Corrections or additions?

This article by Michele Alperin was prepared for the February 14,

2001 edition of U.S. 1 Newspaper. All rights reserved.

Physiome: Simulations of Human Cells

Biochemists, molecular biologists, and medical

researchers

in laboratories across the world investigate the complex and even

noble phenomena of human biology. Each of the structures, processes,

and interactions they study yields a tiny piece of a puzzle so

enormous

that it falls beyond the grasp of human understanding. At the same

time, genomic research is revealing thousands of new proteins to

investigate,

and the old ways of science are not up to the task.

Whereas laboratory experiments alone made sense when there were only

a few proteins and genes to explore, "now scientists are dealing

with thousands, and they must simulate. They can’t do it any other

way," says Jeremy Levin, president and CEO of Physiome Sciences,

a 40-person firm at 307 College Road. What’s happening, says Levin,

is "a complete revolution in the way scientists are thinking."

Currently pharmaceuticals spend hundreds of millions of dollars

testing

potential drug compounds in the laboratory, and they often fail just

as they are ready to become products. "This," says Levin,

"is like building an oil refinery and hoping it will work in the

end." To avoid wasting vast sums of money, he explains, scientists

must do dry bench experiments, that is, virtual experiments on the

computer, before working in the laboratory at "wet bench"

experiments.

Levin has steered Physiome in that direction. To bring simulation

to the foot soldiers of biochemical research, Physiome is perfecting

a vehicle to gather experimental data and produce visual models of

human proteins, cells, tissues, and organs. The result: researchers

can work with a "perpetual cell," a simulated computer model

that can be changed and modified. On February 5 it announced a

licensing

agreement with Janssen Pharmaceutica (the Titusville-based subsidiary

of Johnson & Johnson), and it will triple its space with a move later

this year to 25,000 square feet at 150 College Road.

Levin’s focus on cell software represents a dramatic change. Since

its founding in 1993, Physiome Sciences had been identified with the

throbbing, 3-D human heart displayed on screens by its supercomputers

(U.S. 1, May 13, 1998). But when Levin came on board, he found that

what the pharmaceutical companies wanted was — not finished organs

and disease modules — but the capability to handle the volume

of gene and protein data, and to simulate them.

Levin decided not to deliver "finished organs" but to provide

a simple, standardized modeling platform. This would help the

pharmaceutical

companies develop the internal capability to understand their own

data and incorporate it in models.

He based his tactical decision on the three critical challenges facing

pharmaceutical companies today.

Organizing and interpreting the deluge of genomic and

protein data that is about to multiply geometrically;

Predicting how drugs will be absorbed and metabolized

in the body; and

Comparing the efficacy of different potential drugs, by

ensuring standardized experimental methods.

The new platform — Physiome’s InSilico Cell (ISC) modeling

environment — is reported to be easy to use, flexible, and able

to communicate data easily. Whereas modeling has been restricted to

trained modelers who have created their models in standard computer

languages, Physiome’s ISC supports uniform formatting of modeling

data that can easily be shared over the Internet.

No longer are scientific colleagues left with the impossible task

of reconstructing models from information in scientific publications.

"By giving academics and those who are developing models a

centralized

capability to bank and withdraw models," says Levin, "we

provide

a critical resource for the whole field of modeling." Because

ISC standardizes the model-building process, it can be used by a

variety

of departments, from cardiovascular to oncology.

ISC also supports evolving models that seamlessly absorb legacy data,

accumulated from previous experiments, and incorporate genomic data.

The quantity of data is daunting; 50,000 to 100,000 genes will

translate

to hundreds of thousands of proteins in a cell — all of them not

yet discovered. "What is important is that cell types can adopt

and absorb the data that is emerging from the Genome Project and

become

more enriched over time," says Levin.

Physiome does not try to reproduce every aspect of every cell. "In

the same way that biology has created a natural template for a cell,

there are certain key genes that you need in these cells,"

explains

Levin. "All of our cells have those genes." Physiome supplies

its client partners with template cells that can be adjusted, based

on the scientific intentions and needs of the user, to correspond

to a particular cell type. For example, the user of ISC can mutate

the cell by changing it from male to female or from a kidney cell

to a heart or a brain cell, through a sophisticated process called

computational cloning.

