"The Brain Eater"PBS Airdate: February 10, 1998 ANNOUNCER: Tonight on NOVA, a silent killer attacks the brain and claims its first human victims. Past outbreaks offer chilling clues of how it spreads. Is mad cow disease a threat? The Brain Eater. Major funding for NOVA is provided by the Park Foundation, dedicated to education and quality television. This program is funded in part by Northwestern Mutual Life, which has been protecting families and businesses for generations. Have you heard from The Quiet Company? Northwestern Mutual Life. And by the Corporation for Public Broadcasting, and viewers like you. NARRATOR: It appeared suddenly in England: a strange and horrific plague called mad cow disease. Almost overnight, cattle throughout the country became infected, shaking uncontrollably, turning aggressive, and losing coordination. There is no cure for this mysterious disease, and it is always fatal. Desperate to halt the spread of mad cow disease, England destroyed nearly 2 million cattle. But it was too late. Since 1985, thousands of infected cows may have entered the food chain. It now seems certain that mad cow disease is crossing into a new species. Recently an 18-year-old named Stephen Churchill fell ill with some very curious symptoms. KEITH WRITER: He had very jerky movements, and he could suddenly decide to try and get up and walk when he wasn't capable of doing any kind of action, which would often result in him injuring himself or falling over if there was nobody around to help him. HELEN CHURCHILL: He started hallucinating. It started off as he'd be watching television, and he'd get very enthralled in what was going on. If there was fire on the television he'd feel as though he was burning, or if it was an undersea, an underwater scene, he'd feel as though he was drowning, and then it got to a stage where he was just seeing things that just weren't there. NARRATOR: At the time, the cause of Stephen's illness was a mystery. HELEN CHURCHILL: We saw "CJD" and a question mark written on the notes, and that was the first sign of—they had maybe an idea of what it was. I found out that it was a very strange disease, but I also found out it was only really found in 50-, 60-, 70-year olds, and although a lot of the symptoms seemed to fit, the age group didn't. NARRATOR: Doctors thought that Stephen Churchill might have CJD, or Creutzfeldt-Jakob Disease, a rare brain ailment in the same family as mad cow disease. Called spongiform encephalopathies—spongy brain disease—these illnesses riddle their victim's brains with holes. Did Stephen Churchill get CJD from infected beef? And if so, was the country on the brink of a human epidemic? An outbreak of a similar illness offered a chilling clue. Early this century a strange new disease appeared in the highlands of Papua-New Guinea. It was called "kuru," which means "to tremble with fear" in the native language. Within years it killed thousands of the Fore people, but was unknown elsewhere in the world. In 1957, scientists traveled there to uncover the cause of this mysterious ailment. One of them, a young American pediatrician named Carlton Gajdusek, would one day win the Nobel Prize for this work. DR. PAUL BROWN: They found a population that was dying from this disease, but primarily affecting children of both sexes equally and young adult women. The first symptoms were a little incoordination. They would stagger a little bit when they walked. Little by little, over a period of months, this became sufficiently severe so that they were unable to walk unaided. In time, the people were unable even to stand and therefore became helpless. Most people with this disease died within 9 months. NARRATOR: Scientists investigated every possible cause of this illness, from malnutrition to genetic problems. DR. PAUL BROWN: The answer turned out, in fact, to be very simple: these people were cannibals. It was clearly being transmitted from person to person by cannibalism. NARRATOR: Members of this tribe ate their dead relatives as an act of homage during funeral rites. DR. PAUL BROWN: In the course of cannibalistic ritual feasting, the body was cut up into parts, and the men reserved the best parts for themselves, and the best parts were muscle. The remaining parts of the body, including brain and pancreas and liver and kidney and intestines, were eaten by the women and the children. NARRATOR: The disease was passed on as women and children ate the infected brains of their dead relatives. Many developed kuru, and when they died, they were ritually eaten, escalating this deadly epidemic. This tragic cycle was broken when cannibalism among the Fore people ended in the 1960s, but the incubation period of this disease is so long that the last victims are still dying today. DR. PAUL BROWN: The solution to the way kuru was passed from human to human, together with a number of laboratory experiments conducted over the years since, have without any question brought persuasive evidence to the idea that infection can be transmitted by feeding. NARRATOR: Cannibalism may be the cause of England's mad cow epidemic too: cannibalism among cows and sheep. Scrapie is similar to mad cow disease, but it attacks sheep. It's called "scrapie" because infected sheep scrape their skin raw. Scrapie has existed in England