Race to Design Life Heats Up

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Synthetic biologist Craig Venter, whose team embarked on its quest to whittle life down to its bare essentials two decades ago.

BIOTECHNOLOGY Race to design life heats up Craig Venter’s minimal-cell triumph comes as the CRISPR gene-editing method provides alternative ways to tinker with life’s building blocks.

BY EWEN CALLAWAY industrial products, says that the feat heralds an existing bacterial genome and transplanted the creation of customized cells to make drugs, it into another cell, the genome of the minimal enomics entrepreneur Craig Venter has fuels and other products. But an explosion in cells is like nothing in nature. Venter says that created a synthetic cell that contains the powerful ‘gene-editing’ techniques, which ena- the cell, which is described in a paper released smallest genome of any known, inde- ble relatively easy and selective tinkering with on 24 March in Science2, constitutes a brand- Gpendent organism. Functioning with 473 genes, genomes, raises a niggling question: why go to new, artificial species. the cell is a milestone in his team’s 20-year quest the trouble of making new life forms when you “The idea of building whole genomes is one to reduce life to its bare essentials and, by exten- can simply tweak it? of the dreams and promises of synthetic biol- sion, to design life from scratch. Unlike the first synthetic cells made in 2010 ogy,” says Paul Freemont, a synthetic biolo- Venter, who has co-founded a company that (ref. 1), in which Venter’s team at the J. Craig gist at Imperial College London who is not seeks to harness synthetic cells for making Venter Institute in La Jolla, California, copied involved in the work.

The design and synthesis of genomes Switzerland. “You can add in genes and see from scratch remains a niche pursuit, and is what happens.” technically demanding. By contrast, the use With nearly all of its nutrients supplied of genome editing is soaring — and its most through growth media, syn3.0’s essential genes famous tool, CRISPR–Cas9, has already gained tend to be those involved in cellular chores traction in industry, agriculture and medicine, such as making proteins, copying DNA and notes George Church, a genome scientist at building cellular membranes. Astoundingly, Harvard Medical School in Boston, Massa however, Venter says that his team could not chusetts, who works with CRISPR. “With identify the function of 149 of the genes in much less effort, CRISPR came around and syn3.0’s genome, many of which are found in suddenly there are 30,000 people practising other life forms, including humans. “We don’t CRISPR, if not more.” know about a third of essential life, and we’re Microbiologists were just starting to char- trying to sort that out now,” he says. THOMAS DEERINCK & MARK ELLISMAN/NCMIR/UCSD acterize the bacterial immune system that This has blown Fussenegger away. “We’ve scientists would eventually co-opt and name sequenced everything on this planet, and we CRISPR when Venter’s team began its effort to still don’t know 149 genes that are most essen- whittle life down to its bare essentials. In a 1995 tial for life!” he says. “This is the coolest thing Science paper, Venter’s team sequenced the Each cell of JCVI-syn3.0 contains just 473 genes. I want to know.” genome of Mycoplasma genitalium, a sexually Syn3.0’s lasting impact on synthetic biol- transmitted microbe with the smallest genome more than 1 million DNA bases was anything ogy is an open question. “I think it’s kind of a of any known free-living organism3, and but minimal. George Mallory moment,” says Church, refer- mapped its 470 genes. By inactivating genes one In an attempt to complete its long-standing ring to the English mountaineer who died in by one and testing to see whether the bacterium goal of designing a minimal genome, Venter’s 1924 trying to become the first person to climb could still function, the group slimmed this list team designed and synthesized a 483,000-base, Mount Everest. “‘Because it’s there’ was the down to 375 genes that seemed essential. 471-gene M. mycoides chromosome from which excuse he gave for climbing Everest.” One way to test this hypothesis is to make it had removed genes responsible for the pro- Church says that genome-editing tech- an organism that contains just those genes. By duction of nutrients that could be provided niques will remain the go-to choice for most contrast Venter, together with his close col- externally, and other genetic ‘flotsam’. But this applications that require a small number of leagues Clyde Hutchison and Hamilton Smith did not produce a viable organism. genetic alterations, whereas genome design and their team, set out to build a minimal So, in a further move, the team developed will be useful for specialized applications, such genome, by joining together chemically synthe- a ‘design-build-and-test’ cycle. It broke the as recoding an entire genome to incorporate sized DNA segments. The effort required the M. mycoides genome into eight DNA segments new amino acids. Fussenegger thinks that development of new technologies, but by 2008, and mixed and matched these to see which genome editing will be the favoured approach they had used this method to make what was combinations produced viable cells; lessons for therapies, but that writing genomes from essentially an exact copy of the M. genitalium learned from each cycle informed which genes scratch will appeal to scientists interested in genome that also included dozens of non- were included in the next design. This process fundamental questions about how genomes functional snippets of DNA ‘watermarks’4. highlighted DNA sequences that do not encode evolve, for instance. But the sluggish growth of natural M. geni- proteins but that are still needed because they Even Venter acknowledges that syn3.0’s talium cells prompted them to switch to the direct the expression of essential genes, as well genome, although new, was designed by more prolific Mycoplasma mycoides. This as pairs of genes that perform the same essential trial and error, rather than being based on a time, they not only synthesized its genome task — when such genes are deleted one at a fundamental understanding of how to build and watermarked it with their names and time, both mistakenly seem to be dispensable. a functioning genome. But he expects fast with famous quotes, but also implanted it into Eventually, the team hit on the 531,000- improvements, and thinks that genome syn- another bacterium that had been emptied of base, 473-gene design that became known as thesis from scratch will become the preferred its own genome. JCVI-syn3.0 (syn2.0 was a less streamlined approach for manipulating life. “If you want to The resulting ‘JCVI-syn1.0’ cells were intermediary). Syn3.0 has a respectable dou- make a few changes, CRISPRs are a great tool,” unveiled1 in 2010 and hailed — hyperboli- bling time of 3 hours, compared with, for he says. “But if you’re really making something cally, many say — as the dawn of synthetic instance, 1 hour for M. mycoides and 18 hours new and you’re trying to design life, CRISPRs life. (The feat prompted US President Barack for M. genitalium. aren’t going to get you there.” ■ Obama to launch a bioethics review, and the “This old Richard Feynman quote, ‘what I Vatican to question Venter’s claim that he had cannot create, I do not understand’, this prin- 1. Gibson, D. G. et al. Science 329, 52–56 (2010). 2. Hutchison, C. A. III et al. Science 351, aad6253 created life.) However, the organism’s genome ciple is now served,” says Martin Fussenegger, (2016). was built by copying an existing plan and not a synthetic biologist at the Swiss Federal 3. Fraser, C. M. et al. Science 270, 397–404 (1995). through design — and its bloated genome of Institute of Technology (ETH) in Zurich, 4. Gibson, D. G. et al. Science 319, 1215–1220 (2008).

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