BOSTON -- Jack 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



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."

In order to understand the origin of life on Earth, scientists are attempting to create simple, primitive cells in the lab - perhaps similar to the first cells that arose out of the prebiotic soup 4 billion years ago. The researchers believe their creations will be at least technically alive. The cells will replicate and perhaps even evolve over time into more sophisticated organisms.

1. A man-made "cell", composed of a bubble of fat, contains special master molecules of RNA and unlinked subunits of RNA. The master RNA can fold into a specific shape that allows the molecule to act like a sewing machine, or enzyme, stitching subunits of RNA together to make copies of the master RNA.

2. When subunits have all been used up, the mother cells are shaken or strained to break them into smaller sizes. The broken membranes of the cells will self-assemble spontaneously to make new bubbles. This simulates cell division.

3. The cells may also fuse together. Fusion allows the contents of one cell to spill into another, bringing together enzymes and fresh subunits of RNA. Then the whole cycle starts over again. Eventually the cells may evolve into more complex forms, as small but advantageous mistakes made while making copies of RNA are incorporated.

SOURCE: Jack Szostak