It Kills Horses, Doesn't It?

Borna virus used to be an obscure veterinary problem in Saxony. But it's obscure no more. A couple of German virologists believe the bug may be sending people, in large numbers, to the psychiatric ward.

By Robert Kunzig|Wednesday, October 01, 1997
The patient mostly stands still, with lowered head and an imbecile expression, and pays no attention to her surroundings. . . . She walks slowly and heavily and only when pushed in the rear. . . . While resting, she constantly gnashes her teeth.

The patient, a four-year-old chestnut mare, had been brought to the Royal Veterinary School in Berlin in March 1896. That spring an epidemic was raging through the stables of Saxony; it was centered on the town of Borna, south of Leipzig. The veterinarian there, a diligent keeper of statistics, reported 168 sick horses in a population of 400. Two eminent pathologists in Berlin, A. Siedamgrotzky and M. Schlegel, were charged with investigating the matter. They found that typically the onset of Borna disease, as it later came to be called, was sudden. From one day to the next an animal’s personality would change completely. It would stand unsteadily with splayed legs, its head hanging limp or propped against a corner; it would lose interest in food; it would yawn incessantly.

Sometimes it would walk in circles, tighter and tighter ones, until finally it was just shifting back and forth. And sometimes the subdued suffering would give way to something wilder, and the horse would try to climb into its manger or would shoot headfirst into a wall. That is how some of the victims died: from fractured skulls. More often, though, they simply starved to death. A few, like the chestnut mare, recovered, but almost never completely. The psychic depression remains, wrote Siedamgrotzky and Schlegel.

In 1896 the concept of microbial infection was still new; Louis Pasteur had invented his rabies vaccine just a decade earlier. Pasteur was never able to isolate the rabies agent, and Siedamgrotzky and Schlegel, though they sliced open horse brains and examined them carefully, couldn’t find the cause of Borna disease, either. In both cases it was not a bacterium but a new kind of infectious agent that was eluding detection, an organism so small it passed through the finest filter: a virus. In the case of Borna, that did not become known until 1924, when a veterinarian named Wilhelm Zwick at the University of Giessen in western Germany injected a certifiably bacterium-free filtrate from infected horses into the brains of rabbits--and thereby gave them Borna disease. Zwick found he could infect rats, guinea pigs, and rhesus monkeys too. Apparently the virus was highly flexible, though in nature it was still known only as a scourge of German and Swiss horses and sheep.

Throughout the twentieth century, interest in Borna virus has come and gone, like the disease itself. Troubling as it was to the veterinarians and farmers who encountered it, it was never, even in the worst years, more than a regional curiosity. And in between epidemics the disease would make itself scarce, forcing some of the few scientists who were interested into other lines of research. No one has ever known why or where the virus hides. Since the mid-1960s it has been in deep seclusion: the incidence of Borna disease in Germany has declined nearly to the point of insignificance.

The scientific interest in Borna has not dwindled, though--on the contrary. More has been learned about the virus in the 1990s than in the previous century. Its genes have been sequenced and some of its habits unveiled. It turns out to be very strange--similar to rabies in some ways, including its marked preference for attacking cells of the nervous system, but not too similar. Virologists have had to create a new family, the Bornaviridae, just to accommodate Borna virus.

And the center of Borna research is still Berlin. Two virologists there, Liv Bode and Hanns Ludwig, the latter a student of a student of a student of Wilhelm Zwick’s, are more responsible than anyone else for the recent upsurge in interest in the virus. They claim it doesn’t just attack horses; it infects people too. It doesn’t kill us, though, at least not directly. Instead it hides out in our brains for years or decades, doing nothing most of the time. But every now and then, in some people, the virus starts actively reproducing, blocking the signal traffic between brain cells and thereby affecting the mind. Those people may then suffer a depression--not an ordinary fleeting sadness or ennui but a dark and paralyzing despair that may land them on the psychiatric ward for months at a time. Clinical depression is the fourth most common disabling disease in the world; it often ends in suicide. There has not been a new treatment for it since Prozac was launched a decade ago, and Prozac doesn’t cure. If Bode and Ludwig are right, it will become possible to treat many cases of depression with simple antiviral drugs. They have already begun a small clinical trial of one drug, amantadine sulfate, that was developed three decades ago as a treatment for the flu.

