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This article by B.G. Scott was prepared for the February 19, 2003 edition of U.S. 1 Newspaper. All rights reserved.

From Genes of Mice, Clues to Human Cancer

Finding molecules to fight cancer, relieve pain, and

even control obesity are only part of the research agenda at Lexicon

Pharmaceuticals.

Banking on the concept that by analyzing the physiology of research

mice it is possible to figure out what each gene does — then find

a molecule that can do the same thing for humans — Lexicon plans

to translate genetic findings into drugs.

"We are in a new generation of pharmaceutical companies that use

the power of genetic information to guide the discovery of new medicines,"

says Alan Main, senior vice president and head of Lexicon Pharmaceuticals,

the New Jersey operations of Lexicon Genetics. "It’s an exciting,

focused, very high-energy place to work."

Based in Texas, Lexicon’s New Jersey operations were formerly known

as Coelacanth. Coelacanth (pronounced see-la-kanth) had started out

in 1996 in incubator space in New Brunswick and had then moved to

the futuristic orange building on Princeton-Hightstown Road. The company’s

new Princeton-area home is the complex on Carter Road in Hopewell

formerly owned by Lucent Technologies.

Though business databases list several biotech competitors, Main says

Lexicon’s patented processes are so unusual he feels the company has

no direct challengers. "No other company is doing this genetic

approach on the same scale," says Main. "We own essentially

most of the patent technology that allows it to be carried out. Lots

of other companies are working with cells, yeast, fruit flies, worms.

But we are working with mammals, which is far more relevant."

In addition, Lexicon uses a mass-production research approach. In

the infancy of genetic research, scientists could take years to isolate

and study one mouse gene, Main says.

The genius of Lexicon’s president and CEO, Baylor Medical College

researcher Arthur Sands, was to come up with the idea of finding and

studying 1,000 genes a year. Main says the approach drew on Sands’

business savvy. In addition to his Baylor MD and PhD degrees, Sands

has a Yale University bachelor’s degree in economics.

Expanding on postdoctoral work on the genetics of cancer formation

he did at Baylor from 1992 to 1995, Sands took the concept of creating

a "knockout mouse" — one with a specific gene that had

been "knocked out" or deactivated, and started Lexicon Genetics.

"He gathered some world-class researchers, came up with some funding,

and now it’s a well-oiled machine. Dr. Sands industrialized the process,"

says Main.

Backing up Main’s claim is the fact that Lexicon, though it has yet

to turn a profit for its shareholders, has licensing or other agreements

with more than a dozen pharmaceutical companies. The list includes

Bristol-Myers Squibb, Pharmacia, the R.W. Johnson Pharmaceutical Research

Institute of Johnson & Johnson, and Wyeth.

Nevertheless, no biotech company wants to license away

all its technology, and that is why the Lexicon and Coelacanth merged.

"We were a pure chemistry company and they were a pure biology/genetics

company," says Main. "We were both doing business with pharmaceuticals

and realized the value of we had. Rather than provide services, we

wanted to be a pharmaceutical company."

The mice for the genetic research are housed in Texas, and Lexicon

is putting its New Jersey assets under a single roof on Carter Road.

The laboratories and legions of chemists needed to take the findings

from mouse to pharmaceutical company to human trials are quickly filling

up this 72,000 square foot Hopewell space.

"We have 70 people working here now and we expect to add another

15 chemists by the end of the year," says Main. Including those

who work at the home facility in the Woodlands, Texas, a planned development

community 30 miles north of Houston, Lexicon Genetics has about 500

employees. That is more than double the corporation’s employees in

2000.

Main’s new home has a checkered history. After Lucent downsized and

vacated its property, a fast-growing gene modification company, ValiGen,

moved in. That was in September, 2001, and ValiGen moved out the following

month. Its investors were so shaken by 9/11 that they withdrew promised

funding, and the company went out of business. So Maryland-based Townsend

Capital was able to buy the building at a discount price.

Lexicon has signed a 12-year lease with an option to buy, says Main.

After ValiGen’s short term there, the building needed only minor remodeling

to accommodate more chemistry labs. Lexicon occupies 50,000 square

feet now and expects to eventually use the remaining 25,000 square

feet as well.

The company still leases its architecturally distinct building on

Princeton-Hightstown Road in East Windsor, first occupied by PA Consulting.

The move will be complete by the end of this year.

It will be a relatively minor geographical move for Main, an Australia-born,

United Kingdom-educated, Swiss-trained pharmaceutical researcher who

has worked in the U.S. since 1982 and jokes that he is "culturally

confused."

