From Science Fiction to Science Fact: Genetic Engineering
The Island of Doctor Moreau is a classic 1896 novel by one of the father’s of science fiction H. G. Wells. The text of the novel is the narration of Edward Prendick, a shipwrecked man rescued by a passing boat who is left on the island home of Doctor Moreau, a mad scientist who creates human-like hybrid beings from animals via vivisection. The novel deals with a number of philosophical themes, including pain and cruelty, moral responsibility, human identity, and human interference with nature.
I wonder what Herbet would have said about: CRISPR/Cas-9? A Noble prize worthy technology I have been personally following since early 2015, just around the time the spat first started between the Zhang and the Doudna Labs, an East Coast vs. West Coast beef that still rages on.
Clustered Regularly Interspaced Short Palindromic Repeats — CRISPR (pronounced crisper) are segments of prokaryotic DNA containing short repetitions of base sequences. Each repetition is followed by short segments of “spacer DNA” from previous exposures to a bacteriophage virus or plasmid. The CRISPR interference technique has many potential applications, including altering the germline of humans, animals, and food crops. The CRISPR sequence was first discovered in 1987, but its function would not be discovered until 2012.
Science Fact: Cutting and pasting DNA using CRISPR scissors since 2016
Genetic Engineering Before CIRSPR
Before CRISPR was heralded as the gene editing method, two other (old school) gene-editing techniques dominated the field: Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs).
Like CRISPR, these tools can each cut DNA like the proverbial scissors. Though they are generally more difficult to make and use, these tools do offer their own advantages:
- ZFNs have an easier delivery process to the targeted gene of choice.
- TALENs appear to have a higher precision rate than CRISPR and may cause less “off-target mutations” (i.e. unintended consequences) as a result of gene editing.
Each also has vital therapeutic applications.
Biotech company Cellectis uses the TALEN gene editing technology to make CAR-T therapies for leukemia, while Sangamo BioSciences makes ZFNs that can disable a gene known to be key in HIV infection. Notably, each of these companies hold key IP rights to these specific gene-editing methods, which could make it difficult for other biotech companies to use these tools.
Meanwhile, CRISPR has certainly stolen the spotlight as of late, due to its efficiency, flexibility, and cheap price tag. It’s plausible that CRISPR could face similar IP issues —as already mentioned above — but with such vast applications for this system, research on multiple fronts seems to be moving forward fast.
Early on, the use of CRISPR for genome editing won approval for a revolutionary trial to fight cancer in humans where scientist from the University of Pennsylvania edited the immune systems of 18 patients to target cancer cells more effectively. The experiment won approval from the Recombinant DNA Advisory Committee (RAC), a US federal ethics panel set up at the National Institutes of Health to review controversial experiments that change the human genome (even though China has been way faster at adopting CRISPR editing in humans).
More recently, CRISPR RNA-guided surveillance complexes have been used to target foreign DNA for degradation through RNA–DNA base-pairing and recognition of a unique sequence adjacent to the target DNA called the protospacer adjacent motif (PAM). Addressing how the DNA is unwound during this binding event, and how short 20–30 base-pair target sequences are efficiently located and recognized within entire genomes, has been a recent focus of the Doudna lab’s research. In collaboration with Eric Greene’s laboratory at (my alma mater) Columbia University, these modern day Moreaus have applied a combination of single-molecule and bulk biochemical experiments to resolve the mechanism of DNA interrogation for two phylogenetically unrelated complexes: Cas9, the DNA-targeting protein found in Type II CRISPR–Cas systems (S. pyogenes), and Cascade, the DNA-targeting complex found in Type I-E CRISPR–Cas systems (E. coli). Their results have revealed that the target search is PAM-guided, and that these distinct RNA-guided complexes have converged on a common mechanism for target DNA recognition. Amazing!
From Tactical to Practical
On the private industry side, publically traded CRISPR Therapeutics has also been ramping up the deals and late last year announced a tie-up with both Vertex and Bayer creating various join ventures to discover, develop and commercialize new breakthrough therapeutics to cure blood disorders, blindness, and congenital heart disease using CRISPR-Cas9 gene-editing technology.
In addition to the Ctrl+X and Ctrl+V functionality typically associated with CRIPR, just last week a small company called Mammoth Biosciences decided to explore the Ctrl+F potential of CRISPR, aiming to create a Google type search for rapid disease diagnosis.
Have we finally arrived on the Island? Has science fiction finally become science fact?