High on the list of new things to fear are prions (rhymes with eons), the mysterious proteins in our brains that sometimes mutate into merciless killers. Much smaller than the previously known infectious agents–viruses, bacteria, fungi and parasites–prions normally are harmless. But when they encounter oddball cousins by genetic mischance or from contaminated food, they can change their shape and wreak havoc, causing such nightmares as mad cow disease and, in humans, Creutzfeldt-Jakob syndrome. The identification of prions recently won one researcher the Nobel Prize in medicine, while others are racing to determine the link between renegade proteins and such scourges as Alzheimer’s disease. Major figures include the University of Chicago team led by Susan Lindquist, which recently published a pair of papers showing that prions may be new to us, but they’re not new to nature.
Q: Proteins, which carry on the life-work of cells, are supposed to fold themselves into precise three-dimensional shapes according to their function. The prion problem is believed to occur when proteins do not fold correctly.
Prions have long been suspected of causing a number of disorders that leave the victim’s brain riddled with holes–the first prion disease was kuru, the “laughing death” transmitted by ritual cannibalism in Papua New Guinea. Once tribes were persuaded to stop eating the brains of their dead ancestors, the disease just went away. Daniel Carleton Gajdusek received the 1976 Nobel Prize for that work.
Why do prions remain controversial?
A: There’s no absolute proof yet that they are the mechanism of disease. Even kuru was first thought to be due to some sort of slow-acting virus, and some scientists believe a virus may be behind the diseases we associate with prions today. But a consensus seems to be forming about the proteins, as indicated by the recent selection of Stanley Prusiner, who coined the term “prion” back in 1982, for the Nobel Prize. There is massive evidence now and a growing acceptance. I’d say 90 percent of biologists think the theory is right, 5 percent are absolutely certain, and the remaining 5 percent are just as certain that it’s wrong.
Q: Many infectious diseases are spread by a virus, which can seize the DNA machinery of a cell. How do prions do it?
A: They have the remarkable ability to change shape in a way that attracts other proteins of the same type to join up and change their shapes too. These destructive masses spread from cell to cell, killing brain cells, until the brain begins to look like Swiss cheese. In fact the medical term for this disease is “spongiform encephalopathy,” referring to the fact that the diseased brain looks like a sponge.
Precisely how this spreads from animal to animal is still a mystery. In the laboratory we can show that prions are infectious by directly injecting them into brain cells, but this disease has a low level of infectivity by other means, thank goodness. After all, cattle got mad cow disease only after eating massive quantities of infected sheep brain used as livestock food. What a misguided practice that was.
Q: Your own work has centered on a favorite lab model for genetics research, simple brewer’s yeast. A time-honored rule of thumb in genetics is that if it happens in yeast, it ultimately will happen in people. Nonetheless, how can yeast prions relate to something as complex as the brain?
A: What we now know as yeast prions were first detected three decades ago, long before the public ever heard of mad cows or scientists ever heard of prions. In the case of yeast, the phenomenon involves the passing of a particular biochemical trait from mother cells to daughter cells, rather than an infection that spreads from one individual cell to another. Prions in yeast do not kill the cell, but alter it in obvious ways that baffled scientists because nobody could find the genes that were presumed responsible for this inheritance. After a colleague suggested it might be due to a prion, our lab provided much of the evidence. We’ve shown that this inherited trait in yeast is passed on by proteins that can change their shape. When they change shape, they change their function. Then the reconfigured proteins can cause other proteins of the same type to change their shape too. That maintains the trait for generations.
The same biochemical process that provides inheritance in yeast cells can pass on an infection in the brain of a cow. If someone is unlucky enough to eat that protein, the infection can continue.
The real point is we are dealing with a new form of inheritance–without genes. Actually it’s a very old form of inheritance; it is merely new to us. Changes in a trait can be passed on from generation to generation without any change in the genetic code. That floors me.
We have been learning that changes in the shapes of proteins are going on in all sorts of our cells every day. It is part of the normal process of adapting to the internal signals of our bodies. It also happens when we are exposed to environmental stress and is involved in many diseases.
The issue of protein-folding used to be very esoteric in biology, but it is quickly becoming mainstream because of its connection to diseases of the nervous system.
Q: Let’s be clear here. You are not saying that Alzheimer’s disease is due to prions. Correct?
A: Right. Alzheimer’s is not a prion disease. It is absolutely not infectious. But it is almost certainly caused by the misfolding of key proteins in the brain, resulting in the clumps of plaques and tangles of beta amyloid protein that are the hallmarks of the disorder. That means people with an increased risk of Alzheimer’s have a genetic predisposition for certain of their brain proteins to eventually misfold.
In terms of inheritance, we can pass on the susceptibility to our children, in some cases, but we cannot pass on the result–the misfolded disease-causing proteins themselves.
Q: So how does this relate to prions?
A: We think the process is similar to what happens in prion diseases. In Alzheimer’s, once misfolding gets started, the proteins entice other proteins to misfold as well. By understanding how this happens–and we have demonstrated at least one method–we might provide a new way to approach prevention and treatment of a lot of similar diseases.
Q: Back to yeast cells for a minute: Why would they want to allow their proteins to fold in abnormal ways?
A: There must be some biological reason, otherwise they would get rid of it. Yeast cells, in fact, rapidly rid themselves of any deleterious trait. We have some theories about the purpose of prionlike proteins in yeast, and experiments are under way that should help us find answers. I suspect we will find this phenomenon all over the place in biology, at the heart of a wide variety of normal processes.
Q: It has been proved that it’s not a good idea to eat the brains of our dead relatives. Mad cows got sick by eating sheep that had scrapie. Creutzfeldt-Jakob disease comes from eating infected cattle. You have found similarities to prions in brewer’s yeast. One is tempted to ask, somewhat tongue in cheek, if this means anything to bread, to beer?
A: Absolutely nothing. The yeast prions don’t cause disease, even in yeast. And they only spread their misfolding pattern to other proteins of the same type–from yeast protein to yeast protein. Bread is absolutely safe. Beer, too. Consumed in large quantities, beer may have some other neurological consequences, but that’s not due to prions. I’m certainly not planning on giving up bread or beer.
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An edited transcript
