[Infowarrior] - A Cryptologist Takes a Crack at Deciphering DNA ¹ s Deep Secrets

[Richard Forno]

December 12, 2006
Scientist at Work | Nick Patterson
A Cryptologist Takes a Crack at Deciphering DNA¹s Deep Secrets
By INGFEI CHEN
http://www.nytimes.com/2006/12/12/science/12prof.html?pagewanted=print

Thirty years ago, Nick Patterson worked in the secret halls of the
Government Communications Headquarters, the code-breaking British agency
that unscrambles intercepted messages and encrypts clandestine
communications. He applied his brain to ³the hardest problems the British
had,² said Dr. Patterson, a mathematician.

Today, at 59, he is tackling perhaps the toughest code of all ‹ the human
genome. Five years ago, Dr. Patterson joined the Broad Institute, a joint
research center of Harvard and the Massachusetts Institute of Technology.
His dexterity with numbers has already helped uncover startling information
about ancient human origins.

In a study released in May, scientists at the Broad Institute scanned 20
million ³letters² of genetic sequence from each of the human, chimpanzee,
gorilla and macaque monkey genomes. Based on DNA differences, the
researchers speculated that millions of years after an initial evolutionary
split between human ancestors and chimp ancestors, the two lineages might
have interbred again before diverging for good.

The controversial theory was built on the strength of rigorous statistical
and mathematical modeling calculations on computers running complex
algorithms. That is where Dr. Patterson contributed, working with the
study¹s leader, David Reich, who is a population geneticist, and others.
Their findings were published in Nature.

Genomics is a third career for Dr. Patterson, who confesses he used to find
biology articles in Nature ³largely impenetrable.² After 20 years in
cryptography, he was lured to Wall Street to help build mathematical models
for predicting the markets. His professional zigzags have a unifying thread,
however: ³I¹m a data guy,² Dr. Patterson said. ³What I know about is how to
analyze big, complicated data sets.²

In 2000, he pondered who had the most interesting, most complex data sets
and decided ³it had to be the biology people.²

Biologists are awash in DNA code. Last year alone, the Broad Institute
sequenced nearly 70 billion bases of DNA, or 23 human genomes¹ worth.
Researchers are mining that trove to learn how humans evolved, which
mutations cause cancer, and which genes respond to a given drug. Since
biology has become an information science, said Eric S. Lander, a
mathematician-turned-geneticist who directs the Broad Institute, ³the
premium now is on being able to interpret the data.² That is why
quantitative-minded geeks from mathematics, physics and computer science
have flocked to biology.

Scientists who write powerful DNA-sifting algorithms are the engine driving
the genomics field, said Edward M. Rubin, a geneticist and director of the
federal Joint Genome Institute in Walnut Creek, Calif. Like the Broad, the
genome institute is packed with computational people, including ³a bunch of
astrophysicists who somehow wandered in and never left,² said Dr. Rubin,
originally a physics major himself. Most have never touched a Petri dish.

Dr. Patterson belongs to this new breed of biologist. The shelves of his
office in Cambridge, Mass., carry arcane math titles, yet he can converse
just as deeply about Buddhism or Thucydides, whose writings he has studied
in ancient Greek. He is prone to outbursts of boisterous laughter.

He was born in London in 1947. When he was 2 his Irish parents learned that
he had a congenital bone disease that distorted the left side of his skull;
his left eye is blind. He became a child chess prodigy who earned top scores
on math exams, and later attended Cambridge, completing a math doctorate in
finite group theory. In 1969, he won the Irish chess championship.

In 1972, Dr. Patterson began working at the Government Communications
Headquarters, where his research remains classified. He absorbed through his
mentors the mathematical philosophy of Alan Turing, the genius whose crew at
Bletchley Park ‹ the headquarters¹ predecessor ‹ broke Germany¹s encryption
codes during World War II. The biggest lesson he learned from Dr. Turing¹s
work, he said, was ³an attitude of how you look at data and do statistics.²

In particular, Dr. Turing was an innovator in Bayesian statistics, which
regard probability as dependent upon one¹s opinion about the odds of
something occurring, and which allows for updating that opinion with new
data. In the 1970s, cryptographers at the communications headquarters were
harnessing this approach, Dr. Patterson said, even while academics
considered flexible Bayesian rules heretical.

