By Davide Castelvecchi
Gene sequencing guru J. Craig Venter recently announced plans to redesign the complete genome of a bacterium, trying to find out what is the minimum possible set of genes that make life work. If you think Venter is ambitious, how about the idea of creating an entire artificial, self-reproducing microorganism — from scratch? That’s what biophysicist Steen Rasmussen of Los Alamos National Laboratory and chemist Liaohai Chen of Argonne National Laboratory are up to.
Artificial creatures used to inhabit only virtual worlds, or the dreams of philosophers and computer scientists. But slowly, the feat is beginning to look feasible, and in the near future, entirely artificial bugs could populate test tubes, petri dishes, and perhaps the world. Once people figure out how to make such bugs work, a whole new field of technology will spring up, which could rival or surpass even the most futuristic forms of genetic engineering. And our very concept of life will never be the same.
While any practical applications still belong to science fiction, Rasmussen’s immediate goal is to produce a minimalistic system that can be called alive. The question of what ‘alive’ means has long been the subject of debates. It relates to the problem of the origin of life on Earth, and is essential if you want to know what to look for when searching for life on other planets. The consensus is that the essential features that define life are the ability to consume energy, grow, reproduce, and evolve. Rasmussen’s project would be a solution to that question, aiming at extreme simplicity. “A lot of what we are proposing is really just using existing physics and chemistry in a smart way to do all these things for us,” says Rasmussen.
He and his team came up with the first complete design for what they call a ‘protocell’, although it would probably have nothing to do with the ancestor of today’s cells. Their blueprint involves just three main ingredients: A container, a metabolism, and a set of genes.
The chassis of the protocell will be a micelle, a microscopic blob of lipid molecules called surfactants, the kind of molecules that have a water-loving head and a water-fearing tail. In water, micelles form spontaneously, because surfactants tend assemble into droplets, exposing their water-loving ends on the outer side while “hiding their tails inside,” says Rasmussen. Common soap washes oil away because it contains surfactants, which form invisibly small micelles that swallow up oil’s water-fearing molecules, which would not otherwise dissolve in water. Once a micelle reaches a critical size it will split up into two, thus replicating itself.
The protocell’s genetic heritage will be encoded in an artificial molecule called PNA, or peptide nucleic acid. PNA was invented at the University of Copenhagen in 1991 by biochemist Peter Nielsen, who called it “a cross between DNA and protein.” Like DNA, PNA is a chain of building blocks of four types— the bases A, T, C, and G. But its backbone consists of water-hating peptides instead of sugars, so it readily sinks in a micelle’s outer layer. The protocell will sport its genes on the outside, instead of carrying them inside.
Inside the micelle, Rasmussen’s protocell will ‘breathe’ by using light as the energy source for a rudimentary metabolism based on fatty nutrient molecules. Photoactive molecules embedded in the micelle will play a similar role as the chlorophyll that works out photosynthesis in plants and blue algae. When hit by a photon, the photoactive molecule releases an electron. A nutrient molecule in the micelle captures the electron, starting a reaction that produces new surfactants and new building blocks for PNA.
The PNA itself will facilitate the metabolism, a role that no known cell gives to its DNA. A photo-active substance that lost an electron will be left with a positive charge, while the molecule that gained it will be negatively charged. In most cases, the electron will jump back into the photo-active molecule and neutralize it. So in normal condition, most of the solar energy absorbed by the jumping electrons will be lost. But molecules such as PNA and DNA can act as electric wires, and the PNA will quickly lend an electron to the photo-active molecule. That way, the energy can be used to start the metabolic chain. And here comes the best part: Exactly how fast and how far the PNA conducts electrons depends on its sequence of bases. “Depending on the sequence,” says Rasmussen, “you should be able to encode an efficient or an inefficient metabolism.” Hence the information in the ‘genome’ will directly affect the functionality of the organism, something unseen in ordinary cells.
Rasmussen and his colleagues have demonstrated that the artificial metabolism works even without PNA, though it is too slow to be useful. And they have yet to demonstrate that they can use PNA to boost it.
But the main hurdle, Rasmussen says, will be to make the PNA copy itself, so that when the protocell grows and divides, each daughter cell will have its own PNA.
