The Human Genome Project's Unlikely Hero (2001)
Bryan Bishop
papers that I took from Stanford's biochem 118 class, and one of the
PDFs was about an unexpected hero involved in the human genome project
"back in the day" and was probably overshadowed in that year by some
other gnarly events.
F e b r u a r y 13, 2001, Tuesday
READING THE BOOK OF LIFE; Grad Student Becomes Gene Effort's
U n l i k e l y Hero
http://heybryan.org/books/papers/www/biochem118/cmgm.stanford.edu/biochem118/Papers/Genome%20Papers/grad%20student%20hero.pdf
http://www.nytimes.com/2001/02/13/health/13HERO.html
"""
Asurprising hero helped the consortium of academic scientists decoding
the human genome to avoid a drubbing by its rival, the Celera Genomics
company. Scientists throughout the world are now beating an electronic
path to his Web site, where they can analyze and download the human
genome sequence. He is a graduate student at the University of
California at Santa Cruz, and his name is not Clark but James Kent.
In four hectic weeks last spring, Mr. Kent wrote a computer program
that the consortium's leaders hadn't realized how much they needed,
one that assembles the 400,000 fragments of DNA they had decoded into
a coherent sequence. Using 100 computers that his senior colleague,
Dr. David Haussler, had persuaded the university to buy for the
purpose, Mr. Kent performed his first assembly on the human genome on
June 22, just four days before Dr. Francis S. Collins, the
consortium's informal leader, and Dr. J. Craig Venter of Celera,
announced at the White House on June 26 that each had assembled the
human genome.
Since Dr. Venter has now stated that Celera finished its computer
assembly just the day before, on the night of June 25, it turns out
that Mr. Kent's brilliant improvisation was the first assembly of the
human genome, even though one that had and still contains many gaps.
"Without Jim Kent, the assembly of the genome into the golden path
wouldn't have happened," said Dr. Collins, referring to the nickname
for the GigAssembler, as the program is known.
Dr. Haussler, a professor of computer science, described his student
as a superstar. "He's unbelievable," Dr. Haussler said. "This program
represents an amount of work that would have taken a team of 5 or 10
programmers at least six months or a year.
"Jim in four weeks created the GigAssembler by working night and day,"
Dr. Haussler said. "He had to ice his wrists at night because of the
fury with which he created this extraordinarily complex piece of
code."
Having finished the GigAssembler, Mr. Kent then wrote another program
known as a browser that enables many other kinds of genomic
information to be aligned in tracks above the raw sequence of DNA
bases, the chemical letters in which the human hereditary information
is encoded. This extra information is essential for making sense of
the DNA sequence and in particular for discovering where the genes
are.
How did a mere private see the weakness in the order of battle that
the consortium's generals had missed? Their competitor, Dr. Venter,
had always relied on heavy-duty computation to hedge the enormous
risks he took in his sequencing strategy. In setting up Celera he
ordered a machine with vast processing power and four terabytes of
memory, creating the largest computer in civilian use.
The consortium's DNA sequencing centers had nothing to match it
because their strategy did not seem to require large-scale
computation. The consortium breaks the human genome into large pieces
known as BAC's and works from a simple map that shows how one BAC
overlaps with the next in a tiling path that extends across the
genome.
In December 1999, Dr. Eric S. Lander of the Whitehead Institute, who
heads the consortium's genome analysis group, approached Dr. Haussler
for help finding the genes in the human genome sequence, the first
step in annotating it. Dr. Haussler decided the genome could not be
properly analyzed until the pieces being generated by the consortium
were in the right order.
The pieces of DNA were so small that their average size was less than
that of the average gene.
Most of the consortium's BAC's were unfinished, each one consisting of
up to 80 different pieces of unknown orientation and of unknown order
within each BAC ? hardly worthy of being called a sequence, as Dr.
Venter liked to observe of his competitors' efforts.
Dr. Haussler believed there was enough information, some generated
inadvertently by the consortium and some available from other sources,
to orient and align the BAC fragments correctly.
He immediately started writing an assembly program. He persuaded the
university's chancellor, Dr. Marcia Greenwood, that there was a chance
to make a historic contribution and that she needed to advance him
$250,000 to buy 100 computers with Pentium III processors. It was a
previous chancellor of U.C. Santa Cruz, Dr. Robert L. Sinsheimer, who
in 1985 held the first meeting to explore the idea of sequencing the
human genome.
