After the 'Eureka,' a Nobelist Drops Out
Graphic
A Recipe for Genetic Analysis
Duplicating the Code of Life
By NICHOLAS WADE
ANDERSON VALLEY , Calif. -- Kary Mullis, Nobel laureate
in chemistry, is
jumping up and down at the kitchen table of his cabin,
a place in the
woods several miles beyond where the paved road ends.
His large head
and wiry body shake as if in rage. From his lips comes an
angry buzzing sound.
He is imitating a swarm of yellow jackets,
acting out an episode in which the wily
insects ambushed him, inflicting five
stings around the mouth, after he attacked
their nest. He goes on to tell how he
invented a brew, concocted in his kitchen
blender, that eliminated the aggressors
from his property for a season.
He feels somewhat the same way toward
his former colleagues at the Cetus
Corporation, where he invented the
technique that won him the Nobel Prize.
"None of those vultures had anything to do
with it," he says emphatically. He is
aggrieved that Cetus paid him a mere
$10,000 for the discovery but later sold it
to Hoffmann-La Roche, owned by Roche Holding Ltd., for $300
million.
His invention, known as the polymerase chain reaction or
P.C.R., is used for
amplifying chosen sections of DNA and has quickly become an
essential tool for
biologists, DNA forensics labs, and almost anyone else who
needs to study the
genetic material. Amplifying DNA, a requirement for most
tests, used to be
done in bacteria, a process that took weeks. With P.C.R.,
performed with
chemicals in a test tube, the job takes a few hours.
Science has been just one of the keen interests in Mullis's
life, competing with
psychedelic drugs and women, although he is now happily
married to his
fourth wife, Nancy Cosgrove. His newest interest is writing.
A book of essays,
"Dancing Naked in the Mind Field," was published last month
by Pantheon.
For those who would like to analyze creativity and sell it
in bottles, Mullis
would seem a promising subject. His invention is highly
original and
significant, virtually dividing biology into the two epochs
of before P.C.R. and
after P.C.R. Yet the Mullis formula for creativity, on
closer inspection, is a brew
probably somewhat unsuitable for general consumption.
One ingredient is unbounded self-confidence. "Part of it has
to do with his ego
and belief that he's much smarter than the people around
him," said Dr. Corey
Levenson, a former Cetus colleague now at Ilex Oncology in
San Antonio. "Most
people who launch into an unfamiliar area would first speak
to recognized
authorities and get all the background. Kary saw that as a
waste of time. He
figured it would take less time to do the experiments
himself."
Mullis's friends speak of his physical as well as
intellectual risk-taking. Dr.
Frank McCormick, a cancer biologist at the University of
California, San
Francisco, recalls seeing Mullis in Aspen skiing down the
center of an icy road
through fast two-way traffic. "Mullis had a vision that he
would die by
crashing his head against a redwood tree. Hence he is
fearless wherever there
are no redwoods," McCormick said.
Along with lack of fear comes a lack of concern about
people's opinions. In his
new book Mullis describes episodes that others might keep
private, such as the
time he addressed the Empress of Japan as "sweetie" when
being awarded the
Japan prize, and how he was nearly arrested when he went to
Stockholm for
his Nobel Prize, for playing a laser beam from his hotel
room at passers-by.
His fondness for the heterodox is evident in the account of
a lecture he gave in
April 1994 at a medical society conference in Toledo, Spain.
"Just before the
lecture, he told me he would not speak about the P.C.R. but
would tell his
ideas about AIDS not being caused by the H.I.V. virus," the
ambushed president
of the society, Dr. John F. Martin, wrote afterward in a
letter to Nature.
"His only slides (on what he called 'his art') were
photographs he had taken of
naked women with colored lights projected on their bodies,"
Martin continued.
"He accused science of being universally corrupt with
widespread falsification
of data to obtain grants. Finally he impugned the honesty of
several named
scientists working in the H.I.V. field."
Kary B. Mullis was born in
1944 in Lenoir,
N.C., and grew up in South
Carolina, where
his father was a furniture
salesman and
his mother, who raised him
after a
separation, sold real
estate. He trained as a
chemist at the Georgia
Institute of
Technology and at the
University of
California at Berkeley.
Then, shortly after
getting his Ph.D., he
dropped off the
scientist's usual career
path, first to write
fiction and then, for two
years, to manage
a bakery.
It was a friend, Dr. Thomas
J. White, who
found him jobs back in
science, first at the
University of California,
San Francisco, and
then at Cetus in Emeryville,
Calif., one of
the first biotechnology companies. Mullis's job, essentially
that of a technician,
was to make short chains of DNA for other scientists. When
machines became
available to do the job, he had time on his hands for other
pursuits.
Mullis has often described how the concept of P.C.R. came to
him during a
night drive along Highway 128 to his cabin in Anderson
Valley. He was playing
in his mind with a new way of analyzing mutations in DNA and
suddenly
realized that he had thought up instead a method of
amplifying any DNA
region of choice. Before the trip was over, Mullis has
written, he was already
savoring prospects of the Nobel Prize.
The night journey was made in 1983; the Nobel Prize came 10
years later. But
by then Mullis had dropped out of full-time science again.
He left Cetus in
1986, earning his living by consulting and lecturing. He has
published no more
scientific papers. The divine spark that kindled the idea of
P.C.R. has not struck
again.
"I like writing about biology, not doing it," Mullis says.
"I don't want to go back
to the lab myself and don't want to have people under my
command. Fiction is
my way around doing experiments."
He also enjoys giving lectures. "I love a microphone and a
big crowd; I'm an
entertainer, I guess."
