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Synthetic life forms mimic critical evolutionary events, in Scripps Research studies

Scientists at Scripps Research have published two studies of synthetic life, with a common goal of helping to explain two of the biggest mysteries in the evolution of the earliest forms of life.

One concerns how bacteria merged into other cells to become mitochondria, the power plants of cells with a nucleus, including all plants and animals. That study produced a symbiotic organism from yeast and the bacterium E. coli.

The second explores how life evolved to use DNA as the carrier of heredity, from a presumed earlier stage in which heredity was carried out by RNA. That study yielded a form of E. coli with roughly half its genetic code carried in RNA, half in DNA.

The studies constructed life forms mimicking these hypothetical earlier stages of life and observed how they operated, said Peter G. Schultz, lead author of the two studies and head of Scripps Research.

These two synthetic life forms are purely research projects, Schultz said.

The ability to create symbionts could potentially become of commercial interest, he said. But that's not the point of these two studies.

"It's science for science's sake."

Introducing strangers

The study on the origin of mitochondria was published Monday. It tackled the question of how invading bacteria could adapt to live symbiotically in cells with a nucleus, called eukaryotic cells. Mitochondrial DNA resembles that found in certain bacteria, presumably related to the ancestors of mitochondria.

In eukaryotes, the nucleus stores and replicates genetic information, and the mitochondria supply energy. The last is true of chloroplasts, organelles in plants that perform photosynthesis. These presumably descended from free-living photosynthetic bacteria.

Schultz and colleagues genetically engineered to strain of baker's yeast with defective mitochondria. They also engineered a form of bacterium E. coli that needs the nutrient thiamin, supplied by the yeast.

The bacterium was also engineered to provide energy to the yeast, and to resist being destroyed by the yeast as a pathogen. (Presumably, such defenses of modern yeast would not have existed in ancient ancestors).

"We started with E. coli and yeast because they are genetically tractable organisms- easy to manipulate in the lab," Schultz said.

Then they introduced the two, and watched.

Some of the synthetic organisms survived and produced daughter cells. This took place for more than 40 generations, with no sign of it ending, Schultz said. Moreover, the modified E. coli bacterium even began accumulating mutations that allowed them to survive better inside the yeast.

The scientists took the work further by removing bacterial genes for making other nutrients supplied by the yeast, and found that they could still get a successful symbiosis. They have so far successfully removed 10 genes.

The Schultz team wants to further reduce symbiotic E. coli genomes. The bacterium has thousands of genes, while mitochondrial genomes have just 37 genes.

They are also at work on recapitulating the origin of chloroplasts. The closest equivalent to chloroplasts today are cyanobacteria, also called blue-green algae. These have been likewise engineered to depend on yeast, and the yeast to get energy from the cyanobacteria.

Results from that research should be ready in a few months, Schultz said.

Going back to RNA

E. coli was also used in a study published earlier where it was shown that much of its genome could be replaced by RNA and still survive. That study was published Aug. 30 in the Journal of the American Chemical Society, or JACS.

The scientists were able to engineer a derivative of E. coli with half of its genetic code carried in RNA, the rest in DNA.

This outcome was a surprise. The study's original goal was to produce DNA with different "letters" than the four letters used in nature, A, C, G and T.

But after randomly mutating their engineered strains and seeing the unexpected appearance of genomic RNA, the scientists saw a potential connection to the origin of life in RNA. A widely accepted hypothesis about the origin of life holds that RNA came before DNA, the so-called "RNA world" hypothesis.

"So how do you go from an RNA-based world to a living organism where the DNA carries the genetic information?" Schultz said.

In steps, presumably. That means that a hybrid life form has existed, carrying its genetic instructions partly in DNA and partly in RNA. And that bore a strong resemblance to what the scientists had produced by accident.

"That was shocking," Schultz said. "It was shocking because nobody had ever seen this before."

The first thought was that the RNA detected was a contaminant. Multiple experiments ruled that out. Then the scientists explored the function of this hybrid molecule.

"We still do not understand, remove frankly, exactly how it works," Schultz said.

Proteins from this hybrid DNA / RNA genome also mutated at a higher rate than organisms with pure DNA, the study found. That suggests that in the earliest stages of life, the mutation rate was also high, causing extensive changes to the cellular machinery, Schultz said.

The goal now is to make deliberate changes to the bacterium, and see if the results can be predicted.

"If we can now rationally design a similar organism from scratch, then we can begin to understand it better," Schultz said.

The symbiotic yeast / bacterium study was a collaboration between Scripps Research, the University of California, San Francisco, Oak Crest Institute of Science, and the Genomics Institute of the Novartis Research Foundation. It was funded by the Calibr arm of Scripps Research; the Department of Energy; the National Institutes of Health; and the Chan Zuckerberg Initiative Human Cell Atlas program.

The hybrid DNA / RNA study was a collaboration between Scripps Research, Bay Area Innovation Center and the University of California, Irvine. It was funded by Calibr.


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