Biology Reborn

Can someone...Harshman? read this and explain it?
:)

How accurate is this? I know it comes from the mainstream press so I
have my doubts.

Thanks,
Rodjk #613

http://www.msnbc.msn.com/id/21162106/site/newsweek/page/0/

The Year of Miracles
By Lee Silver
Newsweek International

Oct. 15, 2007 issue - The year 1905 was an annus mirabilis, or miracle
year-a rare historical moment in which key flashes of insight suddenly
made the field of physics take off in new directions. That was the
year Albert Einstein presented four papers that turned the
conventional wisdom about how the universe works, from the
infinitesimal realm of atoms to the vast reaches of the cosmos, upside
down. During the next several decades, Einstein and a handful of other
brilliant physicists went on to shape the 20th century and lay the
foundation for all its technological accomplishments.

A century later, the year 2007 is shaping up to be another annus
mirabilis. This time biology is the field in transition, and the ideas
being shattered are old notions of genes and inheritance.

Ever since 1900, when Gregor Mendel's work on peas and inheritance was
rediscovered, scientists have regarded the "gene" as the fundamental
unit of heredity (just as the atom was regarded as the bedrock of pre-
Einsteinian physics). Crick and Watson's discovery of the DNA double
helix as the carrier of hereditary information did little to disturb
the status quo. In recent months, however, a perfect storm of new
technology and research has blown apart 20th-century dogma. The notion
of the Mendelian gene as a unit of heredity, scientists now realize,
is a fiction.

What's taking its place? Many scientists now believe that heredity is
the result of an incredibly complex interplay among the basic
components of the genome, scattered among many different genes and
even the vast stretches of "junk DNA" once thought to serve no
purpose. Biology has been building up to this insight for years, but
some big puzzle pieces have now fallen into place. Once scientists
abandoned their preconceived notions of genes and looked instead at
individual DNA "letters" in the genome -the four bases A, C, T and G-
they immediately began to see cause-and-effect connections to myriad
diseases and human traits.

The result of this seemingly modest conceptual breakthrough has been a
torrent of new discoveries. In five months, from April through August,
geneticists at the Harvard/MIT Broad Institute, founded by Eric
Lander; at deCODE Genetics in Iceland, founded by Kari Stefansson, and
several other institutions have published papers suggesting that the
key to a deeper understanding of the human genome may finally be in
hand. These scientists have identified specific alterations in the
sequence of DNA that play causative roles in a broad range of common
diseases, including type 1 and type 2 diabetes; schizophrenia; bipolar
disorder; glaucoma; inflammatory bowel disease; rheumatoid arthritis;
hypertension; restless legs syndrome; susceptibility to gallstone
formation; lupus; multiple sclerosis; coronary heart disease;
colorectal, prostate and breast cancer, and the pace at which HIV
infection causes full-blown AIDS. Unlike so many previous "disease
gene" discoveries, these findings are being replicated and validated.
"The race to discover disease-linked genes reaches fever pitch,"
declared the leading British science journal, Nature. Its American
counterparts at Science chimed in: "After years of chasing false
leads, gene hunters feel that they have finally cornered their prey.
They are experiencing a rush this spring as they find, time after
time, that a new strategy is enabling them to identify genetic
variations that likely lie behind common diseases." That the world's
top two scientific journals still use the old language of "genes" to
describe these discoveries shows how new the new thinking really is.

These findings are just a prelude to what's shaping up as a true
conceptual and technological revolution. Just as physics shocked the
world in the 20th century, it is now clear that the life sciences will
shake up the world in the 21st. In a handful of years, your doctor may
be able to run a computer analysis of your personal genome to get a
detailed profile of your health prospects. This goes well beyond
merely making predictions. A new technology called RNA interference
may also allow doctors to control how your DNA is "expressed," helping
you circumvent potential health risks. Many common diseases that have
preyed on humans for eons-devastating neurological conditions such as
Alzheimer's, Parkinson's, cancer and heart disease-could be
eradicated. If this sounds outrageously optimistic, so did the promise
of eliminating smallpox and polio to previous generations.

