Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

About the Author

GEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of “Regular Departments & Columns.”

Could You Be any Cuter? Genome Editing and the Future of the Human Species 

Thursday, May 14, 2015

If you want to see what the future holds for us, let me suggest two recent articles. The first, published in the March 5th issue of the MIT Technology Review by Antonio Regalado, is called “Engineering the Perfect Baby.”  The second, published in Nature just a week later by a group of concerned scientists, is called “Don’t Edit the Human Germ Line.” Both discuss recent advances that, for all practical purposes, turn science fiction into science. It’s an interesting story.

The story goes back three years to the development of CRISPR/Cas-9 technology for gene editing by Jennifer Doudna and Emmanuelle Charpentier. CRISPRs (short for Clustered Regularly Interspaced Short Palindromic Repeats) are short DNA segments in which segments of viral DNA are inserted, which are then transcribed to a form of RNA (cr-RNA). This viral-specific cr-RNA then directs the nuclease Cas9 to the invading complementary viral DNA, which is cleaved.

We do not think of bacteria as either needing or having an immune system, but CRISPR/Cas9 functions as one in the prokaryote/bacteriophage arms race. It is elegant and simple, a profoundly cool invention far down on the evolutionary tree that somehow failed to make it to mammals.

Doudna and Charpentier had the exceedingly clever, and in retrospect quite obvious, idea that this could be used to edit specific DNA sequences. I say “in retrospect quite obvious,” but it is the sort of retrospective obviousness that turns previously obscure professors working in equally obscure fields into Nobel laureates, as their 2012 Science CRISPR/Cas-9 paper certainly will.

Molecular biologists love this technology, and for good reason. With CRISPR/Cas-9 one can add or subtract genes almost at will. The technology, while not perfect (more on this later), is a straightforward, off-the-shelf tool kit that allows practically anyone to manipulate the genome of practically any cell. It is a game changer for laboratory research. The technology has launched an astonishing number of papers, several new biotech start-ups, and (already) the inevitable ugly patent lawsuits over who got there first.

Because bacterial DNA and human DNA are forged from the same base elements, what one can do inE. coli one can do in H. sapiens. Whether it is wise for H. sapiens to reproduce E. coli technology is the real question.

What Regaldo’s article suggests, and what the Nature article confirms, is that we are close to a tipping point in human history. It is easily conceivable that CRISPR tech can be used to edit the genes of human germ-line cells. We will, in the very near future, be able to alter a baby’s genome, with almost unimaginable consequences.

Is this a line we want to cross? Some, unsurprisingly, find this prospect disturbing. The authors of theNature paper suggested a moratorium on gene editing of human stem cells until we can be work out all of the important practical and ethical issues. Let us slow down, they say, take a deep breath, think things through, and then proceed with caution.

A wonderful idea, but a bit too late, as it turns out. March was so last month. A group of Chinese investigators at the Sun Yat-Sen University in Guangzhou took human stem cells (defective leftovers from a fertility clinic) and used CASPR/Cas-9 to introduce the b-globin gene. b-globin mutations are responsible for beta thalassemia, which afflicts a significant population of patients.

The paper was published in the April 18 issue of Protein & Cell (a journal I had never heard of before), reportedly after having been rejected by Nature and Science on ethical grounds. It is rather like when Gregor Mendel published his article on the genetics of peas in Proceedings of the Natural History Society of Brünn, only now we have PubMed and the world is a very small place. I suspect Protein & Cell’s impact factor just took a quantum leap upwards.

The paper suggests we are not quite there yet: of the 86 embryos where the authors used CRISPR/Cas-9 to introduce the gene, only 4 “took”, and many had off-target mutational events, not a good thing if you are trying to eliminate a genetic defect. In other words, don’t expect this to be available at your local fertility clinic next week.

But if not next week, then maybe next year, or the year after: this field is moving at light speed, and the Chinese doctors were (or so a recent Science article suggests) using last year’s techniques. Lots of very smart people are piling into the field. This will soon be feasible, then eventually trivial, technology.

And as for a moratorium on gene editing of human stem cells? It might stick for a while, but I am not sanguine about its long-term prospects. I think it is a given that any moratorium will eventually fail.

To answer why this is the case, just look at the history of attempts to limit the use of new technologies:

First, the atomic bomb. In 1945, after the first nuclear explosion at Alamogordo, a group of Manhattan Project scientists, led by Leo Szilard (who famously first thought of the nuclear chain reaction that would occur once one split the uranium atom), petitioned the President to halt the use of the bomb. The petition, dated July 17, 1945, stated “the nation which sets the precedent of using these newly liberated forces of nature for purposes of destruction may have to bear the responsibility of opening the door to an era of devastation on an unimaginable scale."