for at least 200 years, but it has never crossed into cows. So how did cows get mad cow disease, known by its medical name as "bovine spongiform encephalopathy," or "BSE"? Just as with kuru, food was the culprit. For several decades, cattle feed had included a cheap protein supplement made from the carcasses of other animals, including sheep and cows. BSE probably arose when sheep infected with scrapie or cows with BSE were turned into feed. The feed then infected other cows that ate it, and when those animals died, they were fed back to more cows, creating a rapidly escalating epidemic. It was a kind of cattle cannibalism, frighteningly reminiscent of kuru. And for two years after BSE was known, infected cattle were still allowed into England's food supply, raising fears that people might get BSE. To assess that risk, the British government called upon the scientific community. PROF. SIR RICHARD SOUTHWOOD: Back in 1988 it was very difficult to be confident in one's recommendations. The amount of information that we had about spongiform encephalopathies was very small. We knew there was this disease in sheep fairly widespread, called scrapie, which had been around for 100 to 200 years. It didn't seem to be causing a great deal of problems in the human population, so we based our conclusion that the chance of transmission to humans was remote on the long experience of scrapie. NARRATOR: As an extra precaution, the British government banned the practice of feeding cows and sheep back to each other, and cattle already showing signs of BSE were excluded from use in human food and destroyed. But these measures left people at risk. BSE has such a long incubation period that cattle that appeared healthy but were actually harboring the disease could still be sold and used in human food, and the government continued allowing many organs where BSE accumulates, including the brain and spinal cord, to be added to British meat products. Eventually the British government called for the removal of these parts from all carcasses being slaughtered. But no one knows the extent to which infected cattle and contaminated beef products entered the food chain. PROF. SIR RICHARD SOUTHWOOD: I've often reflected as to whether we wrote our report in too reassuring a way, and in some way this dimmed the urgency which was necessary, and obviously one regrets that. NARRATOR: Critics also charge that the interests of industry were placed above public health. PROF. SIR RICHARD SOUTHWOOD: You may wonder why we were not more alarmist in our report, but you must remember that at that time we were dealing with a very rare disease in cattle, a human disease that was—is and has remained—very rare. Most people had never heard of it. And if we had been too alarmist, we were in danger of upsetting the whole of the meat industry in Britain and elsewhere in Europe. NARRATOR: Outside of England, restrictive steps were taken. The European Community banned the import of most British cattle, although packaged meat products were still allowed. The United States also imposed a ban on British cattle. DR. PAUL BROWN: This country did a couple of things immediately. It first of all banned, as did most countries—all countries perhaps—the importation of living animals from Great Britain. NARRATOR: Going one step further than Europe, the United States banned all British beef products in 1989. Meanwhile, the Department of Agriculture began tracking down the several hundred British cattle that had been imported to the United States before the ban went into place. DR. LINDA DETWILER: We pulled the records for the 496 that were imported, and we had our field veterinarians trace those out, locate the farms where they were now residing, and then monitor those, check them every six months—where they would go out, talk to the owner, check for signs. NARRATOR: Those cattle never showed any symptoms of BSE, and most have been bought by the Department of Agriculture and slaughtered. But imported British cattle was only one issue. The question was brought up: Could American cattle be harboring their own native strain of BSE? In 1985, in the Wisconsin town of Stetsonville, mink being raised for fur came down with a rare spongiform encephalopathy like mad cow disease. Almost overnight, they started showing classic symptoms of the disease, such as loss of coordination. They soon became listless, and died within weeks. The disease wiped out thousands of mink. Richard Marsh, a veterinarian at the University of Wisconsin, was called in to figure out what had caused the epidemic. Marsh thought that something in the feed was spreading the disease. Now deceased, Marsh used to work in Paul Brown's lab at NIH. DR. PAUL BROWN: Since mink are fed carcasses—they are voracious carnivores—the interest very quickly led to the idea that carcasses were at the base of it, and that they were getting infected through sheep—specifically scrapie in sheep—and sheep carcasses were being fed to mink, so it made sense that sheep were the source of mink encephalopathy. NARRATOR: But Marsh began to suspect that on this farm, scrapie was not the cause. DR. PAUL BROWN: No sheep had been fed, but downer cattle carcasses were fed. Downer cattle are called "downer cattle" because they lie down, because they're sick, and they die. And