Massive Genome Editing Could Lead to Human Immunity to All Viruses

Base editing with reduced DNA nicking allows for the simultaneous editing of over 10,000 loci (13,000) in human cells.

Performing this feat in the human genome will require the modification of 4438 Amber codons. They have shown that gene editors that do not cause double- or single-strand DNA breaks can generate a number of edits sufficient to theoretically achieve this genome recoding and pave the way towards making pan-virus resistant human cells. This could have commercial application towards cell-based production of monoclonal antibodies, recombinant protein therapeutics, and synthetic meat production.

Researchers have overcome the toxicity limitation that prevented large-scale genome editing in human iPSCs and expanded the editing boundary by three orders of magnitude. The continued development of multiplex delivery along with non-toxic, high-efficiency DNA editors without DSBs or SSBs is paramount to the success of genome-wide recoding efforts to probe the inner workings of life, ultimately leading to the radical redesign of nature and ourselves.

More in-depth studies will be necessary, however, to assess the impact of this massive editing on normal cell processes, since collateral damage may occur. We expect the thorough on-and off-target analysis at repetitive elements to remain a difficult task to accomplish due to their high level of polymorphism; therefore, strong biological controls as well as new experimental and bioinformatics pipelines will be needed to overcome such a challenge.

Researchers developed a set of dead-Cas9 base editor (dBEs) variants that allow editing at tens of thousands of loci per cell by overcoming the cell death associated with DNA double-strand breaks (DSBs) and single-strand breaks (SSBs). We used a set of gRNAs targeting repetitive elements – ranging in target copy number from about 31 to 124,000 per cell. dBEs enabled survival after large-scale base editing, allowing targeted mutations at up to ~13,200 and ~2610 loci in 293T and human induced pluripotent stem cells (hiPSCs), respectively, three orders of magnitude greater than previously recorded. These dBEs can overcome current on-target mutation and toxicity barriers that prevent cell survival after large-scale genome engineering.

Improving the actual multiplexed eukaryotic genome editing capabilities by several orders of magnitude holds the potential of revolutionizing human healthcare. Combinatorial functional genomic assays would enable the study of complex genetic traits with applications in evolutionary biology, population genetics, and human disease pathology. Multiplex editing has also permitted the development of successfully engineered cell treatments, such as the chimeric antigen receptor (CAR) therapies, which require the simultaneous editing of three target genes. Future treatments may require many more modifications to augment cancer immunotherapies, slow down oncogenic growth, and reduce adverse effects, such as host-versus-graft disease. Furthermore, customizing host-versus-graft antigens in human- or nonhuman-donor tissues may require more modifications than have been made so far, for which the development of genome-wide editing technologies is needed. Special attention should be paid to the safety of the editing and its impact on the functional activity of the transplants, since donor tissues may persist in the patients for decades.

To complete genome-wide recoding and enable projects such as GP-write ultra-safe cells or the de-extinction efforts to regain lost biodiversity, safe DNA editors must be developed to increase the number of genetic modifications possible by several orders of magnitude without triggering overwhelming DNA damage, as well as overcoming the delivery of multiple distinct gRNAs per cell, the latter of which we do not address is this study.

Biorxiv – Enabling Large-scale Genome editing by reducing DNA Nicking

22 thoughts on “Massive Genome Editing Could Lead to Human Immunity to All Viruses”

  1. How do you define wise? From a strictly logical standpoint, the most intelligent thing may be to destroy all possible competition, including other groups. If this isn’t wise — and I agree that it is not — you will need to explain why.

  2. Why can’t you people see the difference between a Homo erectus man and us is less than the difference between us and a intelligence enhanced us. Had you rather be that Homo erectus man? Dying at 40 years? Being prey to about anything with big teeth? Cold and hungary most the time.
    I suppose if you were a Homo erectus and could talk you would say “I don’t want to be one of those greedy humans.”

    And as a side note, is GREED a politically incorrect thing to admit to. Is all greed bad including the greed that drives a man forward to achieve the seemingly impossible?

