Genetic Modification - Part I: A Cure for Human Disease
- Dec 12, 2017
- 4 min read
If there was anything considered sacred or untouchable in the field of medicine of yesterday, it would be the genetic blueprint that a person was born with. The mysterious workings of the DNA could determine, with a fairly predictable level of certainty, not only our physical appearance, but if a person was to have certain inherited medical conditions, and there was nothing an individual or their doctor could do about it, save try to lessen it's negative effects. How could one possibly prevent or cure something which is indelibly written into every single cell, as the very physical code of life?
Human disease caused by genetic mutation is particularly difficult, as it pervasively effects the quality of life, works it's way through families, disrupting several generations, and remaining elusive and incurable. Research has successfully identified, in many cases, the offending gene or base pair which is at the root of the disease process, yet previously, there was no way to directly remedy the abnormality. Most treatments have been focused on addressing symptoms, and more aggressive therapies involving stem cells transplants have not been uniformly successful. With this backdrop, it is hard to imagine that diseases such as sickle cell anemia, cystic fibrosis, Huntington's disease, muscular dystrophies and inherited bleeding disorders might one day in the near future, be treated at the source and cured, rather than endured for a lifetime with symptomatic treatment only.
Science may finally have an answer to genetic disease, with the fortuitous advent of improved DNA editing technology. Significant attention and hope is now directed towards the very promising, literal cutting edge tool CRISPR; a gene modulating complex which has shown itself capable of editing DNA in vitro and in vivo. This protein and RNA complex is able to precisely locate a particular region of DNA, among the thousands of genes which are housed on a chromosome, and effectively bind to and/or and splice out the offending agent.
What is CRISPR and how was it discovered?
CRISPR, which stands for Clustered Regularly Interspersed Short Palindromic Repeats, was actually discovered in Archaea, then bacteria, by scientist Francisco Mojica of Spain in 1993** It is comprised of regular repeating sequences of RNA which are separated by "spacers". These spacers were a primitive memory store, containing the sequences of prior viral invaders of the bacteria. This tool was found to be a major component of the bacterial immune system, used to protect against viruses. CRISPR was first adopted for research in 2013 by the Zhang lab and engineered to edit the mouse genome. Today, there are several different types of CRISPR's in use, as they are each bound to various enzymes, such as Cas-9, Cas-13 or CPF1, localizing differently on the chromosome and having different capabilities.
How does it work?
CRISPR is essentially a re-purposed natural system to edit DNA. The researchers using CRISPR engineer the RNA to target specific sequences of DNA within the host animal or human cell, then use a vector (virus or plasmid) to gain it passage into the cell. CRISPR then uses its natural mechanism of action to identify and bind to the correct DNA sequence, unravel the genetic helix, and use its enzyme, usually Cas-9 to cleave the DNA at the bound segment. The cell then repairs the DNA as it would naturally, inserting random codons into the location of the spliced segment, effectively silencing that segment of code. Check out the videos below and on the home page for simulations of CRISPR, and discussion of the effects. It is truly a powerful and precise tool in many ways, however there is a major caveat.
Why isn't it being used in humans now?
Although it seems like we should be curing genetic diseases with CRISPR yesterday already, there is good reason to be cautious. When the DNA is cut, it may be repaired in a fashion which causes a problem, and the change could affect the permanent genetic code in an unpredictable manner. Although segments may be included with the complex to repair the DNA with, there may be errors in assimilation of the edit, or the assimilation segment may not be used altogether. Once these errors are in the genetic code, they may have disastrous consequences which could not be reasonably fixed without again throwing the dice at another repair, which may be impossible without correct targeting. The strong possibility for DNA repair error with CRISPR must be considered and addressed before the the therapy is fully introduced to humans. Hence more studies are needed before widespread use in clinical trials and treatment. However, researchers are very aware of this danger and the necessity of the approach to "measure twice and cut once." CRISPR research is ongoing, in animal models and cell lines in order to determine the safest and most effective approach. Using different enzymes instead of the cleaving Cas-9, is one of the ways the DNA repair error is being addressed. Nonetheless, the newest secret weapon in the arsenal is using CRISPR to localize the gene, however, not altering the actual DNA, but allowing modulation of the gene expression. This use of epigenetics eliminates the possible break repair error and makes CRISPR that much safer. This may be the crucial modification that bridges the gap between scientific discovery and medical therapy.
What is the future direction of CRISPR ?
CRISPR research continues to improve, and scientists set their sites on previously incurable diseases, such as Thalassemia, Von Willebrands Disease and even diabetes. At least one company, Crispr Therapeutics, has already pledged that their product is ready to enter clinical trials, and they plan to start by tackling beta-thalassemia, the inherited blood disorder. Everyone will be watching this revolutionary next step in the use of this therapeutic agent.
An important bonus of CRISPR use in research is the fact that models of disease can be more rapidly built using animals or cell culture. Previously, the precise targeting and knockout of genes to mimic disease was difficult and imperfect. Now using CRISPR, researchers may accelerate the medical understanding and treatment of all diseases, including cancer, which are able to be studied in this fashion. This important breakthrough allows one to reasonably consider a future where all diseases are curable. Thank you for reading this blog! Check back for Part II of this series on genetic modification and view our other blog posts. Feel free to leave your comments.
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