many different diseases cause this picture in cattle. And the thought was, well, here you've got an outbreak of spongiform encephalopathy in mink that apparently had been exposed to downer cattle and not sheep, and maybe the cattle were the source of the outbreak. NARRATOR: The mink outbreak convinced Marsh that a low-level native strain of BSE exists in the United States, but was going undetected. DR. PAUL BROWN: So the idea that BSE might exist in this country, either producing a disease that wasn't recognizable as BSE or existing as a silent infection, was one that we had to seriously consider. DR. LINDA DETWILER: And because of Dr. Marsh's theory, in 1993 the USDA started to do surveillance on downer cows. We have tried to approach it from a scientific standpoint and say, "Well hey, if there is such a thing, let's look for it." To date, we have looked at over 6,100 brains and found no evidence of BSE. DR. PAUL BROWN: So that's a pretty good piece of evidence that this is not the case in the US, but it's not proof. NARRATOR: Still no cases of BSE have ever been found in the United States. But in England, throughout the 1990s, BSE was spreading fast, and not just in cows. British house cats started contracting the disease from beef in pet food. Like people, cats have never been susceptible to scrapie. DR. JOHN COLLINGE: It was certainly concerning when domestic cats developed a spongiform encephalopathy, and we now know that that is BSE that was acquired by these domestic cats, and now by quite a few wild cats kept in zoos, and some other wild animals kept in zoological gardens. And so that really indicated that BSE had a quite different host range than scrapie—that it was infecting different species that had not gone down with scrapie in the past. So that was certainly a cause for concern for me. Of course that doesn't tell us that humans are going to be at any higher risk, but it does tell us that BSE is rather different than scrapie. NARRATOR: In many illnesses, including scrapie, biological differences between species prevent diseases that originate in one kind of animal from infecting another. This is known as the "species barrier." For example, scrapie has existed for centuries, but no person has ever gotten scrapie from eating lamb. Unlike scrapie, though, BSE has proven highly transmissible, crossing into nearly every species exposed to it. For so many animals, the species barrier against this new disease was turning out to be weak, and there was no way to know whether it would be for people, too. DR. JOHN COLLINGE: It really is quite an unpredictable phenomenon. By and large, we tend to think that animals that are more closely related in evolutionary terms are going to be easier to transmit the disease to, but it's not always like that at all. For instance, it can be extremely difficult to transmit the disease between mice and hamsters, which are quite closely related species. It seems to be relatively easy to transmit BSE to mice, which are a quite distantly related species, so you know, there are really some very strange rules operating here. NARRATOR: When a spongiform encephalopathy crosses a species barrier, a frightening phenomenon can take place. As the disease passes among members of the new species, it can become stronger and more virulent, and its incubation time can shrink. Then this new type of disease may be able to infect other species that were not previously susceptible. DR. HUGH FRASER: We've certainly known since the mid-1970s that when scrapie infection is transmitted to and passaged within a new species, that strain characteristics and disease characteristics can change, and that a phenomenon analogous to mutation can occur, and that as a result of that you can generate a strain with new properties, with new characteristics, with altered neuropathology, and even with an altered host range. DR. PAUL BROWN: Let's assume that BSE is the result of rendered recycled scrapie in the food chain of cattle. There is not a shred of evidence to date that scrapie has ever caused CJD in humans. But scrapie passaged, or going into cattle, might change the host range of the infection, and therefore we cannot predict whether BSE would be or would not be infectious for humans. PROF. SIR RICHARD SOUTHWOOD: We, of course, had no way of knowing at that time whether the BSE agent was exactly the same as the scrapie agent. Work since has shown that it does actually perform in a slightly different way to the scrapie agent. NARRATOR: This news was alarming. If BSE has a different host range from scrapie, could it infect humans, turning their brains to sponge? Answering that question was difficult, because these strange diseases do not behave like conventional illnesses. Most infectious diseases are caused by bacteria or viruses, tiny microbes that can only be seen under the microscope. Bacteria and viruses contain genetic material—nucleic acid such as DNA. Nucleic acid is the essential ingredient of life and allows organisms to reproduce. Bacteria and viruses cause disease by spreading toxins or damaging their host, but spongiform encephalopathies seem to operate differently. Unlike bacteria and viruses, they provoke little or no immune response—signs that the body is fighting infection, such as antibodies. And they have