Main’s father, an electrician, had emigrated from Scotland to Melbourne

but brought the family back to Scotland in the early 1960s. Main decided

to be a scientist when, at age nine, he wrote to the Goddard Space

Center asking for information. "I was so taken with the moon race,

I got excited about space and science," he says. He and his wife

live in Far Hills and have a 13-year-old daughter and an 11-year-old

son.

Main seemed to be the right candidate to replace Coelacanth’s first

CEO because he had both pharmaceutical and biotech experience and

was a chemist by training. A 1975 graduate of the University of Aberdeen,

he earned a PhD in organic chemistry in Liverpool and worked for Ciba,

later Novartis, in Switzerland. When he left Novartis Main had spent

20 years there and been named senior vice president for research.

In 1999 he joined Coelacanth because Nobel Prize-winning chemist Barry

Sharpless "had some revolutionary chemistry ideas," Main says.

Sharpless was a professor of chemistry at the Scripps Research Institute

in La Jolla, California. Naming Coelacanth after a fish that was believed

to be extinct, but which recently has been discovered in ocean waters

off Africa and Asia, he hoped that the firm’s knowledge bases and

automated drug-building platforms would lead to similar unexpected

discoveries in the pharmaceutical world. Co-founder was Seth Harrison

MD, general partner at Oak Investment Partners, the Connecticut-based

venture capital company and entrepreneur scientist David Bolton.

In July, 2001, 18 months after Main joined Coelacanth, his company

was bought by Lexicon for $32 million. Lexicon used part of the $220

million proceeds from its 1990 IPO. Sharpless won the Nobel Prize

four months later.

While many biotech companies are racing to take molecular biochemistry

discoveries and turn them into effective, marketable pharmaceuticals,

none is doing it exactly Lexicon’s way, says Main.

First, he says, that’s because Lexicon is studying living mammals,

that is, mice. The mouse genome is similar to the human genome. So

if Lexicon identifies a gene that regulates fat storage, then finds

the key protein molecule produced by that gene, it is well on its

way to finding an anti-obesity drug — or so the reasoning goes.

There are 30,000 genes in the human genome. Each gene produces proteins.

It is those protein molecules that trigger reactions in the body.

The quest at Lexicon is to figure out first which gene does what.

To do that, Lexicon has found ways to disable individual genes in

its mice, a lab technique that is known as creating "knockout

mice."

Once a gene is disabled, the researchers then scrutinize

the living mouse to see exactly what happens. "These mice get

executive physicals," says Main. "We want to know are their

bones losing density? Does the mouse have a greater propensity for

cancer? What happens to insulin levels?

Each finding can have a direct implication for medicine, he says.

"Fundamentally all cellular biochemistry is programmed by genes

and the proteins they produce. All our fundamental processes can be

understood by genes."

The proteins are the switches in these processes. The Lexicon researchers

working with the mice in Woodland, Texas find out which protein does

what, then chemists in New Jersey try to come up with a pharmaceutical

equivalent.

For instance, if the researchers find a gene that makes the lab mice

thin, they then try to find which protein is responsible. Ultimately,

says Main, that could yield an anti-obesity pill.

Two other companies that work with mice — Medarex and its related

firm Genmab — operate from Princeton and do genetic research elsewhere.

Pressed for a comparison, Main explains that Medarex has "one

type of knockout mouse that mirrors the human immune system. We look

at all the rest of the genes." Medarex’ humanized mouse is patented

and can make human antibodies. "In contrast, we patented our gene

knock-out technology. We study what removing that gene does to the

animal."

Already Lexicon has identified a gene that when disabled makes mice

fat. It has also identified a gene that seems to play a role in making

young mice old, and another gene that may regulate some cells’ natural

defenses against a type of cancer.

It’s all very exciting stuff, he says. Investors have agreed. When

Lexicon went public in April, 2000, it was the largest biotech IPO

ever, according to financial news accounts at the time.

Drug discovery is a long term business, Main says. But by research

standards, Lexicon is moving quickly. "We expect that our systematic

approach to drug discovery will make us more successful than historical

standards, and we are working as fast as we can to bring some drugs

to market."

"New Jersey is a great place to do this because of the wealth

of talent in drug development," says Main. When I was working

for Novartis I had a budget of $250 million, and now I am close to

the science and am having fun."

— B.G. Scott

Lexicon Pharmaceuticals (), 350 Carter Road, Princeton

08540. Alan Main, senior vice president. 609-466-5500; fax, 609-466-3562.

Home page: www.lexicon-genetics.com


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