Some of his agenda seems to have been selected with an eye
to the shock
value of adopting beliefs untypical of Nobel prize-winning
scientists. He
echoes the contrarian belief of the distinguished virologist
Peter Duesberg that
H.I.V. is not the cause of AIDS. He disputes the arguments
that
chlorofluorocarbons are depleting the ozone layer and that
industrial waste
gases may cause the climate to get hotter.
"Scientists are doing an awful lot of damage to the world in
the name of
helping it. I don't mind attacking my own fraternity because
I am ashamed of
it," Mullis says.
He jumps to his feet to swat a yellow jacket that has
infiltrated the cabin.
Given his success as an independent thinker in chemistry,
Mullis's challenges
to other kinds of orthodoxy are not to be lightly dismissed.
But the line
between fact and entertainment in Mullis's world can be hard
to discern. In his
book he professes to believe in astrology, to have been
rescued from a fatal
accident by a person travelling in an astral plane, and to
have conversed with
an alien disguised as a raccoon.
Asked why people should accept his views on AIDS when he has
no standing as
a virologist, he replies, "I don't care, I'm on my vacation
life here."
Vacation life? "I have a spiritual thing in me. After lots
of tough lives I got a
vacation." Is he speaking of reincarnation as a metaphor or
the real thing? "I
believe it," he says. "If reincarnation is a useful
biological idea it is certain that
somewhere in the universe it will happen."
Is it not awkward to accommodate reincarnation within the
theory of
evolution? "I don't think DNA is the whole thing even though
I invented a cool
way of playing with it," Mullis declares.
The invention of P.C.R. may well become a paradigm of
scientific discovery
because of its significance and because Mullis has described
the eureka
moment so graphically. But though the idea was central,
proving it worked was
also important. According to White, the friend who got him a
job at Cetus and
oversaw part of the development of P.C.R., the reduction of
the idea to practice
was done largely by others.
"Mullis as an experimentalist is sort of hit and miss,"
White said. "He got a lot
of data but he was having personal problems and tended to do
uncontrolled
experiments, so it wasn't very convincing when he did get a
result."
Even after a year, Mullis had not developed definitive proof
of his concept, so
White then enlisted another scientist. Within a few months,
Dr. Randall Saiki, a
rigorous experimentalist, produced data that convinced
everyone at Cetus that
the process worked, White said.
Mullis believes his colleagues tried to take credit for the
invention away. White
denies that, saying a plan to have Mullis author the first
paper describing the
theory of P.C.R. went awry because Mullis whiled away the
summer creating
fractal pictures on Cetus's computers instead of doing
experiments.
By default, a paper by Saiki and other scientists on the
applications of P.C.R.
was published first. Mullis's own paper was rejected by the
journals Nature
and Science on the ground that it was not new.
"I feel he has never accepted responsibility for the course
of how the
publications came out," White said, noting that he and
colleagues attempted to
let scientists know Mullis was the inventor, such as having
him describe the
technique at an important conference.
White pays tribute to Mullis's fertile mind, describing how
he came up with
practical ways to improve P.C.R., such as the use of Taq
polymerase, an enzyme
made by bacteria that live at high temperatures. But
managing his friend's
creativity was not a carefree task.
"He's a hard person to know, hard not only on his spouses
but on his friends,"
White said. "In the midst of being extremely charming he
could be extremely
abusive." The two men are no longer close friends, but
White, now vice
president of Roche Molecular Systems in Alameda, Calif.,
owned by Roche
Holding, said that Mullis was "a very unusual person, no
doubt about it -- I am
happy I knew him."
White's version of events is supported by Dr. Paul Rabinow,
an anthropologist
at the University of California at Berkeley, who made a
study of Cetus at the
time P.C.R. was invented. His book, "Making P.C.R.," was
published in 1996.
"Mullis is a brilliant, gifted guy who at Cetus found
himself protected by a very
steadfast character, Tom White," Rabinow said. "The one
person who never said
he wanted credit for P.C.R. was Tom White."
As for the monetary rewards for P.C.R., Mullis says in his
book he was "plenty
wrong" in his assumption that he would be amply rewarded by
Cetus. His
former colleagues consider he did not do too badly. He
voluntarily quit the
company in 1986 at a time when no commercial value had been
established
for P.C.R., and five years before its sale to Roche for $300
million. "If the guy
had been around five years later he would have been
handsomely rewarded,"
White said. Levenson said: "Any invention you make is owned
by the company.
That's the deal."
Mullis has blazed through his friends' lives like a meteor,
leaving so blinding a
trail that few feel they see the core. "I don't know where
creativity comes
from," Levenson said. "He built his model of the universe to
fit what he
observed."
In Rabinow's view, Mullis is "a tinkerer, a bricoleur, he
loves to play with
things, he loves to try things out, he ignores people who
say you can't do it." He
adds, "He was an experimentalist not in the high scientific
sense but the
magician sense."
In Mullis's new profession, as author and lecturer, the
magic is less evident. His
book is amusingly written, but some of its viewpoints seem a
little ad hoc, like
a surprising attack on the Federal Reserve Board as a
"tawdry sepsis."
Mullis repeats the words several times to savor their
resonance. It's a good
fighting phrase, but why apply it to the Federal Reserve?
Mullis explains that
with the Board's ability to intervene in currency markets
its members have
ample opportunity to profit from their inside knowledge. "If
you can get around
the law you do it, and Alan Greenspan is no different from
Kary Mullis," he
declares.
"But Kary, you're not dishonest," his wife protests. "With
money I am," he says
defiantly. The bottle of red wine at his side, full three
hours ago, now stands
empty. The yellow jackets are resuming their campaign. A
mind that made a
brilliant invention is wandering between sense and
solipsism.
--Rohit Khare -- UC Irvine -- 4K Associates -- +1-(626) 806-7574 http://www.ics.uci.edu/~rohit -- http://xent.ics.uci.edu/~FoRK