Bruiseless bananas, vegan cats, pig-to-human transplants, and super-muscular dogs: can you tell the real CRISPR projects from fake ones? It’s getting harder these days, as the latest generation of “gene editing” tools are not only (relatively) quicker, cheaper, and easier than any previous genetic engineering method, but have become “probably the fastest-spreading technology in the history of biology.” As it spreads, researchers the world over are discovering new hacks, complexities, and limitations for CRISPR. Here’s a round-up of recent developments in this booming arena.
Trending globally: gene editing experiments with human embryos
On April 8, news broke that the second paper documenting CRISPR experiments in human embryos had been published. Researchers at Guangzhou Medical University sought to enhance nonviable embryos leftover from IVF with a naturally occurring mutation that confers HIV resistance: CCR5Δ32.
(Image via Wikimedia: Guangzhou Circle)
The experiments were largely unsuccessful: only 4 of 26 embryos wound up with a copy of the desired mutation, and none had the two copies that would be needed to resist the virus. Mosaicism was also a problem. A year prior in April 2015, the first research using CRISPR in tripronuclear human zygotes was reported by a team at Sun Yat-sen University in the obscure journal Protein & Cell, after Nature and Science turned it down. This second paper was reported in “an obscure reproductive journal” published by the American Society of Reproductive Medicine (the same body that releases non-enforceable guidelines into the void of any regulation over assisted reproductive technologies in the United States).
The research team acknowledged the controversial nature of their work amid ongoing debates:
We advocate preventing any application of genome editing on the human germline until after a rigorous and thorough evaluation and discussion are undertaken by the global research and ethics communities.…Despite the significant scientific and ethical issues involved, however, we believe that it is necessary to keep developing and improving the technologies for precise genetic modifications in humans.
Many found the latest CRISPR human embryos experiment to be ethically problematic in design and implication:
“Introducing CCR5Δ32 and trying repair, even in non-viable embryos, is just playing with human embryos.” – Tetsuya Ishii, bioethicist at Hokkaido University in Sapporo, Japan, Nature News
“The paper does not in my opinion strengthen the case that CRISPR’ing of human embryos with reproductive intent is ever something that could work well enough to be done clinically.” – Paul Knoepfler, associate professor of Cell Biology and Humanity at UC Davis School of Medicine, The Niche
“If you were serious about not wanting to go down this path where wealthy people are having children who have been genetically modified to have capacities that aren’t available to the children of poor parents, then the time to try and stop it is now.” – Robert Sparrow, associate professor at the Monash University Centre for Human Bioethics in Melbourne, South China Morning Post
A number of scientists commenting on the new publication distinguished its clear objective of refining human germline engineering for reproduction from the basic research goals of other ongoing CRISPR embryo experiments, including the HFEA’s February 2016 approval for Kathy Niakan’s embryo development research at the Francis Crick Institute in London. George Daley, stem-cell biologist at Children’s Hospital Boston in Massachusetts, categorized the new CRISPR embryo research as a “proof of principle for what would need to be done to generate an individual with resistance to HIV,” meaning “the science is going forward before there’s been the general consensus after deliberation that such an approach is medically warranted.”
“At least in the scientific community, I sense more support for basic-research applications," argued Fredrik Lanner, assistant professor at the Karolinska Institute near Stockholm, who was approved in June 2015 to use CRISPR in embryos to study early human development. In addition to UK and Sweden, a government bioethics panel in Japan on April 22 approved basic research using CRISPR in embryos, but denounced moving forward with clinical germline research.
New tools and research for hacking the CRISPR patent war
Even as CRISPR investments, biomaterials, and research licenses proliferate internationally, the ongoing patent fight between prominent American universities has had a major impact on the landscape. Jacob Sherkow, associate professor of law at New York Law School, argues in Nature that “pursuit of profit poisons collaboration” and the “CRISPR-Cas9 patent battle demonstrates how overzealous efforts to commercialize technology can damage science” by pitting schools against one another and “erod[ing] scientific collaboration.”
