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Dana Carroll
There have been comparisons made between Asilomar 1975 and first summit on human gene editing in 2015. I was at both conferences. There was concern that we culd accidentally turn a lab strain of ecoli into a dangerous pathogen. Nonetheless, people began to exaggerate disaster scenarios.
In 1976, the city of Cambridge, Massachussetts, home of Harvard, MIT put a brief moratorium on this research. Fortunately these fears were unfounded, and in the time since Asilomar, many advancements and therapeutics but no illnesses have emerged from the use of recombinant DNA.
I don't want to imply that the precaution used for recombinant DNA was unwarranted, in fact their caution probably enhanced our standing in the public eye. The point I want to make is that the situation is very different today.
In 2015 and 2018, we have much more precision to the promise of genome editing. We can describe the roots of fulfilling that promise, and enumerate the potential adverse consequences. The discussions of tehcnical and social issues involve a broad range of expertise. It was true of recombinant DNA.
As a result of the discussions now, I think the public is more focused on constructive uses of genome editing technologies than the potential dangers, potentially in the realm of medical applications of somatic cell editing.
TALENs and CRISPR have unquestionably revolutionized the practice of genome research. Bringing these to clinics is difficult. It must first be tested before being approved for broad use. The first applications have been launched. According to a US website, all of the editing platforms are already in use in current and upcoming trials, like for CAR-T cells. CRISPR is being tested as ex vivo treatment based on knockout for viral infection of T cells. All three platforms are being tested for sickle cell disease and others. There are in vivo activations for attempts to inactivate human papiloma virus. There are some trials under way for ZFNs to enhance delivery of therapeutics for hemophilia and others. These are among the low-hanging fruit for gene editing, which has well-defined targets and the changes would certainly have beneficial effect. In many cases, low genome editing efficiency here is acceptable, and the editing occurs ex vivo. The goal of editing is disruption of a genomic sequence.
The full realization of the potential of genome editing will require greater control than we currently possess on the cellular processes on which editing appends. I'm the last person to show a slide like this at this kind of conference, but this is showing how CRISPR works. What the genome editing tools do is to make a targeted break in the chromosomal DNA. Everything that happens after that results from DNA repair activity that is inherent from the cell, and .. into its DNA. Repair can result in disruption of the targeted DNA sequence, or it can result in incorporation of new sequences from a template provided by the experimentalist, which could cause correction of a gene.
At present, we have the ability to effectively disable individual genes. The procedures for making subtle gene edits is still eluding us. In addition, we're learning that some plausible target cells are not tolerant of even a single break of their chromosome. In some cases, we experience difficulty delivering the editing machinery to certain target cells. Conditions involving multiple genomes... present particular difficulties.
A genetic disease doesn't have to be polygenic to be problematic for genome editing. [....]
The mechanical operations for germline editing are simpler in some ways. Target cells are readily accessible. Delivery can be achieved by direct injection. However, in this case, concerns over control of both on-target efficiency and off-target effects are much more prescient. In addition, methods will need to be used to avoid mosaicism. In somatic applications, there's a limited range of secondary targets that are of a particular concern, and only the treated individual is at risk. In germline applications, the entire genome is at risk, and it's not easy to predict the consequence of off-target mutations upon postnatal development let alone subsequent generations. Addressing these limitations requires ongoing policy work, and cannot be resolved by genome sequencing because that would be too upsetting.
There is a lot of work to be done in the laboratory. Widespread benefits even with somatic cell editing are still some distance in the future. The last thing I want to mention are topics that aren't literally human genome editing but will likely have great impact, one of which is animal models with editing to use as models for testing. The other area is agriculture.
I want to add one more aspect that might be of interest. How will the benefits of advanced genetic therapeutics be made available to everyone around the world? I'll use single cell diseases here. There are many people developing somatic cell therapies right now. These diseases reflect defects of single diseases, and the same therapy can be applied to many individuals, editing can be performed ex vivo, and clinical manipulations are very familiar like bone marrow transplant, there are prospects for editing both by sequence disruption and correction, and edits don't have to be 100% efficient. There are many sickle cell patients in wealthy countries around the world. Ameliorating sickle cell disease in Africa is a worthy goal. The vast majority of these patients are in tropical locations in Africa and Asia. At present, it is difficult to see how expensive therapy can be made available in these high risk areas. I don't have any bright ideas, but I would encourage individuals in this audience to make distributions of these therapies something to think about. It wouldbe sad if this technology was only to be used to increase disparity in healthcare.
I recently participated in a symposium called "The end of illness?" which reflected as I said before that people are optimistic about the applications of genome editing. My assignment was to address the topic of whether CRISPR is magic. Well, no. CRISPR is constrained by the laws of nature. Still, the prospects are exciting.
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