Can It Be Created? : Closing In on the Ultimate Riddle: Life

In the University of Miami laboratory of chemist Sidney Fox, tiny spheres of man-made protein dance a lively ballet under the microscope. “This could very well be what the first life looked like,” Fox said.

Fox is one of a handful of researchers who are carrying out experiments that many other scientists consider impractical or impossible, even heretical.

He is pursuing the ultimate biological riddle--nothing less than the creation of life in the laboratory, as most biologists believe it must have been created on Earth more than 4 billion years ago.

To do this, Fox is combining simple chemical molecules that must have been present in the primordial soup of the Earth and subjecting them to artificial lightning and other energy sources. The results are primitive, cell-like spheres unlike anything that exists in the contemporary world.

Enduring Questions

Fox insists that his and others’ efforts to create life are not an attempt to achieve “godhood” or to demonstrate humanity’s mastery over nature. Rather, they are an attempt to answer enduring questions that are at the very root of consciousness: “Where did I come from? Why am I here? What makes me unique?”

If researchers are successful in creating life--or some form of proto-life based on simpler molecules--in the laboratory, the ramifications would be as vast as the universe itself. For one thing, that feat would give researchers new confidence that life started easily on Earth and may have started equally easily elsewhere, such as on other planets in this solar system and on planets orbiting other stars.

Such a discovery may also give hints about why life required more than 3 billion years on Earth to progress from single-celled organisms to the larger creatures that were the precursors of today’s plants and animals.

And finally, on another level, the discovery could provide new answers about not only the meaning of our own lives, but also the larger purpose of life itself.

Fox believes that his protein spheres are a major step toward achieving his goal. “They meet the three classical criteria of a living system,” he said. They carry out chemical reactions identical to many in human cells. They evolve. And they sometimes even seem to reproduce themselves.

“I would call them proto-cells,” Fox said. “From the proto-cell, there could ensue evolution of modern cells. It would take an awful lot of evolution to get to modern cells, but the first cells must have had these same key properties.”

Fox and other researchers are trying to identify the chemical building blocks that must have existed in the prebiotic--before life--world and put them together in the same way that they must have been assembled in the first cells.

Those building blocks include proteins, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is the repository of genetic information, the blueprint of life. RNA serves as a working blueprint for the construction of proteins and other cellular components.

Fox believes that he may be within 5 to 10 years of creating life with his proteinoid spheres. But other researchers consider Fox a maverick and believe that the problem is more difficult. They say such a leap may require another 20 to 40 years, perhaps even more.

Nevertheless, the quest to create life in the lab recently has cleared some significant, albeit preliminary, hurdles. The advances, as well as some illuminating failures, have generated new excitement for a number of scientists.

Intellectual Challenge

The work is not expected, however, to produce organisms that might be of any practical use in medicine or science in the foreseeable future. Although life produced in the laboratory might, in the distant future, be genetically engineered for specific purposes, researchers view their work as more of an intellectual challenge than a practical problem.

This is certainly the case with Stanley Miller and his colleagues at UC San Diego and the nearby Salk Institute, who have made some extremely primitive RNA molecules that, in a sense, replicate themselves, although not very well. “It’s like the dog giving a sermon in church,” Miller said. “It’s not a very good sermon, but you’re surprised that he does it at all.”

Miller and Fox are separated by more than a continent. They are worlds apart in their basic view of how life began. Fox favors the simplicity of proteins, arguing that life could have begun using only these simplest of molecules. Miller, in contrast, argues that only DNA or RNA can carry the genetic information necessary for reproduction.

‘Geneticists vs. Chemists’

“The essential thing of a living organism is that it is self-replicating,” Miller said. “And the only thing we know that self-replicates is DNA and RNA,” molecules that store genetic information in cells.

“It’s always been that way, the geneticists versus the chemists,” said exobiologist (one who studies life off the Earth) Richard S. Young, a consultant to the National Aeronautics and Space Administration at the Kennedy Space Center in Florida. “The geneticists, of course, see the contemporary information-containing molecules as being DNA and RNA, and (they believe that) until one of those molecules was operating in the primitive organism or cell, you didn’t have life.”

Chemists, however, “take a totally different view,” Young said. The first information-carrying molecule “doesn’t have to be as sophisticated as DNA. It could be a much simpler molecule, such as a protein. It just has to carry enough information for the first prototype organisms to replicate themselves.”

Though the debate over whether life was formed from proteins or RNA has few immediate, practical implications, it may play a crucial role in NASA’s search for life elsewhere in the universe by showing what to look for.

The search for life on Mars by NASA probes, for example, was biased toward identifying DNA. Most scientists now believe that the first life did not contain DNA, so that probe may have been preordained for failure.

