Find and Replace: Genetic Engineering in Science and Medicine

Shakespeare’s Hamlet proclaimed, “What a piece of work is a man,” but now, almost half a millennium later, this could be amended to what a set of sequences is man. The nobility, reason, infinite faculty and admirable form can be attributed to the 20,000 or so genes that contain the chemical code for specific protein formation; and the “angel” can be sullied by a missing or garbled DNA sequence rendering the body unable to make a critical molecule or causing synthesis of an abnormal form. Medicine recognizes about 6,000 diseases attributable to this problem. Is it any wonder that “genetic engineering” has been a holy grail sought by scientists since the first tools were developed in the 1970’s that made genomic therapy plausible?

The initial crude attempts using viral vectors to insert lacking genetic material has been supplanted by the identification of the CRISPR-Cas9 system. Clustered, regularly interspaced, short palindromic repeats (CRISPR) can be used by bacteria to make little bits of RNA, which complexed will bind to a complimentary DNA sequence. The protein Cas9, sort of a molecular scissors, recognizes the structure made by the CRISPR-RNA-DNA binding and responds by cutting the DNA precisely at that point. Add a replacement, normal DNA to this brew with DNA repair enzyme and you have a genetic engineering tool that resembles the find and replace function on a word processor. Moreover, the technique for the educated is not proprietary, but relatively simple, transferable and affordable.

 The initial implications are enormous. CRPSPR can be used to introduce or remove a number of genes at a time. Most genetic disorders are not caused by a single mutation, but diabetes, atherosclerosis and autism are all multi-genetic and thus now possibly amenable to gene therapy.  Also, previous genetic engineering technologies have tended to be species specific, working for yeast and E Coli, but not applicable for plants, animals or humans-- this is not true for CRPSPR. Moreover, this technique is affecting stem cell therapies as it allows editing of stem cell genomes before differentiation into specific a cell type, such as neurons or cardiomyocytes.

But now comes the most impressive, and the most worrying, application. Scientists now have the theoretical ability to edit the genome of gametes and a newly created embryo. If done effectively and safely, this would provide the ability to once and for all modify the genes of every subsequent adult cell in the body and ensure that this modified genome would be found in the adult sperm and ova and passed down to all future generations. Human cloning is no longer science fiction. Germ-line modification is now an ethical and moral issue, one that Frances Collins, Head of the NIH, says almost universally a line that should not be crossed for clinical purposes. However, he has neither credence, nor influence over the Chinese group that announced last April that they engineered changes into non-viable human embryos. We will live in interesting times.

By Norman Silverman, MD, with Ryan McKennon, DO and Ren Carlton

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