Even now doctors throughout Germany are offering amantadine to their depressed patients, without waiting for the results of the clinical trial. Bode is actively helping and encouraging them. Although she would not be the one to put it this way, she and Ludwig may be on the leading edge of a revolution in psychiatry. Or, as some of their peers seem to think, they may be so far ahead of their science as to be on the edge of irresponsibility.

Bode is a trim woman in her mid-40s, with neatly cropped blond hair and neat if casual attire--zierlich is how a colleague had described her, which means graceful, dainty, elegant, neat. She seems not at all like the furious Expressionist prints that decorate the walls of her small office, until she opens her mouth. Though her small voice rarely rises, the words spill out of her in a barely punctuated torrent; and when they reach that bend in the river where her passion lies, as they do these days within a few minutes of hello, with nothing so formal as a question required, they dig a deep, eddying pool. Well, she says, taking a parenthetic breath, there we are already in medias res.

The heart of the matter, for Bode, lies in the way depression can destroy a life. It preoccupies her, this disease, so different as it is from the blackest mood of a healthy person, or even from the neurotic residue of an unhappy childhood. In the Diagnostic and Statistical Manual of Mental Disorders that Bode keeps in her office, the American psychiatric manual that classifies every affliction of the soul in five-digit diagnostic code, depression falls under category 296. In particular, subcategories 296.3x, recurrent major depression, and 296.5x, bipolar disorder, or depression that alternates with periods of euphoria rather than normalcy--manic-depressive syndrome, in other words--are the two conditions that Bode is most convinced Borna virus plays a role in. She avoids the word causes. The proximate cause of clinical depression, it is widely agreed, is a disruption of neurotransmitters--the molecules that carry messages from one brain cell to the next. Many factors contribute to that disruption, Bode thinks, or anyway at least three. Bad genes and stress are the first two, the ones everybody agrees on. The third is Borna virus.

It’s certainly a very complex illness, Bode says. But the really astounding thing is that between episodes of very severe depression you can get phases of complete health, complete lack of symptoms, in which the victims cannot be distinguished from normal people. And that’s where we think the virus plays a role--in the recurring nature of the illness. After the first episode, when they’ve had that scare, if they came out of it halfway whole, they may be free for years, and they think they will never be felled by it again--but then it keeps coming back. That’s what’s typical for this type of illness, it’s that it’s a lifelong threat--quite apart from the fact that in any particular depressive phase hardly any activity is possible, and the whole person in all her experience is disrupted. And then there’s the physical weakness and fatigue--all these things are connected with it, not just the desperation itself, not just the feeling ‘It’s never going to get better, I don’t know why I’m even here anymore,’ and thoughts like that, which can be torture, extreme torture, especially because of how long it lasts--you could stand it if it were just a few days, but certainly not weeks or months, and without knowing why, because that too is a not unimportant hallmark of the disease, that it often strikes for no discernible reason whatsoever. Some patients say it’s as if you had flipped a switch--they wake up one morning and they know their disease and they know it has started again.

Bode is not a psychiatrist, nor a medical doctor of any kind. She is a research virologist at the Robert Koch Institute, a small German version of the National Institutes of Health that specializes in infectious diseases. She came there in 1980 from Marburg, where she had taken her degrees in biology. The ivory tower never tempted her; even as a student her interests ran toward tropical medicine and the murderous parasitic diseases of the Third World. At the rki she worked at first in a laboratory devoted to unconventional agents--including the one that is now thought to cause mad cow disease. Later she developed diagnostic tests for hiv. By 1988, though, the aids epidemic in Germany had advanced to the point at which a dedicated center was set up at the rki, and Bode was able to return to basic research. She looked around for a topic she could delve into in a lab of her own. As it happened, she had recently met Hanns Ludwig, a veterinary virologist at the Free University; at the time, he had his lab at the rki, the better to be among other virologists. Ludwig had a topic for Bode: his topic. By then he had been working on Borna virus for 25 years.