Shobita Parthasarathy, associate professor of Public Policy and Women's Studies at University of Michigan, puts forth two important lessons. First, she argues that “patent systems no longer fit the realities of how science works, and patents give their owners significant control over the fate and shape of technologies.” She also notes that licensing decisions by CRISPR patent holders may subjugate democratic deliberation over “what kinds of research will take place in embryos … [and] what kinds of human genetic engineering might become commercially available.”
Meanwhile, researchers are publishing tweaks and upgrades to CRISPR-Cas9 on a near-weekly basis, causing observers to wonder if the patent fight will soon become a moot point—a “historical footnote.”
Recent CRISPR breakthroughs, setbacks, and related research include:
Gene Editing à “Base Editing”
On April 20, researchers reported they had engineered CRISPR to perform edits not just to a genetic sequence but to individual letters of DNA, changing “C” to “U” (“U” is usually found in RNA and is read as “T” in DNA).
(Image via Pixabay)
The lead author of the new "base editing" research, Harvard biochemist David Liu, is a co-founder and scientific advisor at Editas Medicine, the first CRISPR company to go public. Excitement surrounding the new hack led many to speak freely about the limitations of CRISPR, including Harvard biologist George Church who observed “what often passes as ‘genome editing’ would more appropriately be called ‘genome vandalism’” because, as STAT’s Sharon Begley writes, the “molecular machete” triggers the “cell’s DNA-repair machinery to make all sorts of unwanted changes.” While this new base editor method is being described as “pinpoint precision” and the “most clever CRISPR gadget” thus far, it’s unclear to many researchers what its usefulness or application will be moving forward.
“Attempts to wipe out HIV with the CRISPR gene editor only made it stronger” [Source]
A number of researchers have been excited about the potential of CRISPR to deliver a long-sought cure for HIV—in living patients. Using an older gene editing method known as Zinc Finger Nucleases to snip out the CCR5 gene linked to HIV resistance, Sangamo Biosciences (Richmond, CA) is one of a group of biotech companies investigating HIV somatic gene therapies. On April 7, researchers working with CRISPR published some sobering data which showed that using gene editing to disable the HIV virus backfired, as the virus developed mutations near the sites of cuts which blocked RNA-guided CRISPR from making more cuts needed to disable the virus. A number of researchers still have hope for CRISPR providing a one-and-done fix. Some aim to use CRISPR to “carpet-bomb HIV” at multiple sites at once. Others are skeptical about the practicality of CRISPR-ing HIV, given the virus’ renowned resistance, the number of T cells that need to be successfully modified, and the existence of pre-exposure and post-exposure antiretroviral drugs that are being used to manage the disease with increasing success.
A week later on April 27, researchers laboring under the weight of compelling acronyms reported a new CRISPR method dubbed “CORRECT” (COnsecutive Re-guide or Re-Cas steps to Erase CRISPR/Cas-blocked Targets). Given the messiness of the CRISPR-Cas9 system, the research seeks to enable two new capabilities: stopping Cas9 from cutting again and again, and editing one but not both copies of a target gene. Scientists reacting to the news noted with caution that the CORRECT hack requires inserting three to twenty times the number of molecules into cells as does traditional CRISPR. (Others have previously noted delivery challenges with CRISPR due to the comparatively large size of the Cas9 protein.)
CRISPR-ing DNA and RNA
In a new profile, Nature News describes CRISPR co-discoverer Emmanuelle Charpentier as a “quiet revolutionary” who is looking “not to be defined by CRISPR, which is just one of five themes in her lab.” Charpentier’s latest CRISPR research suggests that an associated protein smaller than Cas9 known as “Cp1f1” can cleave RNA in addition to DNA, and “can do the jobs of both tracrRNA and the Cas9 protein.” The CRISPR-Cp1f1 method was first reported by Charpentier’s patent adversary Feng Zhang in September 2015.
