A new wrinkle in cancer therapy has received intense interest from the media after a federal panel approved CRISPR-Cas9, a gene-editing technology, for a study that would target three types of cancer. The clinical trial, to be conducted at medical-research institutions in Philadelphia, San Francisco, and Houston, would use gene editing to modify patients’ T lymphocytes, a type of white blood cell involved in the immune response, to make them more effective in attacking melanoma, multiple myeloma, and sarcoma.
“CRISPR, the genome-editing technology that has taken biomedical science by storm, is finally nearing human trials,” was the lead of a June 22 article in the British journal Nature. Another article from the U.K. was more reserved: “CRISPR gene editing: new chapter in cancer research or blot in the ethical copybook?”
First, what is CRISPR-Cas9? The CRISPR part refers to DNA sequences, in a variety of organisms, that appear in a pattern called “Clustered Regularly Interspaced Short Palindromic Repeats,” while Cas9 refers to a CRISPR-associated protein that is a kind of molecular scissors. Researchers use pieces of ribonucleic acid — guide RNAs (which are complementary to and bind specifically to certain DNA sequences) — to direct different versions of Cas9 to places in the genome where it can snip out genes, which can then be replaced with natural or engineered substitutes. The genetic changes in these substitutes can range from a single nucleotide substitution to quite complex constructions involving multiple genes.
The planned multi-step experiment is quite complicated. The researchers will collect T-cells from 18 patients suffering from the three types of cancers and perform three CRISPR-Cas9 edits on them. The first will be the insertion of a gene that expresses a protein engineered to detect cancer cells and to instruct the T-cells to target them. A second will remove a natural T-cell protein that could enable tumor cells to hide from attack. The third, intended to prevent the cancer cells from disabling the T-cells, will delete the gene for a protein that marks the T-cells as immune cells. To accomplish all this, the researchers will introduce into the T-cells guide RNAs, which tell CRISPR’s DNA-snipping enzyme, Cas9, where to cut the genome.
The thrice-modified cells will then be infused back into the patients, where, it is hoped, they will mount an attack on the tumor.
As incredibly complicated as this experiment seems, it is essentially an extension of the kind of “gene therapy” that was first tried more than 20 years ago (with partial success) and has been used successfully for several genetic diseases since then. Drug regulators in China and the European Union have approved a few gene therapies, including the correction of recurring pancreatitis and rare genetic abnormalities that cause blindness from choroideremia (a disease involving degeneration of the retina). These applications are more straightforward because they involve only the replacement of a missing or defective single gene.
Jumping through redundant, seemingly endless regulatory hoops is a significant burden, courtesy of an alphabet soup of local and federal entities.
The new study is preliminary and will be focused primarily on safety, with efficacy studies possibly to follow, but it is important to remember that medical technologies, in particular, are seldom successful right out of the gate; as they’re applied and refined, they improve, sometimes with astonishing rapidity. When I was a medical student in the 1970s, bone-marrow transplantation was being performed in only a few institutions and as a last resort, and the success rate was abysmal. But the discovery of potent immunosuppressants and other technical advances improved the success rate markedly within a couple of decades, and bone-marrow transplants are now routine in many institutions. As a result, some leukemias that were once a death sentence now have cure rates around 90 percent, and there are many similar stories in medicine, including open-heart surgery, which was remarkably primitive in its earliest incarnation but is now common and usually uneventful.
Many moving parts have to be organized just to get a preliminary experiment started, and the result is a loss of resources and time on the part of academic scientists, who often don’t have much of either to spare. Jumping through redundant, seemingly endless regulatory hoops is a significant part of the burden, courtesy of an alphabet soup of local and federal entities. The approval that occurred this week — by the National Institutes of Health’s Recombinant DNA Advisory Committee, or RAC (on which I served, as the representative of the Food and Drug Administration, from 1980 to 1993) — is only one small step in a lengthy, frustrating regulatory gauntlet.
The law requires that the FDA and Institutional Review Boards (IRBs) review proposals for clinical trials. But if “recombinant DNA” — DNAs from different sources attached to one another, or “recombined” — are used, the approval of the NIH and the RAC is also required — a mandate that is a redundant anachronism. The NIH and RAC reviews add nothing to the process except another hurdle. Because of bureaucratic inertia, attempts over the years to eliminate their involvement have been unsuccessful. And not only does the NIH itself, in addition to the FDA and IRBs, need to grant approval (for investigators who receive NIH research funds), but the NIH’s involvement also gets another player involved — Institutional Biosafety Committees, which are located within research institutions. Moreover, the FDA, a “real” regulatory agency, operates continuously, but the other entities meet only infrequently, further prolonging the process.
This duplicative and wasteful regulation offers a sharp contrast to the degree of oversight of a new surgical procedure, for example, which might be completely unregulated or subject only to the approval of a hospital-based committee.
The media completely missed this overregulation angle and misfired on another — the supposedly unique “ethical” issues raised by this clinical trial. Consider this, for example: “This new type of treatment, as exciting as it may be, also comes with some ethical side effects. . . . For starters, we, as a species, are opening doors to something we haven’t done before, playing with human genes.”
Media completely missed the overregulation angle on gene therapy for cancer.
The reality is that we have been “playing with human genes” to treat diseases in various ways for a very long time. Among the therapies on the continuum:
‐ Organ transplantation. Transplanted organs are a source of genes that are foreign to the recipient, which in turn synthesize functional levels of an enzyme or other substance that is deficient because of genetic disease. Common practice includes lung transplantation for cystic fibrosis and bone-marrow transplantation for severe immune deficiencies and leukemias.
‐Vaccination. Being inoculated results in irreversible changes in the DNA of white blood cells, initiating the synthesis of antibodies that mediate immunity to many viral and some bacterial diseases.
‐Drugs that activate dormant genes. For example, patients with disorders of the synthesis of hemoglobin, the oxygen-carrying molecule of red blood cells, have long been treated with chemicals that “reactivate” fetal hemoglobin genes that are normally dormant after birth.
Over many decades, these therapies have raised all manner of medical and ethical issues similar to those of gene-editing treatments, and physicians, ethicists, patients, and society at large have had to address them. There is no basis for subjecting gene-editing therapy to more regulation or ethical scrutiny than other medical interventions face.
Whatever the eventual success of gene editing as a treatment for genetic defects, cancer, and other diseases, we can be sure of one thing: Their route to the bedside will be far longer and more expensive because of excessively burdensome regulation.