Seeking to Restart Evolution With Life's Simplest Ingredients

By William Booth

Washington Post Staff Writer

BOSTONJack Szostak is no Dr. Frankenstein, but if he succeeds in his

work, the soft-spoken biologist may be the first to create life in

the laboratory.

Szostak and his colleagues at Massachusetts General Hospital here

plan to manufacture not a hulking monster with electrodes in his neck,

but nature's most elemental unit of life: a cell.

Their cell, to be built almost from scratch in the next year or so,

will not be very sophisticated. Little more than a fat bubble containing

bits of genetic material, Szostak's creations will be so simple and

primitive that some rival researchers say it would be almost hyperbolic

to call them life.

"I think it's a perfectly neat thing to do, but really, calling them

cells?" said Norman Pace of Indiana University. "It's probably more

tongue-in-cheek than anything else."

But Szostak is not kidding, and he is not alone. There are at least

three major scientific groups around the country trying to create life

in the laboratory. Szostak himself is convinced that his cells will be

technically alive, at least by his definition. They will replicate. And

as important, they will be playthings for the forces of natural

selection. As such, Szostak believes his little cells could evolve into

more complex beings.

The work of Szostak and his colleagues is designed to address some of

the looming questions of how life originated: How simple can life be?

And what might the first forms have looked like as they began their long

journey toward complexity and variety?

Most people think life as we know it today is quite complicated. But

Szostak and his colleagues are attempting to reduce biology to its

simplest ingredients. In essence, Szostak's recipe is as follows:

LIFE

Fat

Water

Spermidine (a ubiquitous but somewhat mysterious compound of carbon,

hydrogen and nitrogen first detected in human sperm)

A special segment of RNA from a protozoan called Tetrahymena

thermophilia.

Modify the RNA slightly. Set aside. In a separate bowl, mix the other

ingredients. Slowly add RNA to broth of fat, water and spermidine.

Allow soup to sit while fats self-assemble into membranes that curl

up into cell-like bubbles, encapsulating bits of RNA, water and

spermidine. These are the cells.

Replenish periodically with small bits of RNA, which serve as food

for the new cells. Shake vigorously to make cells divide.

Repeat feeding and shaking indefinitely. Check occasionally for

evolution.

The central ingredient in Szostak's cells is the RNA, for ribonucleic

acid, which many scientists believe was the first master molecule of

life, contained in the original cells that arose from the primordial

soup about 4 billion years ago. Today, the master molecule is the

similar but more complex deoxyribonucleic acid, DNA. But in the

beginning, DNA's more primitive and unstable ancestor may have reigned

supreme, in a realm molecular biologists call the "RNA World."

Why wasn't DNA the first molecule of life? All cells living today

rely on DNA to act as their genes, carrying the instructions for making

various specific kinds of proteins, the workhorses of life. But there is�a hitch. To replicate itself - an essential step in the reproduction of

life - DNA needs proteins. Specifically, it needs certain kinds of

proteins to act as enzymes that carry out the DNA replication. So

scientists who study the origin of life are faced with a paradox: Which

came first, the chicken or the egg? DNA or proteins?

RNA offers an answer. A few year ago, Tom Cech of the University of

Colorado discovered that RNA was capable of doing more than its

well-known job of carrying a set of instructions from the DNA in the

cell's nucleus to its factory floor. Cech (pronounced check) found that

a particular bit of RNA from a certain protozoan, or one-celled

organism, could also act like an enzyme, cutting up pieces of RNA and

then splicing the ends together again. For this, Cech won a Nobel Prize

last year. The RNA enzymes are called ribozymes.

Szostak is working with the same segment of RNA that Cech discovered.

However, he and his group modified the RNA so that instead of cutting

and splicing, the ribozyme would only splice. Using itself as a pattern,

Szochak believes his modified RNA could take subunits of RNA, which

Szostak would feed his cells as a kind of food, and splice them into

copies of itself.

RNA, like DNA, is made of four different kinds of subunits than can

be chained in any sequence to any length. Szostak's ribozyme would use

its own special sequence as a template to dictate the sequence in which

to splice new subunits.

All this activity would be happening inside bubbles of a special kind

of fat - the same kind of fat that forms the membranes around all living

cells. Scientists who study special fatty acids called phospholipids

have learned they can do a trick. When simply dumped into water, the

lipids spontaneously aggregate to form thin, impermeable sheets and

bubbles, called vesicles.

"Take a breakfast egg and extract phospholipid out of it and place

the lipids in water and you'll get little vesicles," said David Deamer

of the University of California at Davis. "You'll get a primitive cell

system."

Deamer, who is also working to create life in the lab, has found that

meteorites contain all the ingredients needed to make membranes, adding

credence to the popular idea that the basic building blocks of life were

ferried to Earth from space.Mimicking the Primordial Environment

Once Szostak gets his RNA inside a membrane, and once he gets his RNA

to make copies of itself, he is close to his definition of life. But he

must still figure out a way to get the cells to fuse and spill their

contents into one another. He must also devise a way of encouraging his

cells to divide.

In the primitive world, he speculates, the first cells probably could

not divide on their own. They needed help from nature: from crashing

waves, lightning bolts, hot geysers. Deamer believes that cells in the

lab can be made to fuse and separate by drying and wetting them,

mimicking the cycles of a tidal pool, a likely habitat for early life

forms.

Szostak is considering shaking his cells to mimic wave action or

pushing them through a sieve, which would break them into smaller

vesicles.

"If we could create a system that would begin to run autonomously and

replicate itself, then a lot of people, myself included, would say it's

alive," said Gerald Joyce of the Research Institute of the

Scripps Clinic in La Jolla, Calif., another leading contender in

the race to create life in the lab.

Once their systems are running, Szostak, Joyce, Deamer and others

maintain that their primitive cells would evolve over time, producing

new cellular machinery.

This would happen because as the RNA copied itself, it would make

mistakes. Some of these mistakes would be improvements. The cells with

new and improved RNA would reproduce more prolifically and eventually

replace the losers. Given a few million years, and enough funding,

Szostak and his colleagues say that in theory they could rerun evolution

on Earth.

"I really think we'll learn to make life in the laboratory long

before we find it someplace else in the universe," Joyce said. "The most

likely source of discovery is here on Earth."