Ludwig told Bode of some experiments he had done a decade earlier, while he was still at the University of Giessen. The experiments involved tree shrews--small, long-nosed Asian mammals that superficially resemble squirrels. A friend of Ludwig’s happened to be a specialist in tree shrew behavior. It’s not pretty, ordinarily: they are nasty, aggressive little beasts, not much given to affection and parenting. After pups are born the mother wastes little effort on nurture before chasing them away. Yet tree shrews, while not primates themselves, are considered close to what our earliest primate ancestors must have looked like. Their brains are organized like ours. One evening in the mid-1970s, Ludwig suggested to his friend that they try injecting Borna virus into some of his animals to see what it would do to them. This they eventually did to 19 shrews.

And lo and behold, they didn’t die, like rabbits! Ludwig recalls. Or like horses. Instead they developed a persistent infection. They had antibodies to the virus but no clinical signs--only changed behavior: they became tame. They had a lot of sex. They got their children, and they reared them differently--they lay with them and licked them all the time. It was a disruption of social behavior in animals with a primatelike brain. So that was very exciting. But of course we had no proof that it was the virus that did it.

In 1978, right after their paper on the subject was published and widely ignored--America didn’t believe it, Ludwig says--Ludwig left Giessen for Berlin, where he had gotten a professorship. In his baggage was strain V, the Borna virus strain that Wilhelm Zwick had extracted from horses back in the 1920s and that had been preserved in Giessen all that time in dried-out, vacuum-packed rabbit brain cells. In Berlin, Ludwig met a neuropathologist named Georg Gosztonyi, a Hungarian expatriate at the Free University. Gosztonyi had worked on the rabies virus: he claimed it had the ability to send its genetic material through synapses, from one nerve cell to the next, just like a neurotransmitter. At the time, people didn’t believe Gosztonyi on rabies any more than they did Ludwig on tree shrews. The two men started working together on Borna virus.

Meanwhile, back at the lab in Giessen, a visiting American by the name of Opendra Narayan had made an interesting discovery. If you infected adult rats with Borna virus, they died. But if you infected day-old rats, they lived on, developing a persistent and asymptomatic infection--like tree shrews, only rats are more readily available. Gosztonyi and Ludwig sliced open the brains of such rats. Under a microscope they saw nothing: the brain cells were intact and healthy. But when they stained the slices with antibodies to Borna virus, fluorescent antibodies, the cells in the limbic system lit up. Though the rats did not seem sick in any way, their limbic system was stuffed with virus. The limbic system is the set of structures, including the hypothalamus, that wrap around the tip of the brain stem in the middle of the brain. Those structures are involved in memory, and together they control emotions and desires, in rats as in human beings.

Ludwig’s former boss in Giessen, Rudolf Rott, had actually looked for Borna virus in human beings. But when the results of his search were published in 1985, no one quite knew what to make of them. Rott had hooked up with psychiatrists at the University of Pennsylvania who provided him with blood samples from 285 patients with depression or manic-depression. He found antibodies to Borna virus in 12 of the patients, or 4 percent. In a control group of 200 healthy people, not one was Borna-positive.

The difference between 4 percent and zero was statistically significant--but if Borna virus really was linked to depression, why was it in only 4 percent of the patients? And why was it in 4 percent of the patients in America--where Borna disease was unknown in animals--whereas in a group of psychiatric patients in Germany, whose blood Rott also tested, fewer than 1 percent had Borna antibodies? Rott’s study proved nothing. Still, it seemed worth pursuing. At least, it did to Liv Bode, when she started looking into the subject a few years later.

One thing that seemed suspicious to Bode right from the start was that a rat could have a brain full of Borna virus and not be affected somehow. So she organized a behavioral study of Borna-infected rats. Although such rats looked normal, it turned out they weren’t: they were very slow to learn things--for instance, where the food was in a Y-shaped maze. They also seemed relatively indifferent to electric shocks. Perhaps most surprising of all, they weren’t scared when they should have been. If you put a normal rat at the dark perimeter of an open field, it will linger in the shadows, sniffing around for a long time before carefully, hesitantly venturing into the light. But the infected rats charged right into the middle of this brightly lit space, Bode says, and sat there tranquilly grooming themselves--on a platter, as it were.

