How Gene Editing Can Help Lead to a Cure (Part Two) and the 2017 Nobel Prizes for Science
In last week’s blog post, I discussed the ways in which CRISPR gene-editing technology is allowing researchers to study disease and intervene at the molecular level. There is a sense of euphoria that so many things can be accomplished and, as I noted, the sky is the limit in the potential applications.
What will this mean for myeloma patients and the search for a cure? I expect the applications of gene editing to evolve rapidly over the next couple of years, especially in the following areas:
University of Pennsylvania researchers are already working on CRISPR editing of patient T cells for immunotherapy in a project supported, in part, by Sean Parker, a technology billionaire. This is basically the CAR T-cell approach – a patient’s T cells are extracted, carefully edited (“engineered”) to confer the maximum benefit, then re-infused as anti-myeloma therapy. No data are currently available, but there is enormous potential in being able to fine-tune T cells and/or other types of immune cells to achieve a favorable immune signature for the patient. Alternate immunotherapy strategies include the use of monospecific or bispecific (able to bind to two targets on the myeloma cell surface) monoclonal antibodies to enhance anti-myeloma efficacy.
The US is a bit behind China in bringing gene editing into the clinic. Dr. Carl June, who pioneered using customized T cells to help give a patient's own immune system the ability to fight cancer at the University of Pennsylvania, told Nature News, “I think this is going to trigger ‘Sputnik 2.0,’ a biomedical duel… between China and the US…” A Chinese team led by Dr. Lu You at Sichuan University has already treated lung cancer patients with CRISPR-edited T cells.
The full scope of immunotherapy approaches is hard to predict. However, CRISPR editing of immune cells will undoubtedly play a significant role in the coming years.
2. Molecular biology assessment
Understanding the key mutations driving myeloma growth and sequential clonal evolution is tremendously important. Editing out a gene from a myeloma cell in the laboratory and observing the downstream effect of that edit will reveal the gene's underlying impact. Early in the disease, CRISPR editing will be crucial in revealing which genes drive evolution from monoclonal gammopathy of undetermined significance (MGUS) to smoldering multiple myeloma (SMM), and from SMM to symptomatic myeloma. These genes then become targets for a whole range of potential interventions. So far, only a few studies have been done in myeloma. Findings include:
- CRISPR deletion of a gene called FAM46C promotes myeloma cell growth and survival. Further studies are required to demonstrate how this can be used to explore new treatment options.
- CRISPR/Cas9 editing shows that the anti-myeloma agent selinexor (currently in phase II and III trials) targets the specific gene segment XPO1 (cysteine 528 residue). Identifying a drug target selectively is extremely helpful, both in new drug development and subsequent drug-resistance analyses.
Much more can be expected in the next few years. A CRISPR-Cas9 screen has already pointed to potential vulnerabilities in KRAS-mutated colon cancer. Being able to edit KRAS mutations is significant because mutations of the KRAS and NRAS genes occur frequently in aggressively relapsing myeloma.
3. New opportunities
Last week I described how CRISPR technology could be used to treat HPV (human papillomavirus) and cancer of the cervix by local application of a gel. But how can CRISPR reach myeloma cells in the bone marrow? Gold nanoparticles may provide the answer. With this technique, new DNA (called donor DNA) can be wrapped around a tiny gold ball (nanoparticle) with the Cas9 enzyme plus guide RNA (ribonucleic acid) to replace mutated DNA (deoxyribonucleic acid) with correct DNA. The CRISPR/gold complex could be injected into the bloodstream to deliver the enzyme, plus new DNA, to every cell targeted for editing.
It seems like science fiction, but something like this scenario could pave the way to treat a systematic disease in an adult.
2017 Nobel Prizes: the impact of scientific advances
While CRISPR technology is a harbinger of a brave new world, science of all types is producing real current-day results. The Nobel Prize winners, announced this week, are cases in point. The 2017 Nobel Prize for chemistry went to Jacques Dubochet, Joachim Frank, and Richard Henderson. They developed a cryo-electron microscopy method (“cool microscopy”), which allows researchers to take snapshots of molecules like proteins within cells. It was this technology that allowed researchers to see how the Cas9 protein wraps around the DNA in 3D at the time of DNA editing and repair. Viruses that are being edited out can also be visualized.
The 2017 Nobel Prize for physiology went to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young for their work on circadian rhythms – the biological clock that controls the daily cycle of bodily activities, including hormones, blood pressure, body temperature and the like. Deviating from the normal cycle can result in everything from jetlag to some serious diseases. In addition, there could be an ideal time of day to take treatment for myeloma (or other forms of cancer) to achieve maximum benefit.
And finally, the 2017 Nobel Prize in physics was awarded to Rainer Weiss, Kip Thorne, and Barry Barish, black hole researchers. Although their discovery of gravitational waves “shook the world” in February 2016 when they recorded gravitational waves coming from the collision of two massive black holes, what impact does this have in our daily lives? Besides providing the backdrop for the movie “Interstellar” (for which Dr. Thorne was an executive producer), there are real implications. The observable (visible) stars and galaxies are 4% of what’s out there, but the 96% that remains is not merely empty space, as was once thought, but is filled with gravitational waves, Higgs bosons, and quite a few other things, perhaps including wormholes.
So, the science fiction-sounding gene editing that I’ve described is just the beginning of a scientific revolution of understanding and opportunities. The 94% of everything that surrounds us is not as empty as we thought, but tantalizingly rich in learning opportunities.
For CRISPR technology, it is just beginning. Since predicting the future is not a strong human talent, I will not even venture to offer what myeloma therapy may look like five years from now except to say that most likely it will be very different! Stay tuned.
PS: New book examines environmental dangers
Advances in technology, agriculture, and science can come at a price. For example, introducing approximately 70,000 chemicals to our environment, with many being known carcinogens, has consequences when the toxic potential is ignored. This risk is ably chronicled by journalist Carey Gillam, author of Whitewash: The Story of a Weed Killer, Cancer, and the Corruption of Science. I am honored that my endorsement is included on the book jacket (along with those from Erin Brockovich, Marion Nestle, and David Schubert): “Carey Gilliam is a brave warrior in the mold of Rachel Carson. She has exposed the ruthless greed and fraud that have poisoned our planet.”
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