The goal of the ISC modeling environment is to enable both Physiome’s

own researchers, and as many different scientific constituencies as

possible, to develop, store, and exchange biological models. "The

whole idea is to create a common language so that anyone working in

modeling biology on the computer can develop models that speak the

same language," says Thomas Colatsky, executive vice president

and chief scientific officer of Physiome.

Speaking with fervor about the "living" creations of ISC,

Levin says, "Now instead of having a living cell that eventually

dies, you have a perpetual cell within the computer that you can

experiment

with to your heart’s delight. It lives forever."

Modeling virtual cells saves enormous amounts of time. To create a

new living cell type in the laboratory and make it stable requires

four to six months. The time it would take to do this for the 100,000

cells out there, says Levin, would be far more than the lifetimes

of all the scientists in this country.

But these models are more than time savers. They produce results that

human beings might never be able to predict. Referring to the cellular

proteins and interactions modeled by ISC, Colatsky explains, "They

all add up, in a nonintuitive way, to output which is the behavior

of a cell. It is hard to predict what will happen. It is not a linear

process."

Translating Levin’s vision into "virtual" reality required

substantial capital. In May, 1999, his effort to raise $25-30 million

was vastly oversubscribed. He got $100 million in commitments, but

Physiome’s board decided that $50 million was sufficient to achieve

its business plan. With money in hand, Physiome battened down the

hatches. Explains Levin: "We buried ourselves, with no intent

to talk to our pharmaceutical partners, and focused on developing

a superb technological base."

Now they have come back to the living, with software that can

reproduce

biological form and function. With pride, Levin comments, "We

are there. InSilico Cell is a beautiful platform." His licensing

deal with Janssen uses one of InSilico Cell’s direct applications,

CardioPrism, which simulates cardiac cell behavior and evaluates the

suitability of proteins as targets.

In his 47 years, Jeremy Levin has lived in many worlds,

both geographically and intellectually. He was born in South Africa,

where his father was a direct contemporary of Nelson Mandela. In 1960,

when Levin was about seven, his family fled to Rhodesia. The apartheid

government had asked his father to choose between jail or working

for his political opponents. Levin remembers, "We were so poor

we had to drive across the border to Rhodesia."

In Rhodesia, his father founded the first newspaper for blacks, and

the family quickly became isolated. Just prior to the Ian Smith’s

unilateral declaration of independence, the white government decided

to arrest Levin’s father. He was able to flee when some World War

II army buddies in the Rhodesian security forces warned him of the

impending arrest. Levin’s father left with his sister, and he was

left behind with his mother and brother.

Thinking about his father, who sacrificed such a tremendous amount

for his principles, Levin speaks with admiration, "My father

believed

in truth, justice and creativity. He also believed that what mattered

most was making a difference in whatever you do, but that ultimately

making your society a better place to live was what mattered more

than anything else."

Levin finally made it to England, where he attended a military

boarding

school — all his family could afford. For high school he enrolled

in an early experimental school, whose population was "very

working

class." Being a new immigrant made things difficult. "I was

a foreigner, with a funny accent," he says. Assessing his overall

high school experience from decades beyond, Levin says, "I was

a great rugby player in a useless high school. I got 2 Cs and 2 Ds

at the end of high school, but that was the best in the school."

But with the help of an English teacher at the school, he eventually

made it to Oxford University, on scholarship, as part of an experiment

to see whether graduates from a school like his could succeed at the

university. In Levin’s case, the experiment worked, leading to a

success

story that Levin ruefully calls "kid makes good from foreign

land."

At Oxford, he began an amazing academic career, with top grades,

awards,

and scholarships. He received a scholarship to do a PhD in DNA

structure

at Oxford and a simultaneous scholarship to study pre-clinical

medicine.

In 1978, he moved to Cambridge for clinical medicine, again with a

scholarship, and finished his MD degree in 1981. Levin practiced

medicine

in a number of hospitals and, in 1984, became a European Fellow at

the University Hospital in Geneva, where — while skiing —

he made a contact that changed his life. He met an investment banker

who was evaluating a new biotechnology company. The company was

developing

drugs projected to come to market in two years, which surprised Levin,

who knew from his Oxford work that this estimate was not realistic.