Like DNA, PNA comes in double strands: The sequence in one strand is complemented by the sequence in the other, pairing bases A with T and C with G. In DNA replication, the two strands separate and each acts as a template for its new complement. In real cells, the process is aided by a plethora of enzymes and nanomachines that cut, paste and debug the results. The PNA will reproduce in a similar but drastically simplified way. The two strands must spontaneously separate, and stay apart for long enough that they can template their new complement strands. And once new As are paired with old Ts, etc., the new bases will have to form a stable chain.
“The replication process will be very error-prone,” says Rasmussen, “because we don’t have any repair system.” On the other hand, lots of errors will mean lots of genetic diversity— and if a particular mutation turns out to make life easier, the species will evolve. Natural selection will apply to artificial creatures, and will favor those with a more efficient metabolism. “You can have two different protocells, with different genetics,” says Rasmussen, “and at the end of the day, the one with lousy electron relay chain won’t be able to reproduce, whereas the one with the right sequence will proliferate.”
Biophysicist David Deamer of the University of California, Santa Cruz, a pioneer of the approach to synthesize life using RNA, sees Rasmussen’s project as a long shot, because no one knows if PNA is able to reproduce. “We don’t know for a fact if it’s going to work or not, whereas we do know that RNA can replicate itself,” he says. The hardest part, he says, will be to get the new strands to form chains.
If the protocells actually work, they will be very unusual sorts of bugs. Although they will be made of the same carbon-based building blocks that make life as we know it – such as lipids and amino acids – the protocells will contain no water and no proteins – and thus will not need the complex machinery for making, repairing, transporting and storing proteins.
Thanks to its propensity for swallowing water-fearing molecules the micelle will be the key to the protocell’s simplicity. “Most people have a concept of a container which is very similar to a modern cell, where you have a membrane with a water-filled inside where you put all the good stuff,” says Rasmussen. If you want to use a membrane filled with water, Rasmussen says, “you buy yourself a lot of problems, because you need to figure out how to transport materials in and out of these membranes.” Modern cells, he points out, have complex protein structures in their membranes, to pump nutrients in and waste out.
At 5 to 20 nanometers in diameter, protocells will also be hundreds of times smaller than any bacteria. In terms of weight, Rasmussen says, they will be “millions of times smaller than the lousiest organism we know today”
Rasmussen loves to brainstorm on the potential applications, although he confesses that he has no idea yet how protocells will be engineered to perform different tasks. “It will take a lot of ingenuity to take it to the next step, and design organisms with specific tasks,” he says.
In an ideal future, he says, protocells could help reduce global warming by absorbing the excess CO2, and could help take out pollutants from the environment. “You could design systems that feed on the materials you want to clean up,” he says.
Of course, that is also the promise of genetically engineered bacteria. But design of life forms from scratch could give more flexibility, and probably also a safer alternative to genetic engineering, Rasmussen says. One of the problems with engineering existing bugs to do such tasks is that, in billions of years of evolution, they have learned to adapt to the environment in unpredictable ways. “Whenever they find something else that they like better and is easier to use than the poison you want them to eat, they will do it. It’s very difficult to keep them on task.” He adds, “Also due to the different chemistry of protocells it should be easier to prevent protocell genes from spreading to other organism, which is a growing concern with genetically engineered crops today.”
Protocells, Rasmussen says, could also one day make excellent nano-scale workers, assembling, testing and repairing computer chips and nano-scale machines.
But couldn’t these creatures get out of control, and evolve into environmental calamities? It’s possible, Rasmussen says, but very unlikely. The artificial organisms will probably be designed to operate in very specific environments, such as processing plants, and will be at a loss if they have to compete in an environment populated by ordinary bacteria. “These systems will be extremely fragile,” he says. “A ferocious microscopic predator that has been around for billions of years will gobble up such a high-energy, free lunch.”
Artificial organisms can be a revolutionary, benign technology, Rasmussen says. “Unless, of course,” he adds, “you design them to be bad.” Note: This was the “short feature” I wrote for the feature writing class I took in the winter 2004, as part of the UCSC Science Communication program. In 2005, the story was covered by several magazines, most notably Popular Science and New Scientist.
For additional reading, see:
“Bridging Nonliving and Living Matter,” by Steen Rasmussen, Liaohai Chen, Martin Nilsson and Shigeaki Abe, in Artificial Life, Vol. 9, Issue 3 – Summer 2003 pp. 269 – 316;
“Transitions from Nonliving to Living Matter,” by Steen Rasmussen et al., in Science, Vol 303, Issue 5660, 963-965 , 13 February 2004.