The Next Medical Frontier: Genetic Engineering and CRISPR

If you think about it, medical progress over time has not been a gradual relatively stable process. No, if you look back you will begin to see that it tends to take sudden leaps, forcing us into new possibilities that change everything. Leaps such as, the understanding and realization of the bacterial world, instead of thinking of disease as an imbalance of the ethers, the development of the field of anesthesia and with that, the ability to completely change the field of surgery, the development of antibiotics and the ability to develop vaccines that have nearly eradicated certain diseases from the face of the planet. These new developments did not occur overnight understandably I agree but what became of their development and discoveries quickly change the medical world and changed it forever. We are at another phase of advancement through the next frontier of science and medicine with genetic engineering.

My daughter is in her freshman year at Assumption High School and has a good head for math and science. She knows how to focus in a way most kids do not at her age and knows how to self-teach. This is the skill we need to be teaching our kids in school. Not memorization of facts and dates. That ended with previous generations where large volume information was not easy to quickly come by, so you had to memorize most everything in your field. Medical school was a lot like that in the past and doctors had to memorize volumes of information about disease and medical treatments, but not anymore. Not that memorization is no longer important, but now, it is the one that can efficiently assimilate the vast available data and come to the most appropriate answer to a problem, as opposed to simply regurgitating what they had learned from previous instruction. My daughter, and others like her, will have a leg up on anyone and everyone in the future due to her ability to learn on her own without formal instruction. I attribute her ability to do so to her mother, who homeschooled her from the fifth through seventh grade and focused on teaching her the skill of how to learn, as opposed to the simple skill of memorization for knowledge. She did so well she skipped the eighth grade entirely.

I know it is early regarding her life career choices, but I think the field of genetic engineering would be a perfect fit for her. With that in mind, I have been discussing with her some new recent developments with a genetic engineering tool known as CRISPR. CRISPR, which stands for “clustered, regularly interspaced, short palindromic repeats” came from studying the defense systems of bacteria. CRISPR is a bacterial defense mechanism that is used to recognize and remove foreign DNA from invading pathogens. This is a tool that can be used to modify abnormal DNA by precisely splicing out abnormal genes, giving the ability to correct the error in the genetic code.

Being able to repair genetic defects with this technology or use genetically modified human cells as therapy will be the new leap in medical treatment. This is not exactly a new idea. Older gene modifying system techniques known as zinc-finger nucleases, ZNF, and transcription activator-like effector nucleases, TALENS, has been used successfully. These other tools are used to do similar processes but the CRISPR can do this more elegantly.

While the other modalities work similarly once at the targeted DNA, there are a few aspects of CRISPR that make it more attractive. Target design can be more specific and thereby more simplistic than the older counterpart techniques. This simplicity and improved specificity allow one to create a gene mutation product that is easier and cheaper to make. Another attractive aspect CRISPR has over ZNF and TALEN is it can eliminate the need for virus vectors to get the job done. CRISPR technique avoids the use of viruses. This provides a more efficient modality for creating the needed gene mutation while at the same time reducing a component of safety concern related to virus vectors in vivo. Thirdly, CRISPR can introduce multiple gene mutations in a cell line at the same time.

Now, I won't go into more detail of the specifics as to how they work as you can really start down a rabbit hole so to speak into the minutia. Suffice it to say, all three modalities give researchers more efficient tools to take us into the next phase of genetic engineering; leaping beyond the previously used genetic manipulation of the pioneering genetic engineers of the 1990s and early 2000s. The field is booming. From a practical standpoint and on the short-term scale, CRISPR could help identify target molecules that would significantly affect new drug development. Using CRISPR to activate or inhibit genes, researchers can determine genes and proteins that would cause or prevent disease. This will help identify potential drug treatment targets.

We are now in the stages of study where real research trials are ongoing to treat people with genetic defect associated disease. Ongoing trials in sickle cell and beta-thalassemia are underway in Europe and FDA approval is expected here in the United States for the trial sponsored by CRISPR Therapeutics of Cambridge, Mass., and Vertex Pharmaceuticals of Boston. CRISPR is being used for the first time by directly injecting it into the body for a rare eye condition called Leber’s congenital amaurosis 10, which is a leading cause of blindness in childhood according to Dr. Heidi Ledford in her Nature magazines March 6, 2020 article. Trials are underway at the University of Pennsylvania using CRISPR for cancer treatment involving modified immune cells from patients and reinfusing them back into the patient with hopes that the modified cells will then attack the cancer cells they target and eliminate them. The study has been approved for 18 patients for treatment but further findings from this research will not be available for some time and are being conducted through the VA. Many other research trials are in the pipeline for approval and will no doubt prove to help mold the future of this exciting field. I will be excited to see what research comes from this regarding potential treatments for lung diseases such as cystic fibrosis, interstitial lung disease, alpha-1 antitrypsin, and COPD, etc.

With great power comes great responsibility. Modifying the human genome…. what could go wrong? A ton of things could go wrong, so close peer review and oversight is needed without question. A moral question is at play when talking about genetic modification and ongoing dialogue between scholars will be necessary to assure everyone is on the same page. Gene editing for medical treatments of DNA of an individual patient is one thing but modifications of embryo DNA would run the risk of altering heritable traits. A scientist in China was sentenced to 3 years in prison for altering the DNA of twin girls. He notified the research community in November of 2018 of his study in which he was trying to alter the embryos of the twins to alter a gene that would disable a gene that involves the entry of the AIDS virus into a cell.

The goal was to give the girls the ability to resist the infection. It is not known if the experiment was successful. For medical treatments, gene editing is only being made in the DNA of individual patients. There have been calls for a moratorium on gene-editing of heritable traits by the genetic engineering community according to an article in MIT Technology Review in attempts to stamp any fears about re-engineering the human race.

I believe that this will change everything.

Mark E. Esterle, MD