robert Wood, were published in the February Journal of Allergy and Clinical Immunology.

From routine follow-up tests in his pediatric practice, Wood noticed a few cases in which children with documented peanut allergy no longer

reacted to the allergen. This finding led him to investigate subsequent reactions among 223 young people between the ages of 4 and 20 years with well-documented peanut allergy.

Researchers first conducted skin tests and checked patients' levels of peanut specific IgE, antibodies produced by the immune system that cause allergic reaction. Those patients who met specific criteria--principally an IgE level below a certain point--were invited to undergo an "oral challenge" under a doctor's supervision.

Wood found that 48 of those previously allergic had no adverse effects. And he says that since the completion of the study he has identified at least 20 other patients who no longer have the allergy.

Wood emphasizes that patients must first be tested under a doctor's care before trying peanut products, and says the study results show the importance of regular allergy reevaluations for both children and adults.

"Until now, the rules have been that when you diagnose a patient with peanut allergy, tell them that it is a lifelong allergy, with no chance of being outgrown," says Wood. "I recommend from this study that children with peanut allergy be retested on a regular basis, every one or two years."

Adults who've had no reactions since childhood should also be reevaluated, says Wood, who himself has a peanut allergy.

What did his own test show? Unfortunately, the pediatrician won't be munching on peanut butter sandwiches anytime soon. --Emily Carlson (MA '01)

How aspirin works

Practitioners have known for millennia that aspirin works as a painkiller and an anti-inflammatory. But no one has ever fully understood how. Hopkins researchers recently figured out part of the puzzle. They have determined that the drug affects a protein involved in inflammation.

Reporting in the March issue of Blood, Hopkins assistant professor of clinical immunology Vincenzo Casolaro says his research team found that aspirin inhibits interleukin-4 (IL-4), the protein implicated in various allergic reactions and inflammation. Says Casolaro, "The finding appears to explain some of aspirin's less obvious beneficial effects, such as how the drug might help prevent heart disease or the ravages of rheumatoid arthritis."

The research team originally set out to test the idea that aspirin increased IL-4 production. To its surprise, test results indicated the opposite. Aspirin actually targets part of a complex of DNA binding proteins that form on the IL-4 promoter, which regulates the quantity of protein produced. "We found that aspirin had the opposite effect of what we might have expected, and was clearly acting in a completely novel way," says Casolaro. --Dale Keiger

First in funding... again

For the ninth consecutive year, Johns Hopkins Medicine received the most federal research money among all U.S. medical schools in FY2000.

Hopkins garnered $301 million in research grants, an 18 percent increase over 1999's $255.3 million, according to the National Institutes of Health's FY 2000 report. The University of Pennsylvania School of Medicine ranked second, with $266.9 million in funding, a 12 percent increase over 1999. NIH's report listed Hopkins as second in training grants for which the university received $12.6 million.

Rat model could yield clues in autism

Late at night, when most of us are asleep, rats are playing. Beneath city floorboards and in alleyways, they indulge in rodent rough-and-tumble. They revel in a standard, brain-wired interplay called "pinning," where one rat holds another down for a second or two. You can almost hear their little ratty chuckles-- "gotcha!"--through-out the night.

But not "autistic" rats, says Hopkins neuroscientist Mikhail Pletnikov. "They either don't interact at all or, if they do, it's in a way so inappropriate for rats that the would-be partner backs off quickly." To pinpoint what goes wrong in diseases such as autism and ADHD, illnesses that, current thought tells us, are surely developmental, Pletnikov and colleagues have come up with a rat model that resembles humans in the most telling ways. "The model's probably best for autism or autism-like illness," he says.

The model rats all have Borna virus, a not-uncommon germ that targets birds, dogs, cats, and cattle and that can also infect monkeys and humans. Pletnikov hasn't set out to prove that Borna virus causes autism, though his team may well show, one day, that the virus sparks some forms of it. Scientists have already linked viral infections like measles or herpes in infants to behavioral illness, but the links are frail and controversial. What the world needs, says Pletnikov, is a good model--one that shows, from a most susceptible time after birth, just how genes and nature could derail the brain's course and produce autistic children.

The Borna model, which Pletnikov and neuroscientist Tim Moran have evolved from one first set up at Hopkins by researcher Karen Carbone, follows a wayward interplay of genes and environment. It does this shortly after birth, the same time infants first experience signs of autism.

Newborn rats are injected at an early age with Borna virus, when immune systems are still green; the viruses insinuate themselves into brain cells and quietly change metabolism without destroying cells immediately, as other viruses might. The Hopkins researchers have followed gradual structural and biochemical changes in the brain--notably in the cerebellum and hippocampus, the two brain areas also altered in human disease.