Bode also followed up on Rott’s human data. One of the problems with that study, she decided, was that it hadn’t taken account of the cyclic nature of most psychiatric disorders, especially depression. The patients in Philadelphia had all had their blood sampled only once, and they may have been in a relatively healthy phase at the time. If Borna virus really was related to psychiatric illness, Bode figured, the best time to look for evidence was when the patients were actually ill. She contacted a psychiatrist in Berlin named Ron Ferszt, who worked in the Crisis Intervention Center of the Free University hospital. There Ferszt saw all kinds of patients--depressed ones, psychotic ones, people with anxiety disorders. The one thing they had in common was that they were all very ill when he saw them, all in some kind of crisis that required them to be hospitalized.

Bode and Ferszt and their colleagues started taking blood samples from those patients, once a week or so during their hospital stays, and testing the blood for Borna antibodies. And what they found was that any psychiatric inpatient, no matter what the diagnosis, was more likely than a healthy person to have Borna antibodies in his blood--around 15 percent of the patients in Ferszt’s clinic did, versus no more than 2 percent of people in a normal population. But among the depressives, the prevalence of Borna antibodies went as high as 30 percent--which was far higher than Rott had found, and which confirmed Bode’s hunch that it was important to test people several times during the cycle of their illness. On a number of occasions Bode and Ferszt even observed what virologists call seroconversion: a patient would have no Borna antibodies the first time they tested his blood, but then antibodies would appear during the course of his depressive episode. That suggested an active process of infection and immune response was under way--and that the infection was linked to the illness.

Suggested, but didn’t prove. Antibodies never prove much. Antibodies are like butterflies, says Ferszt. They come and go. The antibodies in a patient’s bloodstream today could always be a residue from some long-ago infection, one that has no more to do with his current psychiatric condition than, say, the chicken pox antibodies in the average adult’s blood have to do with a current case of the flu. To prove a connection between Borna virus and depression, Bode and her colleagues would have to find the virus itself in depressed people. But the whole point about Borna was that it headed straight for the brain and supposedly stayed there, out of reach. A virus like that was not going to be easy to find. It is rarely possible, after all, to take brain samples from a living human being.

Liv Bode needed a lucky break to make progress, and she got a bigger one than she could have imagined: the Berlin wall came down. Suddenly she had access to the countryside that had been East Germany--and in that countryside, to horses that were naturally infected with Borna virus. I traveled around a lot and looked at those horses myself, Bode says. You have to have that experience yourself--that’s very important. I really don’t like engaging in abstract exercises. It was while examining one very concrete and sick horse that she and Ludwig made the discovery that eventually led to all the rest of their still controversial claims.

Hanns ludwig is sitting in a beer garden across the street from his laboratory in leafy Dahlem, an affluent old neighborhood that is home to the Free University. He is wearing clogs, chinos, a button-down shirt, and wraparound sunglasses. The breeze plays with his full gray hair. Between gulps of beer he is telling his version of the Borna virus story, more dramatic than Bode’s, with italics and exclamation points, startling changes of pitch, and frequent lapses into English, sometimes in midsentence.

We had a horse close to Berlin, dying from Borna, he says, recalling the breakthrough that in his and Bode’s view helped establish the virus as a human threat. So Liv Bode and I went to that horse. And said, ‘Oh, we have to investigate the brain.’ His voice quavers mock- dramatically. And then I said, ‘Oh, let’s take blood.’ Liv took some blood. And I said, ‘Maybe the virus goes into the periphery of such a horse.’ Maybe! Indeed it went. We had a graduate student, Falko Steinbach, who had very sensitive techniques, facs analysis--fluorescence activated cell sorting--immediately he found it! Liv said, ‘Steinbach! Look into people, people with depression!’ Immediately he found it. Can you imagine what a breakthrough that was--in people, from whom you cannot take any brain cells?

