A WATERSHED MOMENT IN GENETICS
Several advances in the field of genetics recently were recently headlined in the mainstream media. In the first instance, the FDA just green lighted CAR T-cell therapy by Novartis for the treatment of refractory acute lymphoblastic leukemia (ALL). Final FDA approval should come by the end of September 2017. In more recent news, the journal NATURE reported researchers from the U.S, South Korea, and China, were able to correctable to correct the mutation for hypertrophic cardiomyopathy in preimplantation embryos via the use of CRISPR technology. Both these news events signal we are on the precipice of treating disease at the basic cellular level. In the Novartis study, geneticists were able to modify a human beings immune cells to attack cancerous lymphoblasts in young children; in the genome editing study, scientists were able to directly modify the gene itself. Although the technologies employed were distinctly different, genetic technologies are rapidly evolving and with it many ethical challenges.
The Novartis trial sought to genetically modify T cells in patients with refractory ALL. ALL is a type of leukemia that preferentially affects children. Over 35 years ago, the mortality rate for this disease approached 80% but today, over 80% of patients with ALL achieve remission with traditional chemotherapy and radiation. In the Novartis CAR T-cell trial, the therapy was given to those patients who did not achieve remission with standard treatment. In CAR (chimeric antigen receptor) T- cell therapy, a patient’s cells are sent to the lab and the patient’s own T cells are genetically enhanced via plasmid transfer technology. T cells are basically the scavenger cells of the human body, responsible for eliminating foreign threats such as infection causing microbes, HIV and cancer cells. CAR T-cells are cells whose signaling mechanism, the antigen receptor, is genetically modified to preferentially attack their target cells. The study, which began in 2012, modulated the t-cells of 81 patients with astonishing results. Over 83% of the study participants achieved remission.
The treatment is complicated by the inflammatory response in CAR T-cell therapy. T-cells, like other immune modulators, releases inflammatory cells called cytokines that can cause respiratory distress, fatigue, and bone aches. It is similar to what people experience when they have the flu, only magnified ten times. In severe cases, it can produce respiratory distress and circulatory shock. The first study participant, Emily Whitehead, suffered these complications but is now doing well. The other complication of this therapy is the cost, which is expected to be in the hundreds of thousands.
CAR T-cell therapy is also being explored in the treatment of other hematological malignancies, like myeloma and lymphoma with promising results. Unfortunately, efforts to use this therapy in solid tumors such as lung and pancreatic cancer have met with mixed results and efforts are underway to overcome the roadblock.
In the study first reported in Nature, researchers actually corrected the gene (MYBPC3) responsible for hypertrophic cardiomyopathy in preimplantation embryos. Idiopathic hypertrophic subaortic stenosis (IHSS) is a condition where a portion of the heart is abnormally enlarged leading to heart failure, ventricular arrhythmias, and sudden death. Utilizing CRISPR-Cas9, researchers were able to activate an endogenous, DNA repair response. CRISPR has two components. The first is essentially a cellular scissor that cuts DNA. The other consists of RNA, the molecule most often used to transmit biological information throughout the genome. It serves as a guide, leading the scalpel on a search past thousands of genes until it finds and fixes itself to the precise string of nucleotides it needs to cut. CRISPR actually occurs in nature, but it was not until the past decade that researchers were able to harness this technology to achieve genetic repair. Combined with preimplantation genetic diagnosis, CRISPR-Cas9 has the potential to repair inherited mutations that cause disease such as retinoblastoma (eye cancer) and Wilm’s tumor (kidney cancer) as well as subacute hypertrophic cardiomyopathy. CRISPR applications are expanding rapidly and numerous studies on mice are underway to repair genetic defects in sickle cell anemia, cystic fibrosis, and muscular dystrophy. These achievements are performed in a lab and have not yet translated into clinical practice.
With the announcement of gene editing, opinion pieces in prominent academic journals, newspapers, and periodicals raised the concern that gene editing could be employed for the more nefarious purposes of eugenics. Immediately, one saw expressed concern for “designer babies” and the lack of adequate protections for the disabled. These fears merit justification given the history of eugenics. Hitler’s regime unabashedly applied horrifying, eugenic principles, but they were not the only country. Chief Justice Oliver Wendell Holmes legally allowed for the practice of eugenics in the United States with the Carrie Buck case, although it did not allow for medical experimentation. In the late 1970s, Robert Graham started a sperm bank for only Nobel Prize recipient donors. He wanted to impregnate the eggs from women who were members of Mensa. The bank failed, fortunately, but even today the most popular sperm donors are tall, well educated, and attractive.
However, intelligence, beauty, and height come from a complex interplay of genetic material and are light years away, if ever, likely to be manipulated by gene editing. Others question the ethics of altering the “natural state” of a human’s DNA, as chemotherapy, radiation, antiarrhythmics, and antimicrobials can be used in the treatment of disease. I would argue that these agents are not natural either, and despite their improved efficacy, the use of such agents, particularly chemotherapy and radiation, carry the risk of causing a second malignancy or heart disease in a patient. As a physician and cancer survivor, judicious use of gene editing can relieve untold suffering.
Placing aside the issue of “designer babies’, gene editing will produce a host of ethical and dilemmas, just like IVF did thirty years ago with surrogacy rights in the Mary Beth Whitehead case and the autonomy issues in the Sofia Vergara case concerning the custody of embryos after a couple splits apart. Deaf couples are choosing to have deaf children by choosing a child with a disability via preimplantation gestational diagnosis. Do the autonomous wishes of a deaf couple carry more weight than say the potential autonomous wishes of the child, or of the public good? These are complex issues without fast and easy answers, with valid arguments on both sides. At this point, more immediate and pressing ethical and legal issues will arise from gene editing and we are not able to predict them.
This is a watershed moment in genomic medicine. A quarter century ago, the world wide web was introduced and computers entered the American household. Dial up modems operated at tortoise-like speed and typewriters seemed more efficient. I remember frequently yelling at the computer as I tried to meet deadlines for academic papers, but the next twenty years proved to be transformative. As CPU microprocessing chips improved exponentially, the speed of technological change and innovation went into hyper drive. The field of genetics is at this same moment, right before the introduction of the world wide web and WIFI. Numerous studies on gene editing are being conducted in basic research labs at the moment, and the results will likely change the course of disease in mankind.
Interesting articles if anyone wants to explore these ideas further.
https://www.nytimes.com/2017/08/02/science/gene-editing-human-embryos.html.
http://www.nationalgeographic.com/magazine/2016/08/human-gene-editing-pro-con-opinions/.
http://www.newyorker.com/magazine/2015/11/16/the-gene-hackers.