Cresting controversy

Adept at riding waves, the surfing Nobel laureate Kary Mullis has now taken to making them - he claims that there is no evidence that HIV causes Aids. Ayala Ochert reports.

Kary Mullis has been called "our quirkiest Nobel laureate", and it is true that there are not many winners of the coveted prize who believe that astrology can make good science while disputing the idea that HIV is the cause of Aids. Still fewer would openly admit to having taken LSD. Once a nurse for premature babies and once hired as an expert witness by O. J. Simpson's lawyers, Mullis has led a more varied life than most. Oh, and did I mention, he's an avid surfer?

His unconventional views have led some to conclude that he must be a few sandwiches short of a picnic, that he lost touch with reality once he secured his place in history by inventing the polymerase chain reaction (PCR), a technique that revolutionised molecular biology. They might even compare him to another Nobel prizewinning chemist, Linus Pauling, who spent the last years of his life attacking the cancer establishment just as Mullis now attacks the Aids establishment. But, with his eccentricities, Mullis is better understood as someone who is utterly unafraid of thinking anything on any subject. You could say that all the sandwiches are there, they just have unusual fillings. "I'm one of those people who decided at a very early age there was nothing I couldn't understand. I'm one of the smartest, most open people I know," he says, unabashed.

Arrogant, yet undeniably charming, Mullis has the manner of an exceptionally bright child. Indeed, as he describes it, his childhood in South Carolina in the 1950s was an idyllic time, when no one would question why you might need 100 feet of dynamite fuse, even if you were just 13 years old. This playful attitude towards experimentation has stayed with Mullis to this day, and he still finds it hard to think of science as "work".

Early on, he became addicted to organic chemistry, later specialising in biochemistry. But, as a student at the University of California at Berkeley, he refused to take courses in molecular biology, instead studying astrophysics, reasoning that "all the people I know are going to take molecular biology - they'll tell me if there's anything interesting".

That decision paid off when, in 1968, as a second-year graduate student, Mullis had a paper titled "The cosmological significance of time reversal" accepted by the prestigious science journal Nature. Nearly 20 years later, much to his irritation, that same journal rejected his paper describing PCR.

In the early 1980s, Mullis worked for the biotechnology firm Cetus, where his job was making short pieces of DNA called oligonucleotides. The story of how he invented PCR while at Cetus is now part of scientific folklore. It was a Friday evening, Mullis was driving along Highway 128, his girlfriend, Jennifer, asleep by his side, as they headed towards his cabin in Mendocino. He was mulling over a problem when, in a flash of inspiration, he came up with the idea of PCR. He slammed on the brakes and pulled off the road to consider the significance of what had just occurred to him. Jennifer went back to sleep, but Mullis knew then that he was going to win the Nobel prize.

That story has been retold many times. In some versions he is riding a Harley-Davidson on the more scenic Pacific Coast Highway. Though it is true that he experienced a eureka moment that night, his invention was also inspired by practical considerations.

Mullis's lab at Cetus had seven people all making "oligos". Just a few days earlier, a machine had become available that could automate the whole process and, instead of taking a month to fill orders, they could be met within a couple of days. That meant all seven people would soon be out of a job. "I had to make the demand for these (oligos) higher, so I thought, you had better think of some other things to do with them, because they're too salty to eat!" He suspected that these short sequences of DNA might also be able to "probe" the genome, looking for small errors, such as the single mutation that causes sickle-cell anaemia. But the human genome is three billion bases long, and trying to find one mistake would be like locating the proverbial needle in a haystack, only harder. Using existing methods, it could take months to pinpoint a gene.

Mullis's mathematical training told him that a sequence of just 17 bases would in theory be enough to identify uniquely a single point along a genome of three billion bases, but he was still not sure that he could use these oligos to search the genome. As he drove, he tried to visualise a process to do just that. Then he realised that the process he was thinking of would do more than search the genome, it would double the signal he was trying to detect. The signal would double after each cycle, and the process could be repeated indefinitely. Twenty cycles would increase the signal one million-fold; 30 times, one billion-fold. It was at that moment that Mullis pulled off the road. These short pieces of DNA could enter the genome, find their targets and report back their whereabouts. PCR would be the equivalent of burning the haystack and using a metal detector to find the needle.

