CRISPR in the near term future?

crispr
CRISPR as search term in Google

Remember interactive television? In the mid-1990s Microsoft was betting the farm on this new technology. As it happens they had to make a course correction. The Mosaic browser was the first “killer app” of the internet (sorry e-mail and usenet), creating the world wide web as we know it. The the rest is history. The lesson is that sometimes no one sees a technology coming. And when it does come, it disrupts the whole landscape. It can both create and destroy. This was clear in my recent post for the Genetics Society of America. The discipline is over 100 years old, and yet over the past 30 years we’ve seen genomics go from being invented as a term (in 1986), to revolutionizing the field, finally to a great extent becoming coextensive with the field. Similarly, the internet existed for two decades before the world wide web came along, but rather soon our conception of “the internet” became synonymous with the web (and e-mail and newsgroups have become absorbed into the web architecture as well).

Similarly, genetic engineering has been around for decades. Direct manipulation of DNA sequences emerged as a technique in the 1970s, and the Asilomar Conference on Recombinant DNA agreed upon a set of guidelines in terms of how the method would be deployed. Despite what you might have gathered from movies such as Gattaca genetic engineering was both difficult and limited in its power to effect change. Of course, despite public concern GMO crops have been moving into circulation for years in the United States, while medical research would be hampered without the access to engineered mice. But very few people would assert that genetic engineering is ubiquitous today.

The CRISPR/Cas system has the potential to change this. It is easy, cheap, and fast. It can take genetic engineering from a vital niche, to a pervasive aspect of human culture. CRISPR first began to gain some attention in scientific circles in 2012. As I write now, in 2015, its presence in discussions relating to genetics can seem ubiquitous, even cloying. Seminars with the word “CRISPR” in the title suddenly become standing room. If the world wide web is an analogy to what is going on, then we are in 1993. The implication is that we haven’t seen our first Netscape of CRISPR, nor the emergence of a whole economy built around the technology. Right now it is a scientific superstar, but we’ll known that it’s made the “big time” when we see it mentioned ubiquitously on CNBC.

So what’s holding us back? There are two primary things I can think of. First, fear and uncertainty. The regulatory environment is essential for the success of any technology today (well, except Uber!), and the framework is currently ad hoc rather than formalized. The Chinese scientists who modified embryos were only newsworthy because of the bioethical and regulatory consequences of their actions, not the science. It is certainly more significant that a British group is now asking for permission to do experiments on the developmental genetics of embryos using CRISPR technology. The outrage over the modifications last spring had as much to do with breaking the tacit social norm within science where everyone wants to establish some sort of agreed upon framework for novel human research, rather than concern about the the scientific implications. If the British group receives approval, it will set a precedent which could open the door for other reputable researchers.

But what about in concrete terms in a near term horizon? The ability to “edit DNA” sounds incredible in the abstract, and is almost certainly civilization changing in the long term. But over the next few years it seems likely that CRISPR/Cas will result the reemergence of gene therapies as a means by which Mendelian diseases may be treated. Gene therapy as a field suffered a major blow in the late 1990s due to a series of fatalities, arguably tied to unethical practices by one researcher. But the idea of curing someone of a genetic illness by modifying the gene reBut isponsible for that illness is straightforward in its logic.

Many diseases, such as diabetes or schizophrenia, are complex in their origins. There is no specific gene responsible for the cause in the vast majority of instances. The road to genetically engineer a “fix” would be long and the outcome not assured in these cases. Any risks would have to be weighed strongly. In contrast Mendelian diseases are often due to a single locus, and the cause is due to that precise biological malfunction. And their outcomes are often easy to quantify. Cystic fibrosis takes decades off your life expectancy, and entails hundreds of thousands of extra costs over the lifetime. There is some debate as the frequency of Mendelian disease within the population, but something on the order of ~10% of the American population seems likely using a very liberal definition of disease. If only a a percent or two of these have illnesses which are of some severity, that may still justify intervention if it is feasible and safe.

The feasibility of gene editing to cure Mendelian disease is conditional partly on mode of delivery, which is not a genetic concern per se. That is, how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function? A second concern are “off target” changes. You may be attempting to modify one thing, but modify another, in which case you’ve gone from the frying pan to the fire. Both of these though seem to be soluble problems over the time scale of a decade (CRISPR precision has gotten better even in the past few years). And for diseases such as sickle cell and cystic fibrosis, which entail shortened lives and constant monitoring and treatment, the perfect can’t be the enemy of the good. In the near future the ethical mandate will not be if, but why not.

When that happens you will see a shift in the medical system in the United States. Instead of attempting to tackle symptoms of Mendelian diseases, physicians will plausibly offer up the possibility of eliminating the root cause. This will make some companies very rich, as health care is a growing sector of our economy. Sequencing will be ubiquitous, obligatory, with exemptions necessary, not elective. In a classic sense it will be a “win-win,” as medical costs per individual will decrease, and their lifetime earning power will increase due to greater health.

The effective utilization of genetic engineering to make lives better for a minority of Americans will also change perceptions in the public as to the implications of genetic engineering. Instead of a dystopian future, people will begin to see their own present, and the fear will give away to acceptance. And it is in the time horizon beyond 2025 that I think we may need to start thinking about tackling germ-line modifications and more radical ‘experiments’ in biological engineering….

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