What impressed Levin deeply was the realization that this investment

banker was willing to invest $50 million in a creative biotech

company,

despite estimates that were "out of whack." Says Levin, "I

was totally enthused by the way the investment community would back

the innovative science that the company was showing me."

So began Levin’s life-long love affair with biotechnology. Although

Levin appreciated the day-to-day interactions of medical practice,

he felt stymied by its limitations. "Medicine doesn’t help the

great mass of people," says Levin, echoing his father’s devotion

to improving human society. "Biotechnology offered the possibility

to help an enormous number of people. We couldn’t hope to treat AIDS

and an avalanche of other infectious diseases without it," he

says. "That’s why I find innovative technologies fascinating."

After his transformative meeting with the investment banker, Levin

decided he was ready to be recruited by an American firm. His first

business position, in 1985, was as medical director of Focus

Technologies

in Washington, D.C. The driving idea at Focus, says Levin, "was

that you could predict a disease, find its genetic marker, and then

prevent the disease." While at Focus, Levin worked with a

strategic

consulting firm, Corporate Decisions, and identified an opportunity

in genetic testing. In order to pursue this opportunity, Levin decided

to leave Focus.

Levin raised a tiny amount of money from Crest Ventures in San

Francisco,

bought out a genetic testing company from a public company, turned

the company around, and, in 1990, sold it to Genzyme and "did

well." Levin worked for two years with Genzyme as a vice president

doing mergers and consolidations, and in 1992 was recruited to be

CEO of Cadus Pharmaceuticals in Tarrytown, New York.

The following year, in 1993, Levin was asked by Oxford professor Denis

Noble to look at Noble’s work of 30 years, single-cell models of

cardiac

tissues. Levin says, "I thought that the technology he showed

me, if properly developed, heralded a complete change in drug

discovery.

If properly commercialized, it would be wonderful." Levin promptly

went to friends and family and reached into his own pockets and raised

$2.5 million to continue the research. (Other than talking about his

father and his childhood, Levin declines to discuss his current family

life.) In 1997, as chairman of Physiome, he hired Bill Scott to begin

assembling the infrastructure that has grown into the team at Physiome

today.

Meanwhile, during Levin’s five years at Cadus, he

collaborated

with Bristol-Myers Squibb and other pharmaceutical companies and took

the company public. At the end of 1998 he left Cadus to found the

Perseus Soros Fund, which invests in small biotech companies with

promising products and technologies.

Levin now had to prove that Noble’s technology would work in the down

and dirty world of scientific experimentation. And he did. Physiome

was able to simulate the effect of a particular drug on its virtual

models of the human heart, and to show, to the FDA’s satisfaction,

that it could predict the consequences of using that drug. An apparent

heart problem caused by the drug was proved to be not a potentially

damaging side effect.

In late summer of 1999, Scott indicated that he wanted to step back

from running a company and just sit on boards. Physiome’s board began

looking for a CEO, and despite other outstanding candidates, they

came to Levin to give him one last chance to take the job. Levin

became

Physiome’s CEO last year.

"I love operating companies," says Levin. "I’ve done

mergers

and acquisitions, lots of financing, and a tremendous amount of

building

companies from the ground up — from washing dishes to being

chairman.

I’m not afraid to do anything." He says his philosophy is: "If

you haven’t done it, don’t ask someone else to do it," and if

you cannot do it yourself, then you should hire really smart people

to do it for you.

Physiome’s products support pharmaceutical companies primarily in

the pre-clinical drug discovery area, with some overlap into phase

one, the clinical trials to test safety.

Effectiveness. Physiome’s products may help pharmaceutical

companies decide, early on, whether a product is likely to be

effective

in human beings and, if so, in what types of human beings. For

example,

they can insert genetic variants in Physiome’s model and then

construct

trials to exclude or include variants. Or, researchers can construct

models of male and female cells and assess how a drug might affect

men and women differently. They can use the models to identify drugs

likely to have a toxic effect or to choose which of several dozen

compounds should be put in the testing pipeline.