Why is all this happening now? What has changed between this year and
last? To answer these questions, we need to trace the story of how
mainstream biomedical scientists tried to link the cause of diseases
to single genes and, despite early success, hit a brick wall.
Meanwhile, a handful of renegade scientists, pursuing their own pet
projects, happened to develop exactly the intellectual tools needed to
break through that wall. These biologists are now the leaders of the
new revolution in biomedical science.

The seeds of our new understanding were first sown in the 1960s, when
molecular biologists figured out how genetic information is organized,
regulated and reproduced inside single-cell bacteria. In bacteria, a
gene is a discrete segment of DNA that contains the "code" that tells
the cell how to make a particular type of protein. Bacterial genes are
arranged along a single DNA molecule, one after the other, with only
tiny gaps in between. Since all organisms have DNA and work by
essentially the same biochemistry, scientists assumed that a human
genome would look like a larger version of a bacterium's.

Clues that something was amiss came quickly with the development of
DNA-sequencing methods in the 1970s. The first surprising result was
that genes accounted for only 2 percent of the human genome-the rest
of the DNA didn't seem to have any purpose at all. Biologists Phillip
Sharp and Richard Roberts made things worse with a discovery that won
them a Nobel Prize in 1993. If the gene were the basic unit of
heredity, the DNA required to make any particular protein should be
contained in its corresponding gene. But Sharp and Roberts found that
DNA that codes for individual proteins is often split and scattered
throughout the genome.

Scientists could ignore these signs largely because they seemed to be
making progress. By combining new DNA-sequencing tools with studies of
inherited diseases in large families, medical geneticists identified
the genetic culprits responsible for cystic fibrosis, Huntington's
disease, Duchenne muscular dystrophy and a host of other diseases.
Each of these "all or none" diseases is caused by a mutation in a
single protein-coding region of the DNA. Few diseases, unfortunately,
work so neatly. In particular, the search for genetic bases of common
diseases that affect large numbers of aging people came up empty.

During this lull, a visionary physician-scientist named Leroy Hood,
now at the Institute for Systems Biology in Seattle, was growing
impatient. Genetics, he recognized, was still a cottage industry of
government-funded university professors, who each directed a small
group of students and technicians to study an isolated gene. At the
pace research was progressing, it would have required 100,000 worker-
years of concerted effort to decipher just one complete human genome.

Hood thought it was absurd that genetic scientists spent nearly all
their lab time performing tedious and repetitive mechanical and
chemical procedures. At the same time, he grasped the far-reaching
implications of a fundamental fact: while even the simplest organism
is immensely complicated, the primary structures of its most
complicated parts-DNA and proteins-are very simple. The alphabet of
DNA contains only the four chemical letters (or bases) A, C, G and T,
and proteins are made from just 21 amino acids. Hood saw that this
simplicity would make it possible for robots and computers to read and
write DNA and proteins more quickly, accurately and cheaply than human
beings.

The rest of the biomedical community refused to believe that robots
could analyze something as complex as a living system. And in any
case, no practicing geneticist had the capacity to design such
machines. Unable to obtain government grants, Hood secured private
funding to bring together dozens of scientists, engineers and computer
programmers (far larger and more diverse than any other genetics
team). They proceeded to invent the first generation of molecular-
biology machines. Two read and recorded information from DNA and
proteins respectively (a process known as sequencing), and two others
worked backward, converting digital electronic information into newly
written sequences of DNA or protein.

Hood completely transformed the biomedical enterprise. DNA-writing
machines give genetic engineers an unlimited capacity to create novel
genes that can be studied in test tubes or added to the genomes of
living organisms. And protein-writing and -reading machines provided
drug firms with the ability to create a new generation of protein-
based drugs. The DNA-reading machines suddenly made it conceivable to
crack the 3 billion-base sequence of an entire human genome. In 1990
the U.S. government embarked on a 15-year, $3 billion project to do
just that.