What Steinbach had found, in the dying horse as in the patients at Ferszt’s clinic, were Borna virus proteins in blood cells, specifically in immune cells called monocytes. It is not clear what the virus was doing there; perhaps the monocytes had traveled to the site of infection in the brain and scavenged it. In any case, Bode and Ludwig now had the first direct evidence of a Borna infection in humans--not the antibodies this time but the things the antibodies were attacking, the antigen. It was present in around half the psychiatric patients they tested--and it didn’t seem to matter whether the patients were acutely or chronically ill, depressed or paranoid-psychotic or schizophrenic or something else. That was a little confusing, actually, since by then Bode and Ludwig were already pursuing the hunch that Borna was specifically linked to recurrent depression. Still, the finding of bits of the virus in so many patients was better evidence of some kind of link between the virus and psychiatric illness. And now that it could be got at in blood and not just in brains, Bode and Ludwig had the chance of obtaining conclusive evidence--proof even.

But they couldn’t do it alone. They needed help, especially from an American doctor turned molecular biologist named Ian Lipkin. It was Lipkin and his colleagues at the University of California at Irvine who had shown that, unlike rabies and nearly all other viruses, Borna virus reproduced itself inside the nucleus of an infected cell, and it reproduced itself only in very small quantities, which helped explain why virologists had spent decades failing to isolate it. When in the early 1990s Ludwig finally did succeed in teasing strain V out of cells and purifying it, he sent it to Lipkin in California. It was Lipkin who determined the sequence of the rna genome.

After that, papers came flying out of Berlin. Step one: Bode and Ludwig, collaborating with Ferszt and using bits of Lipkin’s sequence as search templates, discovered Borna rna in the monocytes of four psychiatric patients; they failed to detect it in ten healthy controls. The presence of detectable levels of rna indicated that the virus was actively reproducing itself in humans who were actively ill. Step two: Isolate the human virus. Ludwig had in his lab a line of human brain cells, not neurons but a type of support cell called oligodendroglia, in which he had successfully grown animal Borna virus before. He and Bode gave an Indonesian graduate student, Fedik Rantam, the job of coaxing the virus out of blood cells from Ferszt’s patients and into the cultured cells, where it could be kept indefinitely. Rantam got blood cell samples from 33 patients. For weeks he nursed these cells tenderly with the cultured cells, passaging them repeatedly into new petri dishes so they wouldn’t run out of room to grow, a thousand passages in all.

A thousand passages! Ludwig exclaims, his hand tracing the motion from one petri dish to the next. A lot! Blind! And then this fellow came to Liv Bode and said, Oh! I have five or seven positive!’ Then we broke the code and we said, ‘Wooow! A depressed patient! Another depressed patient!’

In the end Rantam was able to cultivate Borna virus from three patients: two manic-depressives and an obsessive-compulsive, albeit one who was also depressed, more or less all the time. Exciting as the results seemed to be--definitive proof of Borna virus infection in humans; strong evidence of a role for the virus in psychiatric illness--Bode and Ludwig had difficulty getting them published. Though Rantam had worked in a room that had never been used for Borna research before, critics said there was still the risk his petri dishes might have been contaminated with Borna virus--animal virus--that was floating around the lab building. The paper finally appeared last year in a brand-new journal called Molecular Psychiatry. Since then Bode and Ludwig have also extracted the virus from the blood of an American with chronic fatigue syndrome. So far, though, no other laboratory has been able to isolate human Borna virus. Nobody has our know-how, says Ludwig.

Under the circumstances, some researchers might have hesitated to take the next step so soon--but Bode was not in the Borna business as an abstract exercise, and as soon as she had human Borna virus isolates in her hands, in early 1996, even before the results had been published, she started running tests in her lab to see what drugs might be effective against the virus. The pace doesn’t seem fast to Ludwig either. On the contrary, he finds it unfairly constrained by the tight funding situation in Germany. We’re slow, we have only a few people, he says. That is our main problem. In America, Liv Bode and I would have our own institution, I tell you. Because we have all the tools, and we can follow the way, and maybe help a lot of people.