But progress was slow. In May 2000, when Mr. Kent sent an e-mail
message to his colleague to ask how the assembly program was going,
Dr. Haussler said he had to reply, "Jim, it's looking grim."
Mr. Kent sent an e-mail message back that said he felt he could write
an assembly program using a simpler strategy. "I sent back a one word
e-mail, `Godspeed,' " Dr. Haussler said.
Mr. Kent, who turned 41 last Saturday, is a graduate student in his
second career. In his first, which lasted more than 10 years, he ran a
computer animation programming business.
Then he decided to go back to school and become a biologist. He
started analyzing the DNA of C. elegans, the laboratory roundworm.
When Dr. Haussler accepted the human genome assignment, Mr. Kent
started adapting his worm programs to human DNA.
Mr. Kent said he offered to write a human genome assembly program for
the consortium because of his concern that the genome would be locked
up by commercial patents if an assembled sequence was not made
publicly available for all scientists to work on. "The U.S. Patent
Office is, in my mind, very irresponsible in letting people patent a
discovery rather than an invention," he said. "It's very upsetting. So
we wanted to get a public set of genes out as soon as possible."
After receiving his supervisor's "Godspeed" message, Mr. Kent started
work on May 22. By June 22 he had written the GigAssembler together
with subsidiary programs, in 10,000 lines of code, and had completed
his first assembly of the human genome. "The two hard things, one is
the repeat structure," he said, referring to the numerous very similar
sequences of DNA letters in the human genome, "and then for me,
something that makes the engineering very challenging is that you read
DNA in two directions, so you are merging a lot of code that has eight
directions."
The program must decide which of DNA's two strands each of the
fragments belongs to because the sequences of letters in each strand
run in opposite directions.
Mr. Kent then started work on another program, called the U.C.S.C.
browser, which allows the assembled DNA sequence to be viewed in terms
of its structural features, like genes and chromosomes. The browser
allows one to search 21 tracks of information, each aligned with the
underlying DNA sequence. The extra information helps to identify
genes.
Although the consortium had deposited its BAC data in GenBank, a
public DNA database, the U.C.S.C. browser gave biologists their first
opportunity to view the assembled human genome unless they were
subscribers to Celera's database. On July 7 the browser was posted on
the World Wide Web. There was an overwhelming response. On that day
the U.C.S.C. servers put out half a terabyte of information, Dr.
Haussler said, and the browser now gets 20,000 hits a day from all
over the world. "Nothing crashed, we just kept putting it out," he
said. "People wrote back it was fantastic we had put it out with no
intellectual property requirements, a gift with no strings attached."
Mr. Kent has designed the browser so that other biologists can add
tracks of data to it, increasing the wealth of annotation. "It's been
a wonderful stone soup, where other people have contributed bits," he
said.
The consortium now lists the U.C.S.C. browser as the principal source
for viewing its human genome sequence.
The consortium's three major centers, with their large staffs of
computational biologists, did not write an assembly program of their
own because they had not needed one in their pilot project, on the
worm genome, and perhaps did not realize how useful such a program
would be. The National Center for Biotechnology Information completed
an assembly program only recently.
"It's easy for Venter to say of course you should have had this all
planned out," Dr. Haussler said. "But he had the ability to organize
an industrial-scale effort. Given the culture of the public project,
it would have been very difficult to graft on an autocratic new
software project, and if you had assigned a team to build this whole
thing over several months it would have been a very difficult
proposition. So what Jim has done is miraculous in many ways. No one
expected anyone could come in and put this together in four weeks."
An even more telling accolade comes from Dr. Venter, who was
astonished that the consortium managed to put the human genome
sequence together, given what he regarded as the poor quality of its
data.
"They used every piece of information available," he said. "It was
really quite clever, given the quality of their data. So honestly, we
are impressed. We were truly amazed because we predicted, based on
their raw data, that it would be nonassemblable. So what Haussler did
was he came in and saved them. Haussler put it all together."
"""
Andrew Hessel
http://www.expressnews.ualberta.ca/article.cfm?id=685
I met Norm in 1995 and he showed me the then-32 channel prototypes of the automated capillary sequencers. It convinced me that I needed to accelerate my genomics education. Today, I would encourage DIYbio folks to track the state-of-the-art in DNA synthesis technologies. :)