another strange characteristic. In the 1960s scientists found that radiation, which kills viruses and bacteria by destroying their genetic material, has little effect on spongiform encephalopathies. They appear to defy the rules of biology. DR. PAUL BROWN: These agents are almost immortal. They resist alcohol, they resist boiling, they resist hospital detergents. We thought it would be interesting to see what would happen if we buried some of these agents, and so I ground up some scrapie brain and mixed it with soil, put it in a flower pot, enclosed it in a cage, and used my own garden as a burial site—right here. And what we found was that a good deal of the infectivity remained in the soil after three years. We exposed it to temperatures that turned it to ash, and it did not entirely kill the agent, and so every known pathogen of man would have been destroyed by this process, and this was not. NARRATOR: So if these diseases don't behave like other pathogens, what are they? Scientist Pat Merz discovered a tantalizing clue in her New York laboratory. Using an electron microscope which can magnify up to 100,000 times, she was looking for the infectious agent that causes scrapie. At that time, most believed the killer was a slow-acting virus, but her discovery pointed scientists in a new direction. She detected these hazy threads in the brains of animals infected with scrapie. They did not appear in the brains of healthy animals. Merz thought these fibers could be a sign of scrapie, CJD, and kuru. But each of these strands contains millions of particles far too small to be identified even with the electron microscope. A different technique was needed. DR. DAVID BOLTON: What we wanted to look for was what was unique about a sample from the diseased brain that was not in the normal brain. What component, what molecule would be in that diseased brain that was never in the normal brain? And so I did some experiments where I looked at proteins and separated these proteins using a gel to separate them by their size, and they give little different bands on the gel. And when I did that, I didn't really expect to find anything right off the bat, and after one of the experiments, I went into the darkroom to develop the film, and I was very surprised when I saw this, and I knew when I saw this gel that this had to be it. There's a fuzzy band that's here in the gel that's in each of the three samples from the diseased brain, and it's not in the samples from the normal brain. And this is exactly what we had been looking for. We and everybody else had been looking for some sort of a key, some kind of a molecule that we could say was in the diseased brain and not in the normal brain, and that really forced us to conclude that this protein is part of the agent—in fact, might be the only component of the agent. NARRATOR: This band of protein appeared to be the only difference between the diseased brains and the normal brains. They called it the "PRP protein." Finding it didn't solve the mystery, though. It deepened it, because no one thought a protein could be an infectious agent. Apart from water, our bodies are composed largely of proteins. There are thousands of different kinds of proteins, aiding in everything from digestion to thinking. But proteins contain no genetic material—no nucleic acid which would allow them to reproduce. So how could a protein multiply and cause disease? DR. PAUL BROWN: To the best of my knowledge, all infectious agents—all pathogens—require the participation of nucleic acid in order to multiply, to replicate. The idea, therefore, that replication could occur without nucleic acid is heresy. DR. DAVID BOLTON: We couldn't figure out, "How could a protein replicate if it doesn't have a nucleic acid?" NARRATOR: The answer had been suggested decades earlier but dismissed as too outlandish. DR. DAVID BOLTON: I started thinking about it several years before, when I had been doing a literature review and looking in some journals in the library at a paper, and I was looking actually up one paper that was written about the nature of the scrapie agent, and when I went to photocopy it, on the second page of that paper there was another paper, and it was by a mathematician named J.S. Griffith. And in this paper, he talks about self-replication in scrapie, which is one of these diseases, and he outlines three ways that a protein alone could replicate and cause disease. Now, he came up with the idea that you would have two different forms of the protein. One was abnormal, disease-causing, a rogue protein, if you will. And the other was a normal protein that would be in the cell or in the brain of a normal person. And the essential part of the theory was that the abnormal form of the protein could bind to the normal form and convert it—change its structure to make it an abnormal or a disease-causing protein. And now you can see that if one molecule binds to another molecule and converts it, now you have two molecules of abnormal protein, and two combined to two more and have four, and so on and so on, until you have thousands and millions of abnormal proteins in the brain. And pretty soon then you have disease. You have so much abnormal protein in the brain that it would cause disease and cause neurons to die. The most amazing thing