But whether the first life was based on DNA and RNA or on proteins, researchers have set themselves a tremendous task. Trying to synthesize life in the laboratory “is a terribly difficult problem,” said biochemist Gerald Joyce of the Scripps Clinic and Research Foundation in La Jolla. “Nature had a billion years to play with, the entire Earth to play with. We just don’t have the time, so all we can do is try to learn something about the relevant reactions.”

“But difficulty does not mean impossibility,” said chemist Cyril Ponnamperuma of the University of Maryland in College Park. “Just because something is difficult doesn’t preclude it from happening in a primordial environment. We just have to keep going at it. I am optimistic about a solution.”

The scientific search for the origin of life began 37 years ago when Miller, then a young graduate student at the University of Chicago, performed an experiment that forever changed the way biologists viewed evolution.

In a large flask, Miller combined methane, ammonia, hydrogen and water, which were believed to make up the atmosphere of the primordial earth. He then heated the flask and repeatedly passed an electric spark through the vapors.

After two weeks, Miller analyzed the contents of the flask and found at least four amino acids, the building blocks of proteins, as well as a variety of other compounds that play a role in life. Miller had proved what scientists had previously only hypothesized: that the complex chemicals on which life is based could be produced by essentially random processes.

Shed Little Light

Scientists have since repeated Miller’s experiments using a variety of starting materials and conditions and have shown that they can produce all 20 amino acids that are found in proteins, as well as the nucleotides from which DNA and RNA are formed. Because these experiments showed that either or both could be formed spontaneously, they shed little light on the DNA-versus-protein argument.

Many of the chemicals have also been found in meteorites. Spectrographic studies in addition have shown that the chemicals are found on most asteroids, comets, planets and moons in the solar system, as well as in the voids between stars.

The whole universe seems to be awash in organic chemicals waiting for the metaphorical spark that will transform them into living matter.

Most researchers agree that the first life must have been much different than life today. And recently, some geneticists have begun to reach the conclusion that systems containing either RNA or DNA may be too complicated to represent the first forms of life. Some believe that simpler, as yet undiscovered, molecules must have played an important role, and they are trying to decipher what those simpler molecules may have been.

The extremely sophisticated system by which cells function (see graphic) is clearly the result of millions, if not billions, of years of evolution. No one believes that even a rudimentary form of life containing all three components--DNA, RNA and proteins--could have sprung up as a result of random processes.

‘Essentially Unfathomable’

“That such a complex mechanism could have been present at the beginning of organic evolution is, to even the most imaginative scientist, essentially unfathomable,” Fox said.

If the first life must have been much simpler, researchers are forced to ask which of these macromolecular systems can be done away with and still have life--a question that Fox said is the evolutionary equivalent of “which came first, the chicken or the egg?” The geneticists--who include most people working on the origin of life--have eliminated proteins and focused more on the “egg”: DNA and RNA.

Of this pair, RNA seems the more likely candidate as the first component of life, geneticists agree. “It’s been pretty well accepted for maybe 20 years that life couldn’t have started with DNA,” Joyce noted. “There are chemical reasons why it is just not an appropriate molecule. So the focus has been more towards RNA.”

But that focus created a huge problem: RNA is fine as an information carrier, but if the first life were based on it, RNA would also have had to serve as a structural material for primitive organisms and carry out their metabolic functioning--acting as a protein-like enzyme to provide cells with the energy necessary for life.

‘RNA World’

Research in this decade revealed that RNA indeed can function as an enzyme. That realization has led to the conception of a primordial world, christened “RNA world” by Nobel laureate Walter Gilbert of Harvard University, in which RNA served as both genetic material and as enzymes.

But scientists have had very little success in getting RNA to replicate itself and have run into a problem that makes them believe that replication probably could not have happened on its own (see graphic).

That problem “really pushed us over the edge and forced us to say (RNA itself) just doesn’t look like the first starting material.”

So now that geneticists have eliminated RNA, along with proteins and DNA, where does that leave them? Trying to find simpler molecules, “proto-RNA,” that could function like RNA, Miller said.

How will they know if they’ve found the right thing? “There’s sort of a slogan I have,” Miller said: “ ‘If the results don’t come easy, it’s probably not prebiotic.’ ” So anything that could have been a prebiotic precursor of RNA will, by definition, replicate itself easily.

And if they find several chemicals that work? “That kind of dilemma we’ll worry about later,” Miller said. “Right now, we don’t have (even) one.”

But Fox is banking on proteins as the starting points of life. And ironically, by Miller’s definition, Fox’s system could well be prebiotic, for his results come very easy. When he heats a mixture of amino acids at a temperature that could be easily achieved on, say, a dry lake bed in summer, they react chemically to form proteins. When the proteins are immersed in water, they form his “proteinoid microspheres.”