I’m incredulous. you could never do that in the United States. Ian Lipkin is talking about the clinical trial that Bode and Ludwig are conducting with psychiatrists in Hannover. Regardless of how much I like Liv and Hanns, and I do like them, says Lipkin, the bottom line is that they may be right, but they haven’t shown it. If Lipkin were to apply for funding for such a trial in the United States, given the current state of Borna science, the nih would turn him down. If he were to seek permission from the ethics committee of his university, it would be refused. There’s a certain scientific standard that you’re held to, Lipkin says.

Lipkin is not one to scoff at the notion that Borna virus might be linked somehow to psychiatric illness. Earlier this year he himself published one of the first studies to find the virus in the brains--not the blood--of deceased psychiatric patients. He found Borna rna in 9 of 17 schizophrenics, 2 of 5 bipolar patients, and in none of his healthy controls--nor, for that matter, in any patients with recurrent depression. Finding the virus in human brains is an important milestone, but it doesn’t prove anything, Lipkin says. Schizophrenics could simply be more susceptible to Borna infection for some reason.

Moreover, the levels of Borna rna found in human patients are extremely low, much lower than in sick animals--which is why Lipkin, like Bode and Ludwig, had to use an exquisitely sensitive technique called nested pcr to detect it. That technique is also exquisitely sensitive to contamination. An independent lab that Lipkin had some of his brain samples sent to could not verify all his positive results.

Bode and Ludwig have so far not had their blood samples checked in the same way. Some of their peers hold this against them. However, other labs, Ludwig points out, have now reported Borna rna in human blood. Researchers in Japan even found it in 4 percent of randomly selected blood donors, which is disquieting because it raises the question of whether Borna virus--and perhaps psychiatric disease--might be transmitted by blood transfusions. But two other labs in Germany using nested pcr have failed to detect Borna in blood. One of them is at the University of Giessen and is run by Jürgen Richt, like Ludwig a former student of Rott’s. Initially, says Richt, he did find Borna rna in the blood of a few psychiatric patients--but when an independent lab tried to replicate those findings, working with the same type of equipment and the same samples, the results were uniformly negative. That lab, unlike Richt’s--and Bode’s and Ludwig’s- -had no previous exposure to Borna virus. A few molecules on the equipment are enough and the whole thing is contaminated, says Richt.

Richt has also tried to reproduce Bode’s most recent and crucial finding, the one that led directly to the clinical trial: her finding that amantadine sulfate, a cheap and widely available antiviral drug, is amazingly effective against Borna virus, at least in petri dishes. It prevents cells from becoming infected with human Borna virus, and it rapidly drives the virus out of cells that are already infected. Richt and at least two other investigators have tried to repeat her experiments, though, and have failed. In Richt’s experiment, amantadine had no effect on Borna virus whatsoever. Like Bode, he tested it only in cell cultures, not bothering to try it on infected animals. Oh please, he says. That wouldn’t be ethically defensible, not even in animals.

Actually the depressed human beings who are now getting amantadine in Hannover are not running any particular risk. It is known as a relatively harmless drug with minimal side effects. Though ineffective against flu, it is sometimes still prescribed these days for Parkinson’s disease; in some people it relieves the tremors. Were it not for that, and for the fortuitous circumstance that the two psychiatrists at the Medical School of Hannover, Hinderk Emrich and Detlef Dietrich, happened to have a patient who suffered from both bipolar disorder and Parkinson’s, there would not be a clinical trial going on right now.

Emrich and Dietrich came to Bode in early 1995, not long after she and Ludwig had published their report on Borna antigen in human blood. The whole idea seemed plausible from the start, Dietrich recalls. Every day in the clinic he saw people whose depression seemed to go beyond conventional explanations, people who suffered not just from loss of concentration and memory, the typical symptoms, but from a spatial disorientation and a great physical unrest. Some other agent seemed to be at work in those people--just as an infectious agent, the bacterium Helicobacter pylori, had recently been found to be at work in the stomachs of people with common ulcers. That theory too had been controversial when it was first proposed by an obscure Australian doctor, but today ulcers around the world are being treated and cured with antibiotics. The Hannover workers, like Bode herself, draw comfort from that development.

