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From Genes to Drugs: GPC

Last week, an international team of scientists funded

by the U.S. and other governments and Britain’s Wellcome Trust reached

a major milestone on the road to sequencing the entire human genome:

they deciphered and released onto the Internet the complete sequence

of the 33 million building blocks of the genetic code of an entire

chromosome. You can see it at

http://www.sanger.ac.uk/HGP/Chr22/.

One chromosome down, 22 chromosomes to go, in the international effort

known as the Human Genome Project. A significant achievement,

certainly,

but really just the first step in the first step. Mapping our genes

is one thing. Figuring out what they actually do is something entirely

different.

One of the many companies already trying to answer the question of

how our genes function is Genome Pharmaceuticals Corporation (GPC),

a German company that recently opened its first American outpost at

Princeton Corporate Plaza. GPC is trying to map genes that may be

implicated in such diseases as multiple sclerosis, cancer, and

Alzheimer’s

Disease, through a field of study known as functional genomics.

GPC hopes to radically accelerating the process of translating gene

discovery into drug discovery with a set of technologies that the

company hopes will help scientists understand not just the structure

of genes, but also their function.

To understand GPC’s technologies, you need to know a little about

how genes work — how they actually communicate messages from the

genes out to the cells and tissues they control. Genes are made of

something called DNA, or deoxyribonucleic acid. DNA itself is composed

of a number of constituent parts, the most important of which are

the bases A, C, T, and G, for chemicals called adenine, cytosine,

thymine, and guanine. The arrangement or sequences of these bases

on the helix structure of DNA famously discovered by Watson and Crick

in 1953 is how the genes actually contain their genetic information.

But then the DNA needs to get the information out to the cells and

structures it controls. It does this by sending out little genetic

messengers, known as messenger RNA (for ribonucleic acid) or mRNA.

Like DNA, mRNA is made up of chains of bases held together by some

other chemicals. But unlike the genes that express them, mRNA contains

smaller, more specific bits of genetic information that tell cells

what proteins to form and thereby enables the body to use the genetic

information contained on the genome.

Think of the relationship between DNA and mRNA as the relationship

between an architect and a builder. An architect creates a plan for

a house, say, that includes a lot of information — all the

information

in fact needed to create the house. Those plans are kind of like DNA.

But if you have ever looked at architect’s plans, you know that there

are a lot of details that go into it — a drawing of the framing,

the electrical plan, the kitchen cabinets. These details are something

like mRNA, which communicate to the builder not just the idea of

"house,"

but all the specific structures needed to create it.

But even with these detailed plans, you still don’t have a house until

people take the plans and actually build them. In terms of

understanding

how genes work, you can think of the carpenters, the electricians,

the cabinetmakers and all the rest, as being similar to the proteins

that create the structure and functions of cells and tissues.

Which brings us back to GPC. GPC’s integrated technology platform

includes something called OliCode, a method to identify large,

repetitive

segments of the genome known as gene families, which scientists

hypothesize

may cause many diseases. Continuing with the house metaphor, this

part of GPC’s technology seeks to discover the body’s architectural

plans in the form of DNA.

These plans or gene families are then further studied in concert with

the company’s ExpressCode technology, a high-throughput technique

for isolating the mRNA active in tissues known to be implicated in

disease states. Back to the metaphor, these would be the details of

the overall plans. Using both technologies, the company hopes it will

be able to find and map the mRNA sequences active in diseases —

the detailed plans — and then match them to the DNA on the genome

that produced them — the overall plan.

But we still don’t have a house. Crucially important

in understanding the genetic basis of disease in GPC’s model is

finding

out who the carpenters and electricians and cabinetmakers are and

figuring out what they’re up to. This requires an in-depth

understanding

of the proteins involved in actually building the structures of our

bodies and the very complex ways in which these proteins interact.

For this, GPC has a technology called PathCode, a proprietary and

highly automated method of understanding those proteins and what they

do.

And here’s where the drug discovery potential of GPC’s multifaceted

functional genomics technologies can be found. Imagine that you want

to build a house, but the carpenters show up with the wrong plans

and start building a gas station instead. The builder would arrive

one morning and holler, "Stop!" That would be simple. While

far more complex than hollering "Stop!" GPC’s technologies

may enable their big pharmaceutical partners to find drugs to act

like that builder, that figure out what wrong plans the body is using

to create diseases and how to get the proteins to stop what they’re

doing.

Using these technologies, GPC has already identified 20 possible

genetic

targets for antimicrobial drugs and has an alliance with a German

drug company called Evotec to develop new, genomics-derived

antibiotics.

Other targets are infectious diseases of the immune system, cancer,

autoimmune disorders, lymphoid malignancies, stomach ulcers,

pneumonia,

arteriosclerosis, Alzheimer’s disease, rheumatoid arthritis, multiple

sclerosis, and transplant rejection.

Founded in 1997 to enable the government-funded Max Planck Institute

to commercialize its discoveries, 70-employee GPC has raised more

than $35 million in venture capital and German government funding.

Its CEO, Bernd Seizinger, is a former director of the Molecular

Neuro-Oncology

Laboratory at Harvard/Mass General and until 1996 was vice president

of oncology at Bristol Myers-Squibb.

Vice president for bioinformatics Gregory Hamm was until recently

director of the molecular biology computing laboratory at Rutgers,

and is the founder of the data library at the European Molecular

Biology

Laboratory in Heidelberg. The company has partnerships with six

European

pharmaceuticals, including Hoechst Marion Roussel, Boehringer

Ingelheim,

Evotec, and Byk.

These companies are not well known in the U.S., but are important

in Europe, and they seem to believe that GPC has a technology well

worth supporting. But as is true throughout biotech, and especially

on the scientific cutting edge, nothing is certain. GPC’s technologies

may lead to useful discoveries, or they may not.

"It’s like looking at a city from 100,000 feet up and trying to

understand how it functions," says GPC director of database

strategies

Shahid Imran of the company’s functional genomics efforts. "You

try to track what’s going on."

— Barbara Fox and Christopher Mario

GPC USA, 1 Deer Park Drive, Princeton. Gregory

Hamm, vice president. 732-355-1222; fax, 732-355-1225.

http://www.gpc-ag.com.


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