Eight years later, however, the project-parceled out to many U.S.
scientists-was still less than 10 percent complete. Now it was biotech
entrepreneur Craig Venter who was frustrated. Convinced that
government-funded workers were the problem rather than the solution,
Venter enlisted private funding of $200 million to build an enormous
lab filled with hundreds of automated machines, working 24/7, overseen
by a handful of technicians. Within three years, the first reading of
a human genome was essentially complete.

Armed with data from the genome project, scientists figured they'd
surely be able to crack the really hard diseases, like cancer and
heart disease. But a funny thing happened when they began to look
closely at this vast storehouse of genetic information. Geneticists
Andrew Fire and Craig Melo galvanized the field by discovering a key
mechanism that had been completely overlooked-the cellular process of
RNA interference. (They shared a Nobel Prize in 2006 for the work.)

Finding evidence of extraterrestrial life couldn't have come as a
bigger shock. Geneticists had taken for granted that the machinery of
cells involved genes directing the production of proteins, and
proteins doing the work of the cell. Here was a process that didn't
involve proteins at all. Instead, tens of thousands of hitherto
mysterious regions of the human genome-part of the so-called junk DNA-
directed the production of specific molecules called microRNAs
(consisting of bits of RNA, a well-known component of cells). These
microRNAs then oversaw a whole new process, called RNA interference
(RNAi), that served to modulate the expression of DNA.

The good news was that RNAi could open up a whole new approach to
biomedical therapy (more on that later). But RNAi also made it clear
that the fundamental unit of heredity and genetic function is not the
gene but the position of each individual DNA letter.

To make it all harder to fathom, each bit of DNA is susceptible to
mutation and variation among individuals. Of the 3 billion DNA bases
in the human genome, geneticists identified about one tenth of one
percent (millions) that differ from one person to another. Variations
in these particular letters-called "snips," or SNPs, for single
nucleotide polymorphisms-have replaced genes as the unit of heredity.

Many scientists responded to this devastating realization by going
into a funk. "It will be difficult, if not impossible, to find the
genes involved [in common diseases] or develop useful and reliable
predictive tests for them," Dr. Neil Holtzman, director of genetics
and public policy at Johns Hopkins University, said in 2001.

Fortunately, another visionary scientist, Kari Stefansson of Iceland,
was already blazing a trail out of this thicket. If the genome was far
more complex than scientists had thought, they would need to test for
many more variables, and to do that they would need more test
subjects. To find the cause of diseases would now require the
participation of very large groups of genetically related people.

Like Hood and Venter, Stefansson was originally motivated by
frustration with the pace of research. In the United States, where
most of the disease-gene-discovery projects were being conducted, most
people cannot trace their ancestors back more than a few generations,
and the largest families consist of a few hundred living subjects at
most. Subject panels of this size failed to provide sufficient data to
identify the genetic bases for complicated and variable common
diseases. Stefansson decided to solve this problem by taking aim at
the largest well-documented extended family that he knew-his own.

Nearly all the 300,000 citizens of Iceland can trace their ancestors
back, through detailed, public genealogical records, to the Vikings
who settled this desolate European island more than 1,000 years ago.
Stefansson gave up his faculty position at Harvard Medical School to
return to Iceland, where he founded the company deCODE Genetics in
1996. He persuaded the Icelandic government to provide deCODE with
exclusive access to the health records of its citizens in return for
bringing investment capital and high-tech jobs to the capital,
Reykjavik. So far, more than 100,000 Icelandic volunteers have donated
their DNA to deCODE.

Stefansson's project was roundly criticized by international
bioethicists and other geneticists for violating the privacy of
Icelanders (even though 90 percent of the population approved).
Nevertheless, he persevered, placing "the genealogy of the entire
nation on a computer database," together with the health and DNA
records of still-living individuals. The power of large numbers was
soon apparent. In a study of obesity, he directed his software to look
for SNPs associated with subsets of the population who were either
extremely overweight or very thin. Within just a few hours, it began
finding evidence that variations among particular DNA letters indeed
played a causative role, confirming SNPs as the new unit of
inheritance.

