An Ounce of CRISPR Worth a Pound a Cure?
As
the old saying goes, an ounce of prevention is worth a pound of cure. Why treat
disease when you can prevent them all together? Wouldn’t this cut costs and
potential heartaches? If a doctor is able to cut out disease causing DNA why
not? These questions reduce gene editing to something like putting a puzzle
piece in the wrong place. Treating a person requires more than swapping pieces.
The ends cannot justify the means and thus the editing of genes must be shown
to improve the human condition and the benefits can justify the risk. The most
recent FDA approval for this therapy was Casgevy. This was a big step in
translating potential into real-world applications, however the overall process
is hefty, requiring collection of stem cells, high doses of chemotherapy, and
long-term follow up monitoring. Here the argument is not that CRISPR and its
abilities are greatly exaggerated and falls short of its promise. Rather there
are misconceptions surrounding its limitations making the jump from research
and laboratory to clinical applications.
CRISPR-Cas9
is the recent revolutionary gene-editing technology that allows for these
therapies to even be a possibility. Guide RNA matches its target gene and Cas-9
(CRISPR associated protein 9) is an endonuclease that causes a DNA double
strand break allowing access to the gene and the ability to modify it. This
seemingly allows for endless applications in treating and even curing genetic
disorders and diseases. However even though the potential for this technology
is seemingly limitless, CRISPR’s current clinical applications are limited in
scope. Although CRISPR-Cas9 has produced important breakthroughs in medicine,
the ability to edit DNA and the human genome does not make treatment of a
disease safe, effective or appropriate for all genetic disorders.
On December 8, 2023 the FDA approved
the first use of CRISPR/Cas9 for sickle cell anemia and Beta Thalassemia. The
treatment, known as Casgevy, is a somewhat involved and long-term treatment.
First, hemapoetic stem cells are collected from a patient. CRISPR/Cas9 is used
to knock out a regulatory gene, BCL11A, which is turned off shortly after birth
to stop the production of fetal hemoglobin. Before the edited cells can be
reintroduced to the patient, chemotherapy must be used to reduce the existing
bone marrow so the new cells have a place to go. This also reduces the patients
immune system response so that the newly introduced stem cells will be attacked
and rejected. The cells are installed via an intravenous infusion, multiply,
and begin to produce the fetal hemoglobin. The main benefit for this treatment
is essentially eliminating the need for regular blood transfusions and reducing
some of the worst symptoms of the diseases including vaso-occlusive crises
(VOCs). Of the patients, 29/31 initially treated were free of severe VOCs for
at least twelve months in follow-up visits.
While this treatment is evidence of
leaps and bounds in advances for using CRISPR clinically, the door has not been
completely blown open because of some limiting factors. This was a relatively
small sample size of people with a very specific disease. Starting with blood
disorders is fairly simple compared to some other conditions because bone
marrow is more easily removed, edited, and replaced compared to other more
vital organs. For example, if one tried to treat Type 1 Diabetes with CRISPR,
every single immune cell and every pancreatic cell would need to be edited in
order for the treatment to be effective and this is just not feasible. Another
drawback that comes with using CRISPR is the need for high-dose chemotherapy.
Those undergoing chemo are at higher risks for infection, organ failure, and
even the development of secondary cancers. It almost goes without saying that
using CRISPR comes with inherent risks of unintended or off-target genomic
effects because you are editing the genome. One of the main concerns is the
inactivation of tumor suppressor genes like p53 or oncogenic genes like the
KRAS.
All
gene editing is not ethically the same, so where do we draw the line? Editing
someone’s blood stem cells is vastly different from editing the germline where
changes are inherited and consequences are perhaps more unpredictable. One of
the most infamous cases of this occurred in China in 2018. He Jiankui announced
to the world that he had a hand in producing genetically edited babies, a set
of twin girls. Little is known overall about exactly what experiments he was
conducting but he was attempting to change CCR5 gene associated with HIV’s
ability to infect immune cells. Specifically, He was doing this to potential
children whose father was HIV-positive. Very soon after these experiments were
made public, the global scientific community condemned these practices and He
along with two of his colleagues were tried and found guilty of illegal
practice of medicine.
Preliminary
studies done by The International Mouse Phenotyping Consortium reported that
about one-third of homozygous gene knockout mice lines are lethal. These deaths
occurred during development or before weaning and these studies show how some
genes are critical for survival. This is not to say that if similar studies
were (ETHICALLY) done in humans that one-third of genes knocked down would
cause similar levels of lethality. Instead these studies just show the
importance of patience and needing to study the consequence of disabling genes
and their resulting biological outcomes.
Like any scientific advancement, CRIPSR/Cas9 has its controversies and limitations. What on paper seems like a panacea for all human disease is realistically just another tool in our medicinal tool kit. Importantly, we are also limited by our own ethics and regulations for history has proven over and over that the road to Hell is paved with good intentions. He Jiankui is an example of science going too far and crossing ethical and legal boundaries while Casgevy is a proven, ethical use of gene-editing technology. It will certainly be interesting to see how this technology develops in the next coming years.
By Seth Brahney, A Master’s of Science in Toxicology and Cancer Biology student at University of Kentucky
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