was that the paper was published in 1967. He was a mathematician, wrote this one paper, and never published anything again on scrapie. The insight was really very astounding—that someone back then with so little information could see a way that a protein could be an infectious agent. NARRATOR: Since then, the idea has been taken up by many scientists, most notably Stanley Prusiner. He and others found that there are two types of PRP protein in the brain, just as Griffith predicted. One is a normal protein found in all mammals. The other is a disease-causing form of the protein called a "prion"—a term coined by Prusiner. The prion is chemically identical to the original protein, but it has a different shape, which makes it so stable that it resists heat and disinfectants. It appears to have no genetic material, so radiation does not harm it. Once in its abnormal form, this new molecule seems to have the ability to corrupt any healthy PRP proteins that it comes into contact with, turning them into prions, too. This is not replication. It's conversion. DR. JOHN COLLINGE: It's a very strange observation that you have these two quite different forms of the same protein with quite different properties. One of them is a killer. If this protein is present in your brain, you're in serious trouble. The other one is a normal constituent of all our brains, and obviously understanding how one converts into the other and, in the longer term, how to stop it, is a tremendous puzzle. NARRATOR: While scientists are still piecing that puzzle together, they have found that prions can link up in long, indestructible chains that accumulate in the brain. There they kill cells, creating the holes that turn the brain to sponge. If correct, the prion or protein-only hypothesis would be revolutionary, a phenomenon unheard of before in biology. DR. DAVID BOLTON: I very strongly believe in the protein-only hypothesis. NARRATOR: But it remains unproven and controversial. Some believe that prions are not the cause of disease, but the byproduct of it. Others think the infectious agent might turn out to be a virus or something similar, its genetic material hidden in a protective coat of protein. DR. HUGH FRASER: The idea that it is an infectious protein is an exciting and curious idea, but it's one which I do not accept. DR. PAUL BROWN: This would be a novel biological mechanism. It's been difficult to accept because of that, because there's no precedent. NARRATOR: But since no genetic material has been found, the protein-only hypothesis is gaining support. DR. JOHN COLLINGE: This has been an extremely controversial area of science. Prions are novel infectious agents, and there's been a very rapid evolution of ideas. And I think BSE has arrived on the scene in the midst of this scientific controversy. DR. PAUL BROWN: The answer is still not known with certainty, but more and more it looks as though the protein-only hypothesis will turn out to be correct. NARRATOR: While the idea continues to be debated, the 1997 Nobel Prize for medicine was awarded to Stanley Prusiner for his pioneering work on prions. What started out as heresy had become mainstream. But now another issue was taking center stage. DR. JOHN COLLINGE: The burning question became, "Can BSE transmit to humans? And are we going to see an epidemic of human disease following exposure to BSE?" NARRATOR: It was an urgent question, and a special scientific team was formed to look for clues that mad cow disease might be passing into the human population in the form of an illness like CJD. But no one knew exactly what they were looking for or what they would find. One member of the team visited CJD patients before they died, looking for any new or unusual form of the disease. DR. MARTIN ZEIDLER: I would travel throughout the whole of the country to see patients with Creutzfeldt-Jakob Disease, as the geographical distribution is completely random. Most patients with Creutzfeldt-Jakob Disease, by the time that I visit them, are severely demented, so they're unable to communicate. They're usually mute, lying in bed, unable to move. And they have jerking movements of their limbs, what's called "myoclonus." They can also not infrequently be blind, and even though they can't see, their brain is producing hallucinations, which can make them very frightened. NARRATOR: Another member of the team had the job of examining the brain of anyone suspected of dying of CJD to look for links with mad cow disease. But a CJD autopsy requires special precautions. DR. JAMES IRONSIDE: I've now changed into the clothes I'll wear to do an autopsy in a case of suspected CJD, and these garments are disposable because they will be incinerated after the autopsy. These are the gloves. On the top is a chain mail hand piece, and this is flexible and allows my hand to be protected from any cuts while the autopsy's being performed. And I wear another pair of rubber gloves on top of this just to make the whole thing as waterproof as possible. And this is the helmet. I'll just put it on. The instruments that I use in the post-mortem room and the instruments the technicians use in our dedicated laboratory, really, we regard these as being permanently contaminated, so we use those for CJD cases alone, because there is no effective way of guaranteeing