As of September, deCODE has made progress in identifying SNPs that may
play a role in 28 common diseases, including glaucoma, schizophrenia,
diabetes, heart disease, prostate cancer, hypertension and stroke. In
some cases, such as glaucoma and prostate cancer, deCODE's findings
could lead to diagnostic tests for identifying people at risk of
developing the disease. In other instances, such as schizophrenia,
links to particular proteins have led to insight about the cause of
the disease, which could lead to therapies.

Buoyed by Stefansson's success, other geneticists were eager to
perform large-scale family studies, yet few had similar access to
ancient genealogical records. But serendipity would deliver an
epiphany: it's possible to study the entire human population as a
single extended family, provided scientists collect enormous amounts
of data. Eric Lander, an MIT professor and the intellectual leader of
the U.S. government effort to sequence the first human genome,
realized scaling up would require a new approach. In 2004, Lander
persuaded MIT and Harvard to combine their enormous resources toward
the creation of the Broad Institute. Backed by $200 million from
billionaire philanthropists Eli and Edythe Broad, the institute is
driving the development of ever more advanced genetic technologies.
One technology, based on computer-chip fabrication, can identify DNA
base letters present at 500,000 SNPs in the genomes of 40,000 or more
people.

Think of this as a spread*** with 500,000 columns (each representing
a specific SNP) and 40,000 rows (one for each person). To hunt for a
genetic basis for, say, bipolar disease, the computer searches rows of
people who have the disorder, checking column by column for an
unusually high frequency of particular letters in comparison with
people without the disease. As it turns out, a collaboration of
American and German researchers has done this work-and found that
variations of DNA letters in 20 different positions are influential in
bipolar disease.

Incredibly, most disease-causing variants are the most common ones
present in the human population: the strongest-acting one, for
instance, exists in 80 percent of people without bipolar disease and
85 percent of people with the disease. The implication is that these
variants are beneficial in some way, and cause problems only when
their number exceeds a threshold.

To make sense of this complexity, scientists would like ultimately to
build a vast international database that contains the complete
sequence of DNA bases in the genomes of hundreds of millions of
people. Ideally, such a database would be available for analysis by
all biomedical researchers and would provide the foundation for
understanding the genetic components of all human traits. That sounds
like a lot of data-think of a spread*** with 3 billion columns and
100 million rows-but computing power is getting cheaper by the year.
Within a decade, the cost of obtaining a sequence of all 3 billion DNA
letters in an individual's genome will drop from $2 million now to
$1,000. It will be a routine part of a person's health record,
enabling physicians to prescribe genome-specific preventions and
treatments.

The discovery of RNAi, meanwhile, suggests a completely new
personalized form of disease therapy. Whereas drugs act on proteins,
RNAi therapy would act on the expression of DNA itself, potentially
preventing or reversing diseases such as Alzheimer's, Parkinson's,
Huntington's, bipolar disorder, schizophrenia and others. Old-school
pharmaceutical firms have taken notice. The largest ones are betting
heavily on the gene-targeted RNAi therapeutic approach to fill product
pipelines, as the discovery of traditional chemical drugs becomes more
elusive. Novartis and Roche have both signed nonexclusive licensing
deals with the biotech firm Alnylam (founded by Phillip Sharp) for new
therapeutic techniques that are valued at up to $700 million and $1
billion respectively; Merck paid $1.1 billion to buy another biotech
company outright, solely to obtain its contested portfolio of RNAi
intellectual property, and the London-based drug firm AstraZeneca has
a $405 million licensing deal with Alnylam's competitor Silence
Therapeutics.

The explosion of genetic discoveries shows no sign of letting up any
time soon. New diseases are being added to the list every month, and
biologists are rapidly parlaying gene- and SNP-disease links into a
deeper understanding of how proteins and other molecules can misbehave
to cause different medical problems in different people. And other
scientists are working to advance the biology revolution (accompanying
interviews). As a result of their efforts, many children born this
year could very well be alive and healthy at the dawn of the next
century, when they may look back in awe at the annus mirabilis of
biomedical genetics in 2007.

.