Protocell image

A team of biologists and chemists is closing in on bringing non-living matter to life.

It's not as Frankensteinian as it sounds. Instead, a lab led by Jack Szostak, a molecular biologist at Harvard Medical School, is building simple cell models that can almost be called life.

Szostak's protocells are built from fatty molecules that can trap bits of nucleic acids that contain the source code for replication. Combined with a process that harnesses external energy from the sun or chemical reactions, they could form a self-replicating, evolving system that satisfies the conditions of life, but isn't anything like life on earth now, but might represent life as it began or could exist elsewhere in the universe.

While his latest work remains unpublished, Szostak described preliminary new success in getting protocells with genetic information inside them to replicate at the XV International Conference on the Origin of Life in Florence, Italy, last week. The replication isn't wholly autonomous, so it's not quite artificial life yet, but it is as close as anyone has ever come to turning chemicals into biological organisms.

"We've made more progress on how the membrane of a protocell could grow and divide," Szostak said in a phone interview. "What we can do now is copy a limited set of simple [genetic] sequences, but we need to be able to copy arbitrary sequences so that sequences could evolve that do something useful."

By doing "something useful" for the cell, these genes would launch the new form of life down the Darwinian evolutionary path similar to the one that our oldest living ancestors must have traveled. Though where selective pressure will lead the new form of life is impossible to know.

"Once we can get a replicating environment, we're hoping to experimentally determine what can evolve under those conditions," said Sheref Mansy, a former member of Szostak's lab and now a chemist at Denver University.

Protocellular work is even more radical than the other field trying to create artifical life: synthetic biology. Even J. Craig Venter's work to build an artificial bacterium with the smallest number of genes necessary to live takes current life forms as a template. Protocell researchers are trying to design a completely novel form of life that humans have never seen and that may never have existed.

Over the summer, Szostak's team published major papers in the journals Nature and the Proceedings of the National Academy of Sciences that go a long way towards showing that this isn't just an idea and that his lab will be the first to create artificial life -- and that it will happen soon.

"His hope is that he'll have a complete self-replicating system in his lab in the near future," said Jeffrey Bada, a University of California San Diego chemist who helped organize the Origin of Life conference.

Modern life is far more complex than the simple systems that Szostak and others are working on, so the protocells don't look anything like the cells that we have in our bodies or Venter's genetically-modified E. coli.

"What we're looking at is the origin of life in one aspect, and the other aspect is life as a small nanomachine on a single cell level," said Hans Ziock, a protocellular researcher at Los Alamos National Laboratory.

Life's function, as a simple nanomachine, is just to use energy to marshal chemicals into making more copies of itself. "You need to organize yourself in a specific way to be useful," Ziock said. "You take energy from one place and move it to a place where it usually doesn't want to go, so you can actually organize things."

Modern cells accomplish this feat with an immense amount of molecular machinery. In fact, some of the chemical syntheses that simple plants and algae can accomplish far outstrip human technologies. Even the most primitive forms of life possess protein machines that allow them to import nutrients across their complex cell membranes and build the molecules that then carry out the cell's bidding.

Those specialized components would have taken many, many generations to evolve, said Ziock, so the first life would have been much simpler.

What form that simplicity would have taken has been a subject of intense debate among origin of life scientists stretching back to the pioneering work of David Deamer, a professor emeritus at UC-Santa Cruz.

What most researchers agree on is that the very first functioning life would have had three basic components: a container, a way to harvest energy and an information carrier like RNA or another nucleic acid.

Szostak's earlier work has shown that the container probably took the form of a layer of fatty acids that could self-assemble based on their reaction to water (see video). One tip of the acid is hydrophilic, meaning it's attracted to water, while the other tip is hydrophobic. When researchers put a lot of these molecules together, they circle the wagons against the water and create a closed loop.

These membranes, with the right mix of chemicals, can allow nucleic acids in under some conditions and keep them trapped inside in others.

That opens the possibility that one day, in the distant past, an RNA-like molecule wandered into a fatty acid and started replicating. That random event, through billions of evolutionary iterations, researchers believe, created life as we know it.

In a paper released this month in the Proceedings of the National Academy of Sciences, Mansy and Szostak showed that the special membranes, fat bubbles essentially, were stable under a variety of temperatures and could have manipulated molecules like DNA through simple thermal cycling, just like scientists do in PCR machines.

The entire line of research, though, begs the question: where would DNA, or any other material carrying instructions for replication, have come from?

Many researchers have tried to tackle this problem of how RNA- or DNA-like molecules could have developed from the amino acids present on the early Earth. John Sutherland, a chemist at the University of Manchester, published a paper last year demonstrating one plausible way that RNA could have spontaneously been created in the prebiotic world.

Once such molecules existed, Szostak's lab's demonstrated in a Nature paper earlier this summer that nucleic acids could replicate inside a protocell (pdf).

But while many scientists agree the protocell work is impressive, not every scientist is convinced that it contributes to a reasonable explanation for the origin of life.

"Their work is wonderful inasmuch as what they are doing can be," said Mike Russell, a geochemist with the Jet Propulsion Laboratory in Pasadena, California. "It's just that I'm uneasy about the significance of it to the origin of life."

Russell argues that the very first life-like molecules on Earth would have been based on inorganic compounds. Instead of a fatty acid membrane, Russell argues that iron sulfide could have provided the necessary container for early cells.

But UCSD's Bada pointed out that it as unlikely we will ever know how life actually began.

"[Szostak's] point, and how we all view it, is that it's a nice model, but it doesn't necessarily mean that it happened that way," he said.

Szostak suggested that even if life could theoretically or did begin some other way, his lab's hypothesis was (at least) experimentally plausible.

"We're now pretty much convinced that growth and division could occur under perfectly reasonable prebiotic conditions in a way that is not some artificial laboratory construction," he said.

And actually, the most intriguing possibility of all may be that the protocells in Szostak's lab do not closely model earthly life's origins. If that's true, human beings, ourselves the product of evolution from the most primitive organisms, would have created an alternative path to imbuing matter with the properties of life.

"What we have in biology is just one of many, many possibilities," Szostack said. "One of the things that always comes up when people talk about life and universal qualities is water. But is water really necessary? What if we could design a system that works in something else?"