Together they decided to launch a follow-up study of patients suffering from either bipolar disorder or recurrent depression. One of the patients, a 67-year-old bipolar woman, was a regular on the Hannover psychiatric ward. Over the past decade, ever since her disease had first presented itself, one doctor after another had torn his hair out over her. Everything was tried, says Dietrich, and nothing worked. The woman spent three to eight months every year in the hospital, toughing it out, waiting to become normal again. Then between 1989 and 1991 her disease entered a period of rapid cycling, in which mania and depression alternated every month or so and no normalcy was left. Toward the end of that same period she also began to show the first symptoms of Parkinson’s. Eventually her doctors decided they could at least do something for that. In 1994 they began giving her intravenous amantadine in doses so high it made her hallucinate.

The Parkinson’s symptoms didn’t stop--but a week or so after she first got amantadine, she came out of her depression, fast. A few months later she was back in the hospital, depressed again, and got amantadine again. The same recovery happened and was duly noted in her chart. There the matter rested. She didn’t get amantadine again because of the hallucinations. In early 1996 she reentered the hospital with depression and met Dietrich for the first time. He read her chart. She was part of his study with Bode now--and he knew she was Borna-positive. He decided to give her the antiviral again, but orally and in a lower, more continuous dose. Eight days later she suddenly snapped out of her depression, and best of all, she didn’t become manic. When Dietrich saw Bode at a conference, he suggested she test amantadine in vitro to determine its potency against Borna virus. By then she had already tested a closely related compound and found it promising.

By the end of last year Bode and her colleagues were submitting a one-page case report to The Lancet detailing their successful use of amantadine in treating a depressive patient. It appeared in January. The rki issued a press release, and the story was picked up by the German media. The patient really had no prospects anymore for a lasting improvement, Bode was quoted as saying in a Berlin newspaper, the Tagesspiegel. But we now regard her as cured. Depressed people started calling their doctors; their doctors started calling the rki.

Within weeks of The Lancet publication, Bode and her colleagues had sought and obtained permission from Germany’s medical ethics commission to conduct a clinical trial of amantadine. Dietrich and Emrich started enrolling patients in April. Before it is over they plan to give amantadine to between 20 and 40 severely depressed patients who are Borna-positive and to a similar number of moderately depressed ones.

So convinced is Dietrich that the drug will prove effective that he is already giving it to patients who are not enrolled in the clinical trial, without waiting for its results. You have a certain moral obligation to your patients, he explains. When you see you can help some of them by such simple means, then you want it to happen with others too. He has treated about a dozen patients so far outside the trial. One young woman, also bipolar, had a severe depressive episode cut short after only a week of taking amantadine, when typically it would have lasted three or four months.

Meanwhile Bode’s small lab has become a national clearinghouse for the diagnosis of Borna virus infection. Since January doctors have sent her perhaps a thousand blood samples. She has only three people working for her, and they are also supposed to be doing research. Inevitably her research has been delayed--but at this point Bode has deliberately put caregiving before science.

It is possible to admire her motives and still regret that choice. Ron Ferszt is certainly not entirely comfortable with it. I too have gotten many hundreds of calls from people who ask, ‘Do I have the virus, and if so, that’s good, right, then I can have my depression treated?’ When these are all things we don’t know yet! At the moment it’s just an interesting hypothesis. But I’m being overwhelmed by a wave of people who have great hopes and who are very ill, and who think there is a treatment shortcut, that there’s been a breakthrough. Frau Bode’s laboratory is flooded with requests, and it is interfering with research. It would have been better to finish the research first.

Bode herself has no apparent regrets. Behind every case of this disease there is a human being whose whole life is affected by it, she says. Picture yourself knowing you have the disease, and you face the prospect of having depressive episodes again and again, but you don’t know when--you have great difficulty in planning your life when you’re always going to be ambushed anew by a sickness you can’t control.

After we did that Lancet paper, we thought, okay, it’s just one case. But it still could be a new hope for these patients, especially since the drug has been known with all its side effects and approved for 30 years. So we thought, we won’t do what we otherwise might have done, which would be to do studies for years until we had so many statistics we could say it was right. When you see the enormous suffering this disease causes-- it’s a chance you shouldn’t deny these people.

