Although the phrase “war on cancer” was first uttered in 1971, the breakthroughs in biomedical research that have emerged during this decade have supercharged the fight. The introduction of CRISPR-Cas9 — the molecular scissors that can edit DNA — makes the idea of powerful new tools to treat and prevent cancer feel tantalizingly close.
Ambitious efforts to prevent or beat cancer are important, but we can’t overlook or undervalue the incremental breakthroughs that could quickly reach patients and improve lives. What if, for example, we used CRISPR to make chemotherapy a bit less terrible for patients suffering with cancer now? That’s something my colleagues and I are trying to find out.
The broad story of CRISPR, told by researchers and the media alike, is one that focuses on cures or eradication of diseases. That’s understandable. This tool has incredible potential; it can literally rewrite the instruction manual carried in every living thing.
Like so many researchers working with CRISPR, I closely track the ups and downs of this unfolding story. There is a steady flow of research that produces confusing twists, from studies that question the precision of the science (some of which were later retracted) to new questions that are emerging from this quickly advancing field.
Recently, for example, I read a report in the journal Nature that raised concerns about the precision of CRISPR’s edits when trying to repair a cell. The fear is that such “off-target” edits could produce unexpected changes to the DNA. Research has yet to show what specific side effects this could produce in a human or an animal, but the prospects remind those of us in the field to proceed, but with caution.
Headline-grabbing CRISPR stories can feel distant to someone with cancer who is about to start chemotherapy, a potentially lifesaving but unsophisticated and imprecise tool with dreadful side effects. Toxins pumped into the body destroy cancer cells and healthy cells are collateral damage. Anyone who has had chemotherapy (or watched a love one undergo it) knows just how much it can disrupt day-to-day life. From nausea and anemia to infections and hair loss, it can be an awful experience.
I work in the cancer center at the Christiana Care Health System in Delaware. Each day as I see patients fighting cancer, I’m constantly reminded that gene-editing is more than exciting science — it will improve lives.
To stay focused on patients, my colleagues and I meet quarterly with oncologists, nurses, genetic counselors, and others to ask what would help their patients. We consistently hear that even a modest gain in quality of life and survival would mean an incredible amount to patients. Three or four months of higher quality of life — being able to play with children or work or visit with friends — can make a huge difference.
Beating cancer is a wonderful goal, but any new, revolutionary treatments are unlikely to reach patients in the next few years.
So rather than focusing on a way to use CRISPR or other revolutionary tools to replace chemotherapy as a primary cancer treatment, our team decided to find a way to use these tools to make chemotherapy more effective and less disruptive to patients’ lives.
We are using CRISPR to disable an essential gene that is responsible for the development of chemotherapy resistance. To do this, we inject the CRISPR payload into a tumor using an FDA-approved viral delivery system. Our experiments with the Wistar Institute have shown that the virus brings CRISPR to all the cells within the tumor — and no further. Once the payload gets inside cancer cells, it deactivates their self-defense mechanisms.
With this disruption, so the thinking goes, chemotherapy will be more effective because the gene or genes that confer resistance are disabled. Put simply, if we disrupt a cancerous cells’ ability to defend themselves, we can use smaller doses of chemotherapy. That would make the treatment more effective, kill fewer healthy cells, and make the disruption to patients’ lives much more manageable.
By using CRISPR to shut off cancerous cells’ self-defense mechanisms, we avoid concerns about off-target edits since we are seeking to destroy these cells entirely. We’re trying this first for patients with lung cancer, the most common cancer in Delaware.
One important concern is that new treatments based on gene-editing will be incredibly expensive and out of reach for many patients. We believe that approaches that improve upon existing treatments — especially less-expensive ones like chemotherapy — will come at a significantly lower price than the “revolutionary” treatments.
At the University of California, San Francisco, for example, CRISPR is being used to more quickly and affordably create CAR-T cells, which are an approved immunotherapy tool used for cancer treatment. Mammoth BioSciences, co-founded by Jennifer Doudna, one of the developers of CRISPR, is working to use this technology in the development of new medical tests and treatments.
None of this is to say that we shouldn’t be pursuing grand ambitions with CRISPR. The “moonshots” are vital, but they shouldn’t overshadow the potential of gene-editing to make improvements at the margin. That’s where today’s cancer patients live. In fact, I believe that is where some of the most exciting improvements will land first.
To do this, the scientific community needs to stay connected to the patients they seek to help. That means stepping out of the lab to talk to patients, caregivers, and those on the front lines of care. The future of gene-editing is full of big things — big breakthroughs, big ethical questions, and big business — but we must not overlook the value of smaller wins. Those, in fact, can be big wins for patients.
Eric B. Kmiec, Ph.D., is the director of the Gene Editing Institute at the Christiana Care Health System’s Helen F. Graham Cancer Center & Research Institute. The research described here being conducted at the Gene Editing Institute is supported by grants from the National Institutes of Health and the National Science Foundation.
Great to read about the focus of patient-desired outcomes and advanced technologies, Eric!
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