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Jeffrey Macklis, Jason Emsley, and Hande Ozdinler
Jeffrey Macklis (center), Jason Emsley (right), and Hande Ozdinler are part of a team that found why humans carry in their heads the protein that causes a variation of mad cow disease. Now they are working on what to do about it. (Staff photo Maggie Mastricola/Harvard News Office)

Mad cow protein found to have a sane side

It helps make brain cells

By William J. Cromie
Harvard News Office

It's a devastating disease, changing behavior, causing uncontrolled movements, blindness, coma, and, finally, death. And we all have the makings of it in our heads.

When it topples cows, it's known as mad cow disease. The human form is called Creutzfeldt-Jakob disease. In sheep, it's scrapie. It's a rare malady caused by a misshapen protein known as prion protein, or PrP. The big mystery is why people, cows, sheep, and other mammals have so much of the protein in their bodies, particularly in the brain.

"It's intriguing to find that PrP, which, when 'misfolded,' subjects people and animals to these ravaging diseases, is so abundant in our brains," notes Jeffrey Macklis, an associate professor of surgery at Harvard Medical School and Massachusetts General Hospital. "Why is it kept in the system if it has the ability to wreak so much havoc? It must have an important function."

In proteins, form determines function. The strings of amino acids of which proteins are made can twist in one way and be beneficial to a body, but if they fold in another way they can be disastrous to the same body. When a small amount of PrP misfolds, it influences normal PrPs near it, causing them to assume the same shape, a wrecking ball that breaks the brain from the inside out.

Macklis, along with Harvard postdoctoral fellows Jason Emsley and Hande Ozdinler, teamed up with Susan Lindquist and her student Andrew Steele at the Whitehead Institute for Biomedical Research to try to find out what value the Jekyll and Hyde protein might offer.

They studied mice in which the gene that makes PrP was knocked out, and compared it to another group in which the protein was overproduced. Their investigation revealed that PrP is present where nerve cells form in the developing brain of embryonic mice. They also located PrP in a few spots in the adult brain. In both places, PrP increases the number of precursor cells that develop into brain and other nerve cells. In the knockout mice, this new cell production was delayed. But when additional PrP was available, new cells formed at a much faster rate.

"The more PrP a cell has, the faster it becomes a mature nerve cell," notes Steele.

The good side of PrP was discovered. "We found that the normal prion protein is a key player in the fascinating and important process of creating nerve cells. We now want to think of ways to interfere with the misfolding of PrP. There's a very active prion-disease community studying how to block its spread in the brain," says Macklis, who also heads the Nervous System Diseases Program at the Harvard Stem Cell Institute.

Prions win a prize

Only 25 years ago, prions were completely unknown. Then, in the early 1980s, Stanley Prusiner at the University of California, San Francisco, was puzzling over how one of his patients died of dementia caused by Creutzfeldt-Jakob disease. He noted that it resembles another human malady known as kuru, which can be transmitted through cannibalism, specifically consuming human brain or nervous tissue. By 1982, Prusiner produced a speck of infectious protein taken from the brain of a diseased hamster - the first prion had been found.

However, discovery of the rogue protein was greeted with great doubt. Many scientists refused to believe that such a small bit of protein could cause that much damage. But further research proved Prusiner right. He was awarded a Nobel Prize in 1997 for discovering "a new biological principle of infection."

Adults get new brain cells

Despite a hundred years of belief to the contrary, new cells do form in adult human brains, but only in two places. One lies in a tiny subsection of the hippocampus, a structure deep in the brain that deals with memory. The other is in the olfactory bulb, the part of the brain that recognizes odors.

Late last year, Macklis and his colleagues found out what new smell cells do for adult mice. "They respond to odors that are novel," he says. Even if the animal only detects it for a short time, the odor becomes linked to new cells and circuits in the brain. Many scientists are also investigating whether such links occur in a similar fashion in the hippocampus, perhaps to create memories.

The primary place where brain cells form, of course, is in the embryo of a developing mouse or human. That's where PrP is most needed to help create nerve cells.

Macklis' expertise on the birth of nerve cells led to a collaboration with Lindquist. An expert on prion protein, she had been working with Whitehead Institute colleague Harvey Lodish on the role of PrP in the genesis of blood cells. Along with graduate student Steele, they had discovered that stem cells with PrP developed into mature blood cells much faster than those without the protein.

About that time, Steele attended a lecture by Macklis on development of early nervous system cells, and he wondered whether PrP also contributed to their maturity into brain and nerve cells. Macklis enlisted the help of Emsley and Ozdinler to find out. In February, they published a report in the Proceedings of the National Academy of Sciences presenting evidence that normal PrP increases the speed and number of nerve cells that are made both in embryos and in adult brains.

Playgrounds for mice

Could PrP be manipulated to increase the capabilities of human brains? There's no answer to that question yet; a lot more knowledge is needed about what happens to new brain cells once they come into being and what other proteins are required for the process.

When adult mice get extra PrP, their brain cells grow faster, but, strangely, they end up with the same number of cells as mice who didn't get such a boost. "We think that not all of these cells get included in functional brain circuits," Macklis notes. "And cells that do become part of a circuit die in weeks if not used." If a new odor isn't smelled for a long while, the brain forgets it.

To encourage growth and survival of new adult brains cells, Emsley and Steele are setting up playgrounds for mice with and without extra PrP. Usually the rodents live in small, sparse cages. Those in the experiments will enjoy spacious cages, have small balls to play with, wheels to exercise on, tunnels to explore, and cotton to build nests. There will even be hidden granola treats. These rodents will be more like natural mice who search fields and dumpsters for food, explore ways to get into your house, and chase each other around. What will extra jolts of PrP do for them?

Even such insight into mouse life isn't going to tell the whole story, however. As Macklis emphasizes, PrP does not work alone in making nerve cells. "The birth of new cells is too important and complex to rely on a single protein," he says. "We identified PrP as one central and crucial building block, but we're sure other proteins are involved, some of which are known and probably many that are not known."

Copyright 2007 by the President and Fellows of Harvard College