Genomics
Counting the clones...
Incyte's escape clause is called expression analysis. Just by sequencing
an insane number of ESTs the company gets a rough sense of how often each
gene is expressed, i.e., made into its corresponding protein. In the pancreas,
for example, the insulin gene will be turned on to make mRNA and then insulin
protein. There will be hundreds of insulin mRNAs, and so hundreds of insulin
ESTs, from pancreatic tissue, but no insulin ESTs from skin tissue. The
Incyte database has this sort of information for almost all genes in almost
all tissues.
"Now we can do biological research with a picture of the entire human
genome," says Klingler. "The classical approach is to look at
one gene at a time. Having a peek at all the human genes will change the
way you look at a problem. You can take a disease tissue and find all the
genes that you see only in asthmatic lungs. That's never been possible in
the past."
Counting up ESTs is what Klingler calls "low resolution" information.
The future lies in chips that can hold tens of thousands of genes arrayed
in a neat grid. A chip with every one of the 6116 genes of brewers yeast
has just been made by Joe DeRisi and Patrick Brown of Stanford University,
| Link to the home page of the scientists who made this chip |  |
and any number of researchers and companies are busy lining up
collections of human genes. Those who are keen (and have a lot of spare
time and $25,000 for parts) can even make their own chips and chip-readers
using DeRisi's
instructions. The two leading chip companies are
Affymetrix,
which in a confusing turn of events is both collaborating with Incyte and
suing it for patent infringement, and Synteni, which was bought by Incyte last January.
Researchers using the chips first collect mRNA from two different sources,
such as diseased and non-diseased tissue, or normal and drug-treated cells.
The mRNA from diseased tissue can be labeled with a green dye, and non-diseased
mRNA with a red dye. The mRNAs are then allowed to stick to their corresponding
genes on the chip. If there is far more of mRNA from gene 216 in the diseased
state, position 216 will light up green, but if there is more mRNA 216 in
the normal state it will be red. Equal expression gives a yellow spot. With
one experiment the researcher can tell how every gene has reacted to the
change.
The flood of data from these methods is just beginning. "Probably 99%
of the data collected using this technique haven't been published yet,"
says Brown. "It's a fast-moving and exciting field." Brown is
looking at how yeast coordinate switching hundreds of genes on or off when
they have more or less food, but the pharmaceutical companies will be looking
at their favorite drug target. If the gene they proposed as a breast cancer
target is also turned on in pancreatic cancer they should expand their clinical
trials. And, given a choice, they should opt for the target that is not
made in the stomach or blood, to minimize the chances that their drug will
cause digestive and immune problems.
Finding a made-to-order gene that is on in one situation and off in many
others used to be either a fluke or impossible. The chips make it a matter
of a few experiments. That makes researchers like Klingler ambitious. "Our
real goal is to understand the molecular basis of human biology," he
says. "That's not going to happen in a traditional molecular biological
way, one gene at a time."
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