Gene Evaluation. Sifting through the human genome to find

the genes that are critical in human diseases is one challenge. And,

says Levin, because genes work in complex inter-relationships,

evaluating

one gene at a time can, and does, give spurious results. The

consequence

can be very expensive mistakes, as scientists move out of the test

tube and into animal and human testing.

Five years ago the idea of a computer experiment before

a bench experiment was ludicrous. Now, an array of software

applications

tools are supported by Physiome’s modeling platform, ISC, which has

its roots in the 3-D virtual heart, the organ model for which the

company achieved fame. This ISC environment can be compared, says

Levin, to a Microsoft Office where the work of the day is biological

modeling rather than the creation of budgets, reports, and business

presentations.

Just as Microsoft Office supports numerous applications that support

specific office functions, so does InSilico Cell support modeling

applications that focus on specific diseases or therapies. The

platform

also offers specialized tools that enable the modeling of a range

of diseases and molecules. A number of the tools and applications

are web-enabled:

1. CardioPrism, a suite of cardiac models, helps assess and

predicts drug-induced heart abnormalities — how a chemical might

cause an abnormality of a heartbeat or how it could interrupt an

abnormality.

CardioPrism also assesses whether a compound will be toxic, from the

cell through the organ levels.

A pharmaceutical firm can license a model framework of CardioPrism

and customize it using Physiome’s own rich databases. Or it can create

models behind a firewall. "They are able to take a look at

something

unique without having someone else look at the same data," says

Levin. The latest licensing of this application was to Janssen, and

he sees a huge marketplace for it.

But the heart is no longer the entire focus. "Physiome started

with a whole heart," says Levin, "but now we are capable of

and have started building lungs, bladder, and other major products

important to the pharmaceutical industry."

Physiome is also developing models of immune system cells, which will

be ready shortly, and framework models of blood coagulation.

2. The Drug Browser application is a set of models that

overlay drugs that have run into trouble at the FDA. By testing a

drug on the Browser, researchers can see how each drug causes its

side effects. The goal is to help customers and others better

understand

what classes of drugs cause abnormalities in the heart. The issue

of side effects on the heart is an enormously important problem: three

out of seven drugs that fail the FDA are rejected because of

abnormalities

they caused in the heart. Every major class of drugs has some effect

on the heart — even some antibiotics and antihistamines.

3. The Pathway Editor allows researchers to understand,

organize, and evaluate the incredibly complicated protein pathways

that signal events on a cell surface and transmit that signal into

the interior of the cell. Abnormalities in these pathways form the

basis of diseases as varied as inflammation, cancer, asthma,

coagulation

cascades, and cardiac abnormalities. The faulty signals in these

pathways

are important drug targets.

For example, a series of abnormal pathways occur in cancer. Each

pathway

may comprise as many as 50 different proteins that interact with each

other in different configurations, yielding a huge number of potential

interactions. Only a small number will be faulty. Whereas a human

being can analyze only a few interactions, the Pathway Editor

evaluates

all possible faulty signals and highlights the most likely drug

targets

for further consideration.

4. The Cell Editor, another Physiome tool, is used to

build whole cells.

Physiome partners with academic researchers and

institutions

across the country and the world for its beta testing. Princeton

University’s

Jim Broach, for instance, is studying the response of yeast cells

to changes in the environment.

Using the virtual model he creates with ISC, Broach can stimulate

the virtual cell with a particular nutrient and watch the effects

on the biochemical pathway controlling the growth of the yeast cell.

If the results in the virtual cell do not match what he sees in the

living cell, he knows the model is missing something. If they do

match,

however, he cannot conclude that the model correctly represents the

cell, but only that it is consistent with the cell’s actual behavior.

"We need software like this to help us understand complex

biological

systems," says Broach. "There is a continuing convergence

of biology, physics, and computer science that will define how we

do biology in the next millennium or century. Physiome is on the

forefront

of taking that step."