In the rats, changes come first to parts of the cerebellum, which are still developing at birth, the researchers say. The cerebellum coordinates motor movements, and the model rats indeed have an odd, unbalanced gait, Pletnikov notes. After a few months, the hippocampus--also still developing in newborns--goes under attack. Neuroscientists have long known the hippocampus' role in fear reactions as well as in learning and memory. There, key cells waste away, replaced by the glia that serve as a sort of neurological filler.

How, then, does this change rat behavior? For one thing, the animals fail miserably on "plays well with others" tests, says Pletnikov. Like humans, rats at play begin with a subtle solicitation, Pletnikov says, a stereotyped series of signals that says, in effect, "I'm OK to play with." The Borna rats either lack this altogether or they display an odd, prematurely adult way of soliciting, which puts partner rats off.

"The rats also become clearly hyperactive," says Pletnikov. Humans with autism may show an excess of motion: rocking, finger tapping, ritual grooming, sometimes whirling in circles. The Borna rats, too, move constantly, often rearing on their hind legs in a rodent hallmark of hyperactivity. "We believe this is actually a response to fear or stress, rather than something specifically wrong with the rats' motor system," Pletnikov explains. "It's one way to relieve anxiety."

One puzzle of autism is its variability. Though it does run in families, it may vary widely in its extent or nuances. In the team's most recent work, which Pletnikov presented last fall at the Society for Neurosciences meetings, the team stretched the model to show how basic genetic differences between the animals shine out as variations in symptoms of the rats' autism-like disease.

The scientists observed two different strains of rat: Lewis rats and Fisher rats, which, Pletnikov says, lie at opposite ends of biology in their response to environmental insults. Fisher rats tend to overreact and are much less apt to engage in social play; studies show their hippocampi may overproduce or overrespond to serotonin.

By contrast, Lewis rats are "laid back," unfazed by bright, open-field test conditions or other novel situations that would drive other rats to pacing. They undersecrete stress hormones, for example, and move around very little. Their response to serotonin is apparently damped-down. With humans, Pletnikov adds, this specific system is also the one to go awry in autism: "Hyperserotonemia is the most characteristic biochemical change of the disease."

So what happens when the researchers inoculate the two strains of rat with Borna virus? A pilot study showed both strains became hyperactive and displayed abnormal motor and other typical physical anomalies that characterized the lab's earlier work. But the rats also showed sharp differences in play behavior. "Fisher rats with the virus stopped playing, pretty much altogether, " says Pletnikov, "while the Lewis rats would interact somewhat, but those interactions were inappropriately similar to adult rats." Could this reflect differences in human autism, say, with high- versus low-functioning forms of the disease? "We aren't saying there's a direct parallel," says Pletnikov, "but we can see that the genetic background apparently makes a difference.

"The take-home message," Pletnikov says, "is that the Borna virus causes these really suggestive chemical and behavioral parallels with people when animals get infected at an early age." --MC

A new center for "bold" discoveries

The bold new world of stem cell research will become a major focus at Johns Hopkins Medicine, thanks to the establishment of the new Institute for Cell Engineering (ICE).

Believed to be the first initiative of its kind at an academic center, ICE received its start-up funding from an anonymous donor's $58.8 million gift, the largest single donation to the Johns Hopkins Medical Institutions and the second largest in the university's history.

Said university president William R. Brody, "The recent groundbreaking research in stem cells has opened our eyes to ways cells might be used to regenerate tissues and perhaps, ultimately, entire organs. This research forms the basis for a bold new cross-disciplinary endeavor in cell engineering at Johns Hopkins."

Drawing on Hopkins researchers and new recruits, ICE will serve as a center for fundamental research on human cells. Specifically, cell immunologists will investigate how to remove characteristics of stem or other cells that trigger transplanted tissue rejection. Researchers in cellular reprogramming plan to experiment with DNA to create new, highly specialized cells. Neuroscientists will focus on the regeneration and repair of nerve tissue via engineered cells. With the help of departmental labs throughout Hopkins, these discoveries will be translated into therapies for Parkinson's disease, ALS, spinal cord injury, diabetes, stroke, and heart failure. The institute will take up 40,000 square feet--about one-third--of the new Broadway Research Building in East Baltimore, expected to be completed in 2003.

"The intent of the institute is to assemble the very best minds in the world who work on cell engineering problems, and to have them do it right here at Hopkins," says Elias Zerhouni, executive vice dean of the School of Medicine and a driving force in the institute's creation. "They will interact with each other in such a way as to advance the field on a fundamental basis, not just an applied basis." --Emily Carlson (MA '01)

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