decontamination in this disease. NARRATOR: A third member of this was on the lookout for the emergence of any new patterns of CJD cases. DR. ROBERT WILL: There are a number of possible things we could look for, including a change in the number of cases that might be identified every year, for example, looking at change in occupation to see whether the people who were in contact with cows or with BSE tissue might be more at risk, and also to look at any change in the age of the patients or the other clinical features, and finally to look at the neuropathology to see if that had changed in any way. DR. JAMES IRONSIDE: We really had no idea what we were looking for. Our mission statement, if you like, was to identify every case of CJD in Britain and to study the clinical and pathological features to monitor any change. NARRATOR: In the spring of 1995, changes began to emerge. At 19, Stephen Churchill died from what doctors thought was CJD. This puzzling case of CJD in someone so young caught the attention of the surveillance team. DR. ROBERT WILL: June 1995, we heard about one young patient with CJD, a teenager with CJD. And this was clearly very unusual. And then a few months later, we heard about another case in another teenager. And this was clearly exceptional. In December, we began to be referred to a number of other younger patients with CJD, in their 20s and 30s, with a very unusual clinical presentation. DR. MARTIN ZEIDLER: They didn't show the typical appearances, which is in the brain recordings that we see in sporadic Creutzfeldt-Jakob Disease. This is a brain wave recording from a patient with sporadic Creutzfeldt-Jakob Disease, and it shows the classical appearance associated with CJD. These sharp waves are occurring in all the—all across the tracing, coming from the various parts of the brain, and they occur regularly, usually once or twice every second. However, in the new patients, none of them had that classical appearance. And what we saw was just slow waves. They didn't show the typical appearances associated with the sporadic form of the disease. DR. JAMES IRONSIDE: The first time I saw the new variant of CJD was in a brain biopsy from a young patient. And I can remember being very struck, even in this very small piece of tissue. The changes there were very different from anything that I'd ever seen before. NARRATOR: This was the first confirmed case of a new type of CJD. But what had caused it? HELEN CHURCHILL: Somebody came down with a questionnaire and asked us questions about lifestyle and eating habits, where we'd been on holidays and that sort of thing. Obviously with Stephen being 19, Mum and Dad knew exactly the medical treatments he'd had, his eating, that sort of thing, because he was still living at home at that time. Steve was no different to anybody else. He didn't have any operations that would have put him at risk. He didn't eat anything strange. He just—He was a normal child, and he was a normal 18-year-old up until he became ill. KEITH WRITER: He did eat beef burgers, but he ate sausages, he ate all sorts of things, no more or no less than most other people, so completely normal in that respect. NARRATOR: Eventually other cases like Stephen's emerged. And to confirm their suspicion that they had a new form of CJD, the team used a computer to compare brain slides from the randomly-occurring or sporadic form of CJD and the new cases. The microscopic holes that accumulate in the brain were outlined in red. DR. JAMES IRONSIDE: When we first set up the project, we were anticipating that perhaps the changes would be rather subtle. However, when the first new variant cases emerged, the changes were so striking, even on initial examination, that we were overwhelmed by the differences. As well as the spongy change in the tissue, there were large numbers of these plaques, these aggregates of prion protein, but it wasn't just the plaques. They had a particular shape. They were large, they were rounded, and they were surrounded by a ring or a halo of spongiform change. And I had never seen anything like that before. I think I realized then that undoubtedly this was something different, something new, something very disturbing, and something for which we had no explanation. DR. MARTIN ZEIDLER: I think we all had to agree that this was something unexplainable, and that we couldn't just put it down to a chance occurrence. NARRATOR: By early 1996, 10 cases of the new variant of CJD had appeared throughout Great Britain, all in young people. While there was no hard scientific proof that mad cow disease had caused their deaths, the circumstantial evidence was overwhelming. The news that BSE might have infected the human population shocked the world. Nations across Europe banned British cattle and meat, just as the United States had done in 1989. Fear struck home when the public learned that the practice of feeding cows the rendered remains of other animals was still legal in the United States. OPRAH WINFREY: Cows should not be eating other cows! It has just stopped me cold from eating another burger! NARRATOR: While British beef was still for sale, some restaurants and fast food chains throughout England removed it from their menus. But was mad cow disease really the cause of the new disease? DR. ROBERT WILL: The timing of these cases is possibly of some importance, and the reason for that is that if the population of the UK were exposed to the BSE agent in the mid-1980s, it would not be unexpected, if there were a link, that cases would start to occur in the mid-1990s. DR. JAMES IRONSIDE: The striking similarity in both the clinical features and the pathology in these cases suggests that a common agent is operating, and this I think points towards BSE as the most likely cause. DR. MARTIN ZEIDLER: I think the most likely explanation is that these cases have occurred because of BSE. DR. PAUL BROWN: If these 10 people have died from BSE, then essentially the entire population of Britain is at risk. NARRATOR: But with so few cases, scientists could not accurately predict the extent to which the human population would be affected. In the first year of the cattle epidemic, only 10 cows fell ill. Eventually the death toll exceeded 170,000 cows. Would the human epidemic follow the same course? DR. JAMES IRONSIDE: One of the main questions we have to address now is why only this small group of patients has developed this disease. If you believe that this is BSE, then potentially millions of us in Britain have been exposed to the agent in the food chain, so what is special, what is different about these people that in a way allowed them to develop the disease? NARRATOR: One of the only clues so far has been found in the genetics of those who fell ill. DR. ROBERT WILL: There is some evidence from CJD that people of a particular genetic make-up are particularly susceptible to CJD. NARRATOR: The gene responsible for the prion protein seems also to affect our susceptibility to prion diseases. Along this gene, DNA codes for two different types of amino acids, Methionine and Valine. A person whose DNA codes for one Methionine and one Valine seems less susceptible to prion diseases. Someone who has two Valines is more vulnerable. And those who have two Methionines are called "Methionine homozygotes," and seem to be the most susceptible to the new kind of CJD. DR. ROBERT WILL: The first two published cases were known to be Methionine homozygotes, and earlier this year we began to get the results back on the other new variant cases, and this established that there was a link between them, and that was that they were all Methionine homozygotes. NARRATOR: All 10 of the new variant CJD cases bore this genetic trait, but this offers little comfort. DR. ROBERT WILL: Looking at the distribution of Methionine homozygosity in the United Kingdom population, it's not really all that reassuring, because about 18 million people in Britain are probably Methionine homozygotes. NARRATOR: Testing so many people is out of the question. And scientists are unsure just how much one's genetic type confers protection or vulnerability. In addition, there are still many other mysteries about the risk BSE presents to humans. DR. JOHN COLLINGE: It's very hard to try and perform any sort of real risk assessment as to what the outcome of this might be, how many people might get infected, what sort of exposure might be a risk. We really know so little, in fact none, really, of the key ingredients that you'd need to know to make a risk assessment. NARRATOR: For example, no one knows how many British cows contracted BSE, or how many entered the food chain. Complicating risk assessments even further is the mystery of how much infected material a human being would have to eat to trigger disease. Using a herd of test cattle, the British government has established a minimum dose fatal to a cow. Eating just one quarter of a teaspoon of BSE infected brain is enough to kill it. But what about humans? It takes a much larger dose to pass infection from one species to another than within the same species. But no one knows exactly how much, or whether seemingly insignificant amounts of BSE can accumulate in the body until they reach a fatal level. DR. JOHN COLLINGE: We don't know yet whether there's a cumulative dose effect. We know in animal models that there's a minimum dose that you have to give to produce the disease. We don't know yet, if you divide that dose up into small portions and give it over a long period of time, whether it would also be effective. And this is an important issue with respect to BSE in humans. It may be that you have to have a very large exposure to BSE over a short period of time to get the disease; it may be that small amounts over years could build up to produce the disease. And we really don't know the answer to that question. But there's likely to be some cumulative element to it, simply because the infectious agent itself is so persistent in the body. It can stay there for a long period of time, so it's bound to build up to some extent. NARRATOR: In addition, experts have not determined whether BSE exists throughout an infected animal's body, or just in the brain and spinal cord where it accumulates. Flesh, muscle, milk and blood have never been found to be infectious, although these tests are not definitive. But the greatest mystery is how easily BSE can cross the species barrier from cows to humans. A strong species barrier would protect most people, but a weak one would leave many more susceptible. DR. JOHN COLLINGE: The species barrier between cows and humans