Buffer “Superhero” Genes
Headlines recently proclaimed:
The story was that researchers had worked through almost 600,000 human DNA sequences—the majority from 23andMe users—and found 13 profiles whose medical records showed a lack of symptoms despite the fact they carried a genetic mutation linked to one of eight Mendelian diseases. The researchers have no way of contacting the individuals to confirm their “superhero” status, but the study has excited some researchers about the potential gold to be found at the end of the precision medicine rainbow: a deus ex machina buffer gene to fight monogenic disease. As several observers noted, these “lucky 13” could also lead to dashed hopes at the human margins of sequencing errors.
The genetic unicorns study conjures a handful of philosophical questions relevant to the future of gene editing: What are the biological mysteries that determine phenotype beyond genetics? What are the implications of widespread embryo screening for genetic conditions when false positives are rampant and embryo mosaicism is poorly understood? What unknown unknowns in the realm of genetic mysteries might forestall the precise genetic modification of future human beings? What known social and political realities caution against gene editing future generations regardless of technical safety?
Resisting genetic determinism, embracing scientific modesty & democratic futures
Creative and potentially exciting, recent CRISPR and related research papers speak to the vast ocean of biological uncertainties that face those venturing into the genome with the intention of divining the cut-and-paste malleability of the human condition. On the eve of a major annual meeting on gene therapy in D.C. on May 4-7, Jocelyn Kaiser writing for Science culled a long list of additional obstacles for researchers to overcome in an article titled “The gene editor CRISPR won’t fully fix sick people anytime soon. Here’s why.”
What harm can a bit of enthusiasm do? For starters, unchecked techno-optimism frustrates the scientific enterprise. It also thwarts the funding of basic public health measures whose impact would be felt more broadly, beyond the upper echelons of biomedical access.
Several recent articles have explored these and related concerns. Columbia law professor Patricia Williams cautions against “a rat race to the patent office, a lunge to own all parts of the genome… A race against time. A race to market. A race to better babies.” As piecemeal gene editing innovations move forward, their value may be difficult to discern over the blaring refrains of the industry hype machine.
Jonathan Latham recently pointed to the “gospel of precision” floating the sails of the CRISPR moonshot and argued for historically minded caution:
The hubris is alarming; but the more subtle element of the propaganda campaign is the biggest and most dangerous improbability of them all: that CRISPR and related technologies are “genome editing”…That is, they are capable of creating precise, accurate and specific alterations to DNA …
Why is this discussion of precision important? Because for the last seventy years all chemical and biological technologies, from genetic engineering to pesticides, have been built on a myth of precision and specificity. They have all been adopted under the pretense that they would function without side effects or unexpected complications. Yet the extraordinary disasters and repercussions of DDT, leaded paint, agent orange, atrazine, C8, asbestos, chlordane, PCBs, and so on, when all is said and done, have been stories of the steady unraveling of a founding myth of precision and specificity.…
[W]e are once again being preached the gospel of precision. But no matter how you look at it, precision is a fable and should be treated as such.
As with many “disruptive” technologies in biotechnology, CRISPR pipedreams are rapidly assembled, dismantled, reassembled; moonshots are breathlessly announced, then fail to rise, then quietly recalibrate. A world cleansed of genetic disease is repeatedly cast as the carrot to be dangled before an American public starved for more basic health investments. Will the CRISPR revolution bring vegan cats? Who decides what the future of (synthetic) biology looks like?
Previously on Biopolitical Times:
Image via Pixabay
Posted in Assisted Reproduction, Biopolitics, Parties & Pundits, Biotech & Pharma, Elliot Hosman's Blog Posts, Eugenics, Global Governance, Inheritable Genetic Modification, Media Coverage, Medical Gene Transfer, Patents & Other IP, Personal genomics, Sequencing & Genomics, Synthetic Biology, US Federal
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