In 1980, Dr. Patterson moved with his wife and children to Princeton, N.J.,
to join the Center for Communications Research, the cryptography branch of
the Institute for Defense Analyses, a nonprofit research center financed by
the Department of Defense. His work earned him a name in the cryptography
circle. ³You can probably pick out two or three people who¹ve really stood
out, and he¹s one of them,² said Alan Richter, a longtime scientist at the
defense institute.

In 1993 Dr. Patterson moved to Renaissance Technologies, a $200 million
hedge fund, at the invitation of its founder, James H. Simons, a
mathematician and former cryptographer at the institute. The fund made
trades based on a mathematical model. Dr. Patterson knew little about money,
but the statistical methods matched those used in code breaking, Dr. Simons
said: analyzing a series of data ‹ in this case daily stock price changes ‹
and predicting the next number. Their methods apparently worked. In Dr.
Patterson¹s time with the hedge fund, its assets reached $4 billion.

By 2000, Dr. Patterson was restless. One day, he ran into Jill P. Mesirov,
another former defense institute cryptographer, and mentioned his interest
in biology. Dr. Mesirov, then director of computational biology at the
Whitehead/M.I.T. Center for Genome Research, which later became the Broad
Institute, hired him.

³Really, what we do for a living is to decrypt genomes,² Dr. Mesirov said.
Cryptographers look at messages encoded as binary strings of zeros and ones,
then extract underlying signals they can interpret, Dr. Mesirov said. The
job calls for pattern recognition and mathematical modeling to explain the
data. The same applies for analyzing DNA sequences, she said.

One common genomic analysis tool ‹ the Hidden Markov Model ‹ was invented
for pattern recognition by defense institute code breakers in the 1960s, and
Dr. Patterson is an expert in that technique. It can be used to predict the
next letter in a sequence of English text garbled over a communications
line, or to predict DNA regions that code for genes, and those that do not.

Dr. Patterson said he also has a well-honed instinct about which data is
important, after seeing ³a lot of surprising stuff that turned out to be
complete nonsense.² Dr. Lander of the Broad Institute describes him as a
great skeptic, with the statistical insight to tell whether a signal is
³simply random fluctuation or whether it¹s a smoking gun.²

Making that distinction is one of the great difficulties of interpreting
DNA. In studying the human-chimp species split, the genomics researchers
strove to rule out possible errors and biases in the data.

Dr. Reich, with Dr. Patterson and Dr. Lander, and two other colleagues, used
computer algorithms to compare the primate genomes and count DNA bases that
did not match, like the C base in gorillas that had become an A in humans.
Because such mutations naturally arise at a set rate, the researchers could
estimate how long ago the human and chimp lineages separated from an ancient
common ancestor.

A DNA base can mutate more than once, however. To correct for that, Dr.
Patterson worked out equations estimating how often it occurred; Dr. Reich
revised their computer algorithms accordingly. Two strange patterns emerged.
Some human DNA regions trace back to a much older common ancestor of humans
and chimps than other regions do, with the ages varying by up to four
million years. But on the X chromosome, people and chimps share a far
younger common ancestor than on other chromosomes.

After the researchers tested various evolutionary models, the data appeared
best explained if the human and chimp lineages split but later began mating
again, producing a hybrid that could be a forebear of humans. The final
breakup came as late as 5.4 million years ago, the team calculated.

The project was ³our hobby² Dr. Reich said of himself and Dr. Patterson
said. Their main work, in medical genetics, includes devising a shortcut to
scan the genome for prostate cancer genes.

Whether studying disease or evolution, Dr. Patterson noted, genomics differs
from code breaking in one key respect: no adversary is deliberately masking
DNA¹s meaning. Still, given its complexity, the code of life is the most
open-ended of cryptographic challenges, Dr. Patterson said. ³It¹s a very big
message.²