is unknown. You can't just assume that it's going to be an absolute one. Of course we can't measure it, because that would involve injecting humans with BSE, which clearly we wouldn't do. NARRATOR: Scientists need to know more about what controls the species barrier. DR. JOHN COLLINGE: And the only way to find out is to do the experiments. You can't just sit down with a piece of paper and work out how easily it will go from one species to another. It's something you have to determine experimentally. NARRATOR: One of those experiments focuses on how the species barrier works on a molecular level. DR. SUZETTE PRIOLA: Evidence from other labs has suggested that the type of PRP protein that an animal makes can determine whether or not that animal is going to be susceptible to infection with the agent from a different species. So what we know is that this protein, this PRP protein, is composed of a sequence of what are called "amino acids," which are linked in a long chain, and that the amino acid sequence of PRP from an animal like a sheep differs from the sequence in an animal such as a cow. And what we're interested in determining is if it's those differences between these two types of PRP that can affect whether or not this species barrier is broken and infection can occur. NARRATOR: Priola is investigating how scrapie is passed between two closely related animals, hamsters and mice. Curiously, mice can't be infected with hamster scrapie, but hamsters can be infected with mouse scrapie. To understand why, Priola analyzed the differences in their PRP proteins. DR. SUZETTE PRIOLA: Between the mouse PRP and the hamster PRP, there are 16 amino acid differences. And what we were able to do is show that you can control formation of this protein by changing just one amino acid. So one change out of 254 amino acids could be enough to allow the formation of this abnormal protein. If you get the formation of this abnormal protein, you're probably going to get disease. One of the things that this piece of work implies is that very minor changes in the PRP proteins between two different species could really have a dramatic effect on whether or not you get formation of this abnormal protein. NARRATOR: This work indicates that the species barrier against BSE can be breached fairly easily, which would seem to have grave implications for humans. Experiment after experiment is confirming that this is already happening, leaving little doubt that new variant CJD is, in fact, the human form of mad cow disease. To date it has killed more than 20 British people. So far, the United States has been lucky. No cases of BSE or new variant CJD have ever been found here. But can it remain that way? DR. PAUL BROWN: I think the likelihood of BSE existing in this country is small. It's not zero, but it's small. And I think the phenomenon that BSE is widespread in this country is simply not true. NARRATOR: To prevent BSE spreading in the food chain, the United States government has at last banned the practice of feeding most—although not all—animal remains to cows and sheep. Thanks to similar measures in England, BSE is now on the decrease there and may even be eradicated from British cattle herds early in the next century. But it remains to be seen what direction the human disease will take. DR. JOHN COLLINGE: It's far, far too early to say what sort of epidemic that's going to be, whether it's just going to be 20 or 30 cases over several years, or whether it's going to be hundreds or potentially thousands of cases. We have to wait and see. DR. PAUL BROWN: If the two dozen-odd cases of CJD in Great Britain are most of the cases that we will ever see, that is to say, if what has happened basically represents a few susceptible people, then I think even if BSE existed in this country, it would not be especially panic-producing. If, on the other hand, within two or three years we start to see hundreds or thousands of cases of CJD in humans in Great Britain, then that's going to be cause for concern all over the world. ANNOUNCER: Are prions behind this dreaded disease? Do they even exist? Follow the raging debate. Log on to NOVA's Web site at www.pbs.org. Educators can order this show for $19.95 plus shipping and handling by calling 1-800-949-8670. And to learn more about how science can solve the mysteries of our world, ask about our many other NOVA videos. Next time on NOVA: James Randi, magician and investigator of psychic phenomena. Explore the world of the paranormal, examine supernatural claims, and journey with Randi to Russia to challenge their psychics. What is real, and what is an illusion? "Secrets of the Psychics." That's next time on NOVA. NOVA is a production of WGBH Boston. Major funding for NOVA is provided by the Park Foundation, dedicated to education and quality television. This program is funded in part by Northwestern Mutual Life, which has been protecting families and businesses for generations. Have you heard from The Quiet Company? Northwestern Mutual Life. And by the Corporation for Public Broadcasting, and viewers like you. This is PBS. Coming up on NOVA: Climb the world's highest peak to explore the limits of the human body. Will the summit claim a new victim? "Everest: The Death Zone." 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