These microspheres dance around under the microscope, impelled by random impacts with water molecules--the same Brownian motion that causes dust motes to dance around in the air.

Typical of Life

But the proteins in the microspheres carry out reactions typical of life, Fox said. Some catalyze the breakdown of molecules. Others do the opposite job of building molecules. In fact, Fox said, he and other researchers have found artificial proteins that carry out the same types of reactions as every class of enzymes found in living organisms.

The microspheres even undergo a primitive form of “reproduction.” Under the microscope, they can be seen to form buds on their surface, just like yeast and certain bacteria. These buds break off from the parent, and then grow by absorbing unaggregated proteins from the solution. Eventually, these “daughter” microspheres bud themselves, and the growth cycle is repeated.

But these proto-cells cannot be considered alive because they cannot survive away from the “life-support system” provided in Fox’s laboratory. Left to their own devices, they would simply dissipate.

Fox first produced the proto-cells about 20 years ago and has been studying them ever since--while futilely trying to persuade the geneticists that he is right and they are wrong. It is difficult to pin down exactly why they disagree with him so strongly.

Argument Over Proteins

One problem, said chemist James P. Farris of Rennselaer Polytechnic Institute in Troy, N.Y., is that “I have trouble finding anyone--or at least very few people--who would agree that proteins store information.”

Fox, however, argues that the proteins in his proto-cells do carry information, that the order of the amino acids in the proteins is not random. “They line up in quite strict order due to the interactions of the amino acids with each other,” he said.

All that would have been necessary for life to begin, he added, was the appearance of a protein that could copy itself and other proteins as well. Evolution would then have made small changes in the order of the amino acids, leading to more efficient copying. Through his proto-cell research he is now trying to find such proteins and observe evolution.

This scenario is supported by the fact that the amino acid order that appears in the proteinoid microspheres persists today in conventional proteins, he adds.

Order of Amino Acids Studied

Chemists Orlin Ivanov of the Bulgarian Academy of Sciences in Sofia and Berthold Fortsch of the Max Planck Institute for Biochemistry in Martinsried, West Germany, have studied the order of amino acids in 2,898 proteins--all the proteins for which such information was available when they began their study in 1984.

They concluded that all the proteins were descended from a small group of primitive proteins, and that those primitive proteins had amino acid sequences similar to those observed by Fox.

Nonetheless, Fox remains the proverbial voice crying out in the wilderness. “I think it is embarrassing to them (the nucleic acid proponents) to recognize that there is an answer which shows that the way they have been thinking for so long is falsely based,” he said.

But even Fox’s supporters believe that he occasionally goes too far. “Every now and then he even implies that these things are, in a sense, alive, that he has demonstrated most of the characteristics of life,” Young said. “I think he goes a bit far there, but up to that point I am inclined to agree with him.”

And some observers believe that the line between mere sophisticated chemistry and actual life is so fine that neither side may be able to conclusively prove its case. “If there had been an intelligent observer watching the Earth (during its first billion years), would he have been able to decide when life originated?” chemist Daniel Atkinson of UCLA asked. “I think he wouldn’t have. It probably took thousands and thousands of years.”

THE SEARCH FOR FIRST LIFE

Most scientists agree that life as it exists now is too complicated to have arisen spontaneously. Current life depends on an intricate interaction of DNA, RNA and proteins. Genetic information, the cell’s blueprint, is carried in DNA in the order of its individual chemicals, called nucleotides, in the same way that information in a sentence is contained in the order of the letters that compose it.

When the cell needs to synthesize a structural protein, for example, the protein’s DNA blueprint is copied into RNA. The RNA serves as a working blueprint for synthesis of the protein from individual amino acids. Because this system is so complex, most researchers believe the first life must have incorporated only part of it. Many scientists believe that RNA in the first cells fulfilled the functions of both DNA and proteins.

IN NATURE RNA is composed of four chemicals, known as bases, called adenine (A), uridine (U), cytidine (C), and guanine (G) that are linked to the RNA backbone by a sugar called D-ribose (DR). Genetic information in RNA is encoded in the sequence of the four bases. When RNA is replicated, that information is preserved because A always pairs with U and C always pairs with G.

IN THE LAB In the laboratory, researchers have been able to get RNA to replicate itself in only one instance, a short piece of RNA composed of only four bases--two Gs and two Cs. When the molecule is placed in a test tube with two smaller molecules, each containing one C and one G, they bind to it and react chemically with each other.

IN TROUBLE But researchers have run into a major problem in considering how RNA could have been the basis of the first Life. RNA contains only D-ribose, but when ribose forms in the primordial soup that must have existed on early Earth, both D-ribose and L-ribose, which are mirror images of each other like gloves for the left and right hands, are formed in equal quantities. And if L-ribose is incoporated into growing RNA, it brings the synthesis to an abrupt halt.