And what, in Broach’s view, does Physiome stand to gain from sharing

its software? "Physiome is learning how to refine their models

and their software on the basis of the successes and failures we have

in modeling the biology of this relatively simple microorganism,"

says Broach. "That gives them the ability to use the software

more effectively with more complicated cells, and then they can

interact

with large pharmaceuticals or biotechs to pursue drug discovery."

Physiome’s agreements with laboratories like Broach’s give Physiome

exclusive rights to the technology that emerges. Physiome does not

"own" the scientists, says Levin, and, on the contrary, wants

them to publish as much and as frequently as possible. With groups

at the University of Aukland and Oxford University, however, Physiome

also has rights to research and inventions achieved with the software.

Physiome is actively working to make CellML the world-wide standard

for biological modeling. "The goal of the CellML website,"

maintains Levin, "is to make it possible for as many different

constituencies as possible to develop and create biological

models."

To support this effort, Physiome is attempting to create a single

set of standards for biological modeling. "Corporate goals are

served by having everyone playing on a level playing field with regard

to modeling," says Levin. Levin likens this standardization effort

to the early struggles between Beta Max and VHS, where the adoption

of a single standard helped everyone to produce better products and

to get wider acceptance for them.

An alternative view is offered by Christina Kalb, a spokeperson for

Entelos, a company that has models for simulating human disease.

Entelos

also has a standardized method and language for developing its models

but does not want to make them publicly available as tools. "We

think it is a little early for standardization," she says.

"Usually

you don’t know what your language needs to be capable of until you’ve

encountered a lot of different problems." Until researchers have

identified all of the problems they want to address with the

technology,

Kalb believes that standardization may limit rather than enhance.

Physiome, however, is promoting CellML as the standard and wants to

preempt the creation of other modeling languages. "Our goal is

to have CellML used by all," says Levin. To promote CellML,

Physiome

has advertised widely and created an impressive advisory board to

develop modeling standards. The board comprises scientists from

diverse

areas of research, to ensure representation of a broad spectrum of

biochemistry. "We want to make sure that the specifications for

the language actually incorporate as much real biology as they

can,"

explains Colatsky. "We don’t want to take a limited view of what

models have to do."

At the board’s first teleconference, which included scientists from

New Zealand, Great Britain, and across the United States, members

agreed on a charter, goals, and near-term milestones. Colatsky sees

that first teleconference as revolutionary, "because no one has

been able to bring together as much diversity in biology and try to

unify it with a common approach." The advisory board will meet

face to face in March.

Peter Kramer, a business development consultant in the biotech

industry,

injects a note of caution. "Today, we just don’t have a sufficient

understanding of biological processes or information on protein

pathways

to enable simulations to predict useful results without extensive

biological experimentation," says Kramer. Kramer does see

Physiome’s

modeling capabilities as a potential bridge to a future in which

models

are more reliably predictive.

Levin realizes that the company’s success will hinge on a number of

variables — advances in technology, ability to recruit top-level

people, availability of capital, and a healthy pharmaceutical

industry.

Yet he maintains that science and business are about to be partners

in the modeling enterprise.

"In the past year," he says, "modeling has exploded in

the academic world, and it is about to explode in the business

world."

Physiome plans to provide the pharmaceutical companies with modeling

capabilities that can accommodate the huge amounts of data on the

horizon. By enabling pharmaceutical companies to do modeling for

themselves,

using their own data, says Levin, "We are providing a new

industrial

base for pharmaceutical companies."

Musing on how his own path is similar to that of his father, Levin

says, "I have tried to follow the same guiding principles."

Embracing his father’s belief in using creativity to make the world

a better place, Levin believes that Physiome’s technology will

eventually

change the pharmaceutical industry and "will provide a completely

new way of looking at our living world."

"Physiome is a completely different type of company," says

Levin. "We are breaking down the walls between computers and

biology

in extraordinarily creative ways." And meditating on his own role,

Levin says, "What an honor to have the chance to participate in

that process."

Physiome Sciences, 307 College Road East, Princeton

08540. Jeremy M. Levin, CEO. 609-987-1199; fax, 609-987-9393.

Www.physiome.com.


Next Story


Corrections or additions?


This page is published by PrincetonInfo.com

— the web site for U.S. 1 Newspaper in Princeton, New Jersey.

Facebook Comments