  3. Nope, what effect will greed do to us when we can have anything and everything we desire? You’re thinking about the problems now, not what it might be in the future.

  4. de-extinction efforts to regain lost biodiversity

    I assume this means recreating T-rexes and releasing them into the wild.

    As it should.

  5. Bullshit, with enhanced intelligence of even 4 fold you have no idea of even your own motives or thoughts. Intelligence seems to go hand in hand with wisdom. I know what you will immediately say but the differences in the human race of intelligence is very small. Even the difference between Einstein a a normal person is very small.
    A virus has less wisdom than a ant. A ant has less wisdom than a dog. A dog less than a monkey. A monkey less than man. No one can say with certainty but a four fold increase in intelligence perhaps will lead to a much wiser human race.

  6. Fair point, greedy people have no use for <checks notes> intelligent scientists, engineers, doctors, etc.

  7. There are currently way more viruses in the human body than cells. Clearly some have a beneficial impact.

  8. This is the near future. But the greatest advancement for the human race is not the enhanced immune system or even our immortality that this technology will achieve, but rather the enhanced intelligence it could bestow on the whole human race. With enhanced intelligence and this technology at our disposal we will see really great and quick enhancements to make us ALMOST seem like Gods.

  9. You say that as if it would be difficult for the same hacker to bypass our own natural immune system as well.

  10. There will likely be so many paths chosen by various entities (and with considerable constant crossover) that defining them all may be somewhat problematical other than by basic attributes.
     
    Attributes of an entity include body, brain, and mind. Some entities are partially defined by only having one or two of these. For each of these attributes, there are a number of possibilities.
     
    Body: Organic, GMO, inorganic, virtual, or some combination of these. NOTE: For some offshoots, such as hive minds, body can be bodies (plural).
     
    Brain: Organic, GMO, inorganic, or some combination of these, with the caveat that brains can be in the body or at a remote location. Inorganic brains can also use dedicated hardware, or have no fixed hardware location (i.e. they are in the cloud). Any of these can be further augmented in a variety of ways, although this can change their designation.
     
    Minds: Organic human, GMO, synthetic, and lifted animal, but this only refers to initial origin. Any of these can be further augmented by changes to the brain and, in some cases, by training, education, and conditioning.
     
    Additionally, some entities will accept some technologies, while refusing others, likely resulting in human fundamentalists at one extreme, and emerging gods at the other.
     
    It doesn’t look like we will ever encounter real aliens, but that hardly matters, our descendants will most likely become them.

  11. Recoding the genome to render us immune to *existing* viruses would be great if we can pull it off. Using that as an excuse to ditch our immune system’s other means of dealing with viruses? That wouldn’t be so smart, because it wouldn’t be that hard for some hacker to recode a virus in the same way, to bypass the defense.

  12. We are becoming the aliens in “war of the worlds” that die because they are from a world without viruses…

  13. “Genome-wide recoding”; A bit more detail here would have been appreciated. What are we talking about, altering some fundamental aspect of the genetic code so that viral genes would either produce non-functional proteins or fail to transcribe at all?

    It’s an old idea, and it’s not incidental that this would produce a new species by the usual “can they produce fertile offspring?” criteria. Still, it’s been obvious for decades that you could produce complete viral immunity by this approach.

  14. Making monoclonal antibodies in virus resistant cells is soon going to be a redundant technology. Chemically synthesised alternatives to antibodies such as aptamers or bicyclic peptides will be much cheaper to manufacture and iterate on.

    better cellular manufacturing could be used for the manufacture of highly specific proteases, now that highly specific proteases can be designed via directed evolution using the PrECISE method in yeast.

    These could have very important implications in areas like Alzheimer’s disease as they can degrade toxic protein amyloids both extra cellularly (amyloid beta) and within the cellular cytoplasm (tau).

    This is one of the approaches to removing tau that the Anderson lab at the Buck Institute is taking with funding provided by the SENS Research Foundation:

    https://www.fightaging.org/archives/2017/02/sens-research-foundation-and-buck-institute-to-collaborate-on-a-new-approach-to-clearing-neurofibrillary-tangles/

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