Mullis had a hard time persuading Cetus to let him work on this new idea, and it was several months before he proved that it worked. But once they realised how important PCR would be, his bosses wanted to claim all the credit for themselves, Mullis says. "The first paper came out in 1985, and my name was in the middle of about seven names, meaning I had nothing to do with it," he recalls with disgust. Then the chemical company Du Pont decided to file a law suit against Cetus, claiming the patent on PCR was invalid. It was an unpleasant time. Cetus offered Mullis a derisory $10,000 bonus for his invention, and eventually sold the rights to pharmaceuticals company Hoffman La Roche for $300 million. But he was finally vindicated by the courts, which judged that he alone had invented PCR.

Today, there is not a molecular biology lab in the world that does not use the technique. It is particularly useful in forensic science - tiny amounts of DNA can be detected at a crime scene, and even ancient DNA can be analysed successfully. But its most significant social impact may be yet to come, as simple genetic tests become routinely available.

If PCR had a big impact on our lives, the Nobel prize had an even more significant impact on Mullis's own life, allowing him the independence he craves. In recent years this has led him into conflict with Aids researchers. Never one to shrink from controversy, Mullis has gone out against the Aids establishment all guns blazing. Chief among his concerns is, he says, that he cannot find any research to support the notion that HIV is the probable cause of Aids.

"I can stand up in front of an audience of a thousand Aids researchers and say, if any one of you has a paper that you can send me the reference for that can show me that HIV is the probable cause of Aids, I will publicly recant my position. That's all I'm saying. I can't find one. Where is it?" Mullis says.

According to Mullis, the disease we call Aids came along at a time when the US Center for Disease Control was in a quandary. It was the early 1980s, and its budget of $3 billion was severely threatened by Congress, whose members wondered why America was spending so much money on controlling infectious diseases when these had largely been dealt with through vaccination programmes. "The head of the CDC sent out memos saying, 'Our agency needs a plague'," Mullis claims. A plague was what they needed, and Aids was what they got. Then, in 1984, Bob Gallo of the National Institutes of Health announced in a press conference that he had found the virus that causes Aids. The human immunodeficiency virus, Gallo said, was responsible for the disease that was now to be known as acquired immune deficiency syndrome, and a vaccine and a cure were sure to follow quickly from this discovery.

As far as Mullis is concerned, Aids is not so much a disease as a social phenomenon - a number of diseases that have been lumped together for purely financial reasons. And Mullis also has reservations about HIV tests. "There's a very complicated relationship between what is in our blood and what they measure. It's not a simple thing - HIV-positive or HIV-negative," he argues. The trouble is that other things can show up as HIV antibodies in blood tests, including antibodies to malarial parasites, which is why, he believes, so many Africans appear to be HIV-positive.

But if the rest of us are not sceptical enough about Aids, Mullis says, then we are not open-minded enough about other matters - astrology, for instance. Like many people of a scientific bent, Mullis never paid the subject much attention until he was repeatedly confronted by the uncanny ability of strangers to guess correctly that he is a Capricorn. When he calculated that the probability of three consecutive strangers guessing his star sign correctly to be one in 1,728, his interest was piqued. He has since discovered that it is a fact well known to scientists that people in particular professions seem to group around certain star signs - doctors cluster around Gemini and Cancer, biochemists cluster around Sagittarius. "Why be upset about it?" Mullis asks. "Why not just say, that looks like a fruitful field for investigation? It doesn't matter that we don't know how it works."

Mullis is highly critical of what he regards as the unscientific behaviour of other scientists, whom he sees as overly interested in furthering their reputations. "What most experiments aim to do is to prove the hypothesis of somebody who's going to make some money out of it. Most scientists are just businessmen in another mode," Mullis says. He claims not to be a competitive scientist himself, and it would certainly be hard to accuse Mullis of attempting to further his own reputation. Sometimes it even seems as though he is trying to do the opposite, even to the point of exaggerating his own use of LSD to make a point. His outspoken advocacy of the drug almost deterred the Nobel committee. But it does annoy him that so few other scientists will admit to having taken the drug in the 1960s. He believes it could help to further our understanding of how the mind works. "LSD is a sort of experiment on yourself," he says.

LSD may also have been the reason that, although he was hired by O. J. Simpson's lawyers, he never got to testify in that trial - once the prosecution found out, they used it to discredit him before he was even due to take the stand.

Science remains his first love, and Mullis's latest venture is as vice-president of the start-up Burstein Labs, a company involved in medical diagnostics. Here he hopes to use his imagination to create something that can rival PCR in its ingenuity and usefulness.