September 3, 2008

There’s a Life in My Soup!

By Simon Hadlington

Scientists are cooking up primeval ooze in the laboratory to try to discover how life on Earth first developed. Simon Hadlington lifts the lid on their brew

A time traveller steps out of his machine on to the early Earth, around three billion years ago. The rocky landscape looks like modern-day Mars, except that there are lakes of water. It is bleak and barren: to the naked eye, it is literally lifeless. But if our intrepid explorer dips a jam jar into a pool of sludgy water and looks at it under a microscope, he might, just might, be able to make out a population of small, hollow spheres a few thousandths of a millimetre across.

Every so often, these spheres can be seen to split in two, grow a little fatter, and split again. These "protocells" could have been the first stirrings of life on Earth. And now scientists want to try to make them in the laboratory, to recreate what could have been the primeval ancestor of the modern biological cell.

Dr Daniel Frankel, a researcher at Newcastle University, is one of these scientists. "We want to create life in a test tube, from scratch," he says. "That way we will get a better understanding of how life on Earth might have started."

The origins of life on our planet have perplexed scientists for centuries. After decades of scientific research, it remains unclear how the fundamental building blocks of life - the molecules that form genes and proteins - first arose, and how these then assembled themselves into complex biochemical entities that could grow, replicate and evolve: in other words, living cells. But small pieces of the jigsaw are beginning to emerge. Scientists have discovered that a 3.6-billion-year-old meteorite that fell to Earth in Australia nearly 40 years ago contains two molecules that are key ingredients for genes - supporting the idea that the molecules of life could have been brought to primordial Earth from space. Other experiments suggest that simple molecules already on Earth, such as ammonia and methane, could have reacted together to create simple biomolecules. But what Frankel is more interested in is the next step along the road to life: how did these molecules spontaneously assemble themselves into the complicated biochemicals capable of kick-starting life?

"There is a widely accepted view that life came into being from inanimate matter - basically, molecules that were floating around in some kind of soup, and that somehow life sprang up from these," says Frankel. "This implies that it should be possible to synthesise life in the lab. If we can do this, we could get a real handle on the origins of life."

One approach to the question involves creating a "protocell", a primitive precursor to a modern cell. In its most basic form, a protocell consists of a membrane containing some kind of genetic code that can be passed on to subsequent generations. A modern cell is a hugely complex biological entity, containing thousands of different types of molecule. Many of these are elaborate proteins such as enzymes and transporters that work together to carry out a vast range of functions in the cell. A protocell would have none of these sophisticated proteins.

One of the leading researchers in protocells is Professor Jack Szostak of the Howard Hughes Medical Institute in Chevy Chase, Maryland. "A lot of the recent work we have been doing is to figure out what are the simplest components that can self-assemble into membranes," he says. The membranes of "modern" cells consist largely of molecules called phospholipids, but these are complicated structures and are highly impermeable - they do not readily allow molecules to pass across them. These facts pretty much rule them out of playing a part in protocells. Instead, Szostak has concentrated on fatty acids, simpler molecules that could well have been present on the early Earth. Under the correct conditions, fatty-acid molecules in water can coalesce and form vesicles - tiny hollow spheres. These vesicles can also "recruit" more fatty-acid molecules from the environment and grow bigger. "We are working on ways that would enable these vesicles to divide naturally and we are confident that this problem can be solved," Szostak says.

"What you then need is to have some genetic material inside these structures that provides a useful function for the cell - and this material must be passed on to the daughter cell," he continues. Szostak is a leading proponent of the idea that in ancient protocells this material could have been RNA, a chain-like molecule consisting of smaller links called nucleobases. RNA can act as a piece of biological code, which can be "read" by other molecules, such as amino acids, which are the building blocks of proteins.

But, crucially, RNA can also act as a biological machine in its own right: it can assist in its own replication, for example, as well as act on other molecules.

In a groundbreaking paper published in the journal Nature earlier this year, Szostak showed that nucleobases can diffuse across a fatty-acid membrane to the internal space enclosed by a vesicle. By placing an appropriate molecular template inside the protocell, Szostak showed that the nucleobases could join together, or polymerise, to create something that resembles a gene.

"Once you have a genetic polymer that can replicate itself, you have all the elements for Darwinian evolution," says Szostak. For example, a particular short strand of RNA could act as a catalyst to join together a handful of amino acids to make a small protein. This simple protein then gets lodged in the fatty-acid membrane and allows certain sugars or salts to enter the cell more easily. This in turn makes the internal environment of the cell more favourable for the RNA to replicate itself. This protocell is then more likely to survive and prosper.

Back in Newcastle, Daniel Frankel believes that surfaces of minerals on the ancient Earth could have played a key role in this basic chemistry. "The whole idea of life arising from a collection of molecules floating around at random requires the concept of self- assembly," he says. Frankel has shown that small biologically important molecules such as amino acids and nucleobases can sit on a crystalline surface and adopt the geometry of the underlying crystals. In this way, such molecules could "stick" to a surface and find themselves forming chains - which is exactly what is required for early life. "I would hope that in 10 years' time, we would have the various technical issues solved and will be watching a protocell grow, divide and evolve in the laboratory," Szostak says. "We will then hopefully have a better understanding of how life might have started on Earth, and will also have some clues about why modern biology is the way that it is."

They came from outer space: the ingredients of existence

*For life to exist, one key ingredient is needed above all: water. In our solar system, there is a relatively narrow 'habitable zone' where water is, or was, present. This essentially means that only Mars and the Earth are candidates for sustaining life.

*Despite having water, the Earth's own geochemistry is relatively poor in terms of the chemical elements needed for the molecules of life - carbon, nitrogen, hydrogen, oxygen and sulphur. So could compounds containing these elements have been 'imported' on meteorites?

*"The molecules of life do occur in space - that is an unquestionable fact," says Professor Mark Sephton, a meteorite expert at Imperial College London. "The early solar system was populated with organic molecules, and meteorites contain all the major compounds of life - amino acids, sugars, nucleobases. All the molecule classes to make genetic material and a cell membrane are present."

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