The powers that be were not amused. The US government had spent two billion 1945 dollars developing the A bomb as a war measure, it faced the likelihood of an invasion of Japan with untold potential casualties, and it had little sympathy for Japanese civilians. It also saw the bomb as a long-term source of political and military power. The niggling objections of the atomic scientists (and by no means all objected) were ignored, and literally within weeks Hiroshima and Nagasaki ushered in the Atomic Age, in all its frightful glory.

That decision tells you that technologies rapidly get out of control of those who create them. In the Atomic Age, one at least needed a well-heeled nation-state to back you if you wanted to build a bomb, a partial barrier (though only partial: impoverished Pakistan, two generations later, is capable of immolating its neighbors). And nation-states, since 1945, have thankfully not used these weapons on other nation-states, though nuclear proliferation sadly continues.

But in the Genome Era, just about any college biology graduate soon will be able to insert genes that eliminate defects or increase function. For practical purposes, Lichtenstein and Monaco could be the biologic equivalent of today’s nuclear powers five years from now. Unless the moratorium is worldwide, all you would need to do would be to fly somewhere that didn’t share the biomedical ethical stance of the Nature authors. And if I knew I carried a deadly genetic defect, I would do anything to save my children from the same fate.

By the way, you might say that comparing the atom bomb to CRISPR/Cas9 is a somewhat ridiculous comparison given the relative significance of the two. And you would be right, though perhaps not in the way you might first think: CRISPR/Cas9 is likely to be far more significant in the long run. A technology that allows a species to intentionally evolve new characteristics is far more important for the history of that species. Gills, anyone? Chlorophyll rather than melanin in your skin? All those pesky vitamins we don’t make ourselves? Edit them in.

The somewhat more pertinent analogy, and one commented on by many, is the Asilomar conference. After Cohen and Boyer performed the first recombinant DNA experiments, there was a similar terror of Dr. Frankenstein experiments by mad scientists. The city fathers of Cambridge, Massachusetts, appropriately frightened by the proximity of Harvard and MIT, passed a law banning the use of recombinant DNA technology within its city limits.

The then-small community of molecular biologists met at the Asilomar conference center (near San Francisco) in 1975 and voluntarily developed limits on certain types of genetic experiments until their safety could be determined. It was a highly moral stance by the leaders of a new biologic revolution, but also a highly practical one, as it decreased public opposition to recombinant DNA technology.

The moratorium turned out to a brief one (no one, to my knowledge, has ever been killed by recombinant DNA, at least not yet), and with its lifting the biotech industry was born, and we never gave those early qualms a second thought.

I’ve been to Asilomar several times: my Oncology division at Stanford holds its annual scientific retreat there. It is a lovely state park on the Pacific coast, and a great place to hold a conference: watching the sunset over the ocean at Asilomar is an awe-inspiring experience.

But Asilomar is just not the right model for what is happening today. Molecular biology is ubiquitous, a global enterprise carried on by tens or hundreds of thousands of scientists, not the small handful in the 1970s. A few academic scientists no longer drive it; big pharma and biotech call the shots, and can be expected to remain highly ethical just so long as no obscene profits can be made from a new technologic development.

Jennifer Doudna has suggested that we need an Asilomar equivalent for CRISPR/Cas9 gene editing of embryos, and indeed there has already been a preliminary meeting of scientists, lawyers, and bioethicists in Napa Valley’s Carneros Inn earlier this year. By the way, the Carneros Inn is even nicer than Asilomar: one should always hold scientific retreats at great resorts in wine country. It greatly improves the meeting outputs.

The Asilomar scientists had what were, in essence, short-term concerns: will recombinant DNA, let loose on the world, be the scientific equivalent of the Four Horsemen of the Apocalypse? Well, no, and we knew the answer quickly.

But CRISPR-Cas9 stem cell germ-line editing, once the technical wrinkles are worked out, is a technology whose medical and social implications will take generations to play out. The pressure to use it for medical purposes will be enormous. Edit out or fix a gene that causes some dreadful neurodegenerative disease (a Huntington’s chorea or its equivalent) and no one will notice the difference for forty or fifty years. These diseases will go away, and who will miss them? And who among my great-grandchildren will even care, it having been something they have always lived with?

Perhaps (one already knows the objections) we should not assign God-like powers over creation to ourselves, but how long will that dike hold when a Senator’s or a billionaire’s or a dictator’s misbegotten embryo needs genomic resuscitation?

And edit in something that makes one smarter or faster or—dare I say—cuter? Cosmetic editing will be popular the moment we figure out how to do it. Pretty much the first law of the consumer electronics industry is that every new technical advance (viz: VCR, CD-ROM, streaming video) is used almost immediately for pornography. I can only imagine what will happen with gene editing.

I simply do not trust us not to use CRISPR/Cas-9 germ-line editing. There is a certain technologic imperialism that renders it inevitable. We always want to play with the cool new toys, and this one will be really, really easy to play with. What will my descendants look like? Probably not like me. And there are those who would say that is a good thing.