Large-Scale Multiplex Genome Engineering

c-net |  You've heard of startups building computer chips, delivery drones and video chat apps. One called Colossal has a different goal: bring the woolly mammoth back from extinction by 2027 using CRISPR, a revolutionary gene-editing technology.

The plan isn't to re-create true woolly mammoths, but rather to bring their cold-adapted genetic traits, which include small ears and more body fat, to their elephant cousins, creating a hybrid that can wander the tundra where mammoths haven't been seen for 10,000 years. Colossal's co-founders are Chief Executive Ben Lamm, who started five companies before this, and George Church, a Harvard Medical School professor with deep CRISPR expertise. 

"Our true North Star is a successful restoration of the woolly mammoth, but also its successful rewilding into interbreeding herds in the Arctic," Lamm said. "We're now focusing on having our first calves in the next four to six years."

It's an interesting illustration of an imperative sweeping the tech world: Don't just make money, help the planet, too. Tesla's mission is to electrify transport to get rid of fossil fuels that hurt Earth. Bolt Threads wants to replace leather with a fungal fiber-based equivalent that's easier on the environment than animal agriculture. Colossal hopes its work will draw attention to biodiversity problems and ultimately help fix them.

Colossal has raised $15 million so far, led by investment firm Tulco. The startup's 19 employees work at its Dallas headquarters and in offices in Boston and Austin, Texas, and it's using its funds to hire more.

Artificial wombs and other technology spinoffs

Church said he expects spinoffs from the company's biotechnology and genetics work.

"The pipeline of large scale genome engineering techniques can be applied to many other applications beyond de-extinction, and therefore [are] most promising for commercialization," he said.

One technology ripe for commercialization is multiplex genome engineering, a technique Church helped develop that speeds genetic editing by making multiple changes to DNA at once.

Colossal also hopes to develop artificial wombs to grow its mammoth embryos. Just growing 10 woolly mammoths with surrogate elephant mothers isn't enough to get to the large-scale herds the company envisions.

At the foundation of Colossal's work is CRISPR. This technology, adapted from a method bacteria evolved to identify attacking viruses and chop up their DNA, is now a mainstay of genetic engineering, and Church has been involved since CRISPR's earliest days.

There are other ways Colossal hopes to help. Its gene editing technology could artificially add genetic diversity to species with only small surviving populations, Lamm said.

Next Up Pissants - CRISPR crRNA Therapeutic "Vaccinations"

nature |  The recent dramatic appearance of variants of concern of SARS-coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape from host immunity and antiviral therapeutics. Here, we employ genome-wide computational prediction and single-nucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved >98% silencing efficiency in virus-free models. Further, optimized and multiplexed Cas13b CRISPR RNAs (crRNAs) suppress viral replication in mammalian cells infected with replication-competent SARS-CoV-2, including the recently emerging dominant variant of concern B.1.1.7. The comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches does not impair the capacity of a potent single crRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 strains in infected mammalian cells, including the Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint for antiviral drug development to suppress and prevent a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.

The remarkable capability of RNA viruses to adapt to selective host and environmental pressure is highly dependent on their ability to generate genomic diversity through the occurrence of de novo mutations⁴⁶. Mutation-driven viral evolution can generate drug resistance, immune escape, and increased efficiency of transmission and pathogenicity, all of which are detrimental to the host. Although our understanding of SARS-CoV-2 mutation-driven escape mechanisms remains limited, the emergence of new variants, which possess increased infective potential⁸ or are resistant to recombinant monoclonal antibodies and antibodies in the sera of convalescent patients and vaccinated individuals^7,8,17,18,36 are of major global concern. In this study, we leveraged an innovative CRISPR-pspCas13b technology and employed two key strategies to silence SARS-CoV-2 RNA and counteract its intrinsic ability to escape standard therapies through the generation of de novo mutations.