Last February, a few weeks after the article in The Lancet appeared, the 67-year-old woman in Hannover checked back into the hospital- -not quite cured, apparently. Her depression, says Dietrich, was less severe this time. A blood test showed that Borna virus antigen had reappeared in her bloodstream; Dietrich thinks the problem was that he had reduced her dose of amantadine too much. She is very overweight, he says, and the fat tends to absorb the medication. Under the circumstances, he thinks her relapse supports rather than undermines the theory that Borna virus causes depression. After three months in the hospital, she was able to go home again.

In a booklet published to celebrate its centenary in 1991, the Robert Koch Institute described the aftermath of the event that led to its creation--Koch’s discovery of tuberculin, the antibody against the tuberculosis bacterium. Tuberculin is still used today in skin tests for the disease, but a century ago it seemed possible to Koch and to others that he might have found a cure. For the first time in the history of infectious diseases, the possibility of a specific therapy against an infection seemed to be becoming real, the rki booklet says. But the highly charged expectations were followed by a deep disappointment. Experimental treatments of tuberculosis patients were tried all over the world with great hope but with much too great haste--and often with too high doses--and they all failed. Koch was hurt deeply by this sobering setback. . . .

In the end, though, Koch left a huge legacy to medicine: his method. Koch’s postulates are still the standard criteria for determining whether a microbe causes a disease. I know absolutely, says Hanns Ludwig, and Liv Bode knows absolutely that there’s a connection between virus infection and brain disturbance--but their evidence does not yet satisfy Koch’s postulates. To begin with, it is not even clear which disease Borna virus should be linked to--to recurrent depression and bipolar disorder, as Bode proposes, to schizophrenia, as Ian Lipkin’s recent brain study and much other evidence suggest, or perhaps to chronic fatigue syndrome? To all of them? If one limits the argument to depression, the evidence still fails Koch’s first and most basic test: the putative infectious agent is not present in all people with the disease.

Bode is not sure it needs to be. Her model of how Borna virus is involved in psychiatric disturbance is one that permits it to be one of many causes--a risk factor, the way smoking is for lung cancer--and to have one of many effects. Gosztonyi’s observations suggest that the virus, in passing from one brain cell to the next, occupies neurotransmitter receptors on the target cell. During periods when the virus is active, the internal traffic in the limbic system could be severely disrupted--only to resume in a normal way when the virus retreats into latency. Other things besides Borna virus could snarl neurotransmitter traffic, and some people could be more vulnerable to such disruptions than others. Depending on the nature of their vulnerability, the result might be depression or it might be schizophrenia. It is all very complicated, and all very vague at this point.

Another great unknown is how the virus might be transmitted to human beings. Some people live in close proximity to German horses, and Bode has found that the virus is far more widespread among horses than had once been thought; for every animal with visible Borna disease, there may be half a dozen asymptomatic carriers. But transmission from horses could hardly explain the worldwide prevalence of depression among humans. In recent years a Swedish veterinary pathologist named Anna-Lena Lundgren has shown that Borna disease is also endemic among cats in the vicinity of Stockholm. Many of the symptoms are much the same as in horses: depression, loss of appetite, weak hind legs--so weak the animals can’t jump on the couch. However, there is no evidence yet of Borna virus being transmitted to humans from cats. Nor any indication of how this virus might travel from one human to another. In a blood transfusion? Through a handshake?

Into this sea of doubt and skepticism and unanswered questions Bode, Ludwig, and their Hannover colleagues have plunged with their clinical trial. Though their approach may seem hasty, a success would not be unprecedented. Louis Pasteur never satisfied Koch’s postulates; he died before viruses had even been discovered, but his rabies vaccine survived him and saved many lives. Bode and her colleagues may, as she so fervently hopes, cure people of depression before they have proved their case for what causes it. The cure itself would be powerful proof. The size of the antidepressive effect we can achieve in infected people may show us how big a role the virus plays in the illness, says Bode. The results of the trial are expected by the end of the year.
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