Story behind tool to edit DNA
Method called Crispr set to revolutionise biotechnology
SOME of the greatest benefactors of our species are not the recognised do-gooders but those paid to satisfy their curiosity: the scientists.
Such pure and unsullied inquiry has yielded thousands of valuable by-products, including antibiotics, vaccinations, X-rays and insulin therapy.
Jennifer Doudna and Samuel Sternberg’s A Crack in Creation describes another fortuitous discovery, a method that promises to revolutionise biotechnology by allowing us to change nearly any gene in any way in any species.
The method is called Crispr, pronounced like the useless drawer in your fridge. In terms of scientific impact, Crispr is right up there beside the double helix (1953); the ability, developed in the 1970s, to determine the sequence of DNA segments; and the polymerase chain reaction, a 1980s invention that allows us to amplify specified sections of DNA.
All three achievements were recognised with Nobel Prizes. Crispr – developed largely by Doudna and her French colleague Emmanuelle Charpentier – also has a strong whiff of Nobel about it, for its medical and practical implications are immense.
The story of Crispr is told with refreshing first-person directness in this book. (Sternberg was Doudna’s student, but the book uses Doudna’s voice.) It is not often in science writing that the actual discoverer puts pen to paper – rather, the story is usually told by a science writer or colleague – so this insider account is especially engaging.
Crispr, an acronym for “clustered regularly interspaced short palindromic repeats,” is a way to edit DNA.
“With Crispr, we can change a sequence from ATTGGCG to ATTGGGG or to CCCCCCC, or to anything else. There are other recently developed ways to do this, but they are uniformly unwieldy, time-consuming and inefficient.
“The joy of Crispr is that it allows us to edit genes painlessly: It is easily applied and seems to work well in whatever species or cell type we choose.”
The history of Crispr is a prime example of the unexpected benefits of pure A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, by Jennifer A Doudna and Samuel H Sternberg research, for it began with a handful of curious scientists not intent on changing the world.
In the late 1980s, scientists observed a bizarre section of DNA in some bacteria, consisting of short, identical and repeated “palindromic” sequences that read the same way backward and forward (for example, CATGTTGTAC).
The repeated palindromes were separated by 20-letter segments of unique DNA, segments eventually found to come from viruses that infect bacteria.
People soon realised that the Crispr region was the bacterium’s immune system against dangerous viruses.
Crispr helps bacteria “remember” previous viral attacks and thus prepares them for future attacks by the same virus.
This is analogous to our immune system, which also “remembers” intruders: If you have had measles once, you won’t get it again because the first exposure preps the immune system for subsequent exposures.
The way bacteria do this is by storing a segment of the virus’s DNA from the first attack.
When the same kind of virus strikes again, the bacterium recognises that the alien DNA segment has reappeared by matching the stored segment to the intruder DNA.
Having identified the intruder as a bad guy, the bacterium can snip up, for example destroy, the intruder’s DNA, guided by the same stored Dna/intruder-dna match.
Doudna and Charpentier realised that it was possible to subvert the Crispr system: Instead of viral intruder DNA, we can use the DNA sequence we’re interested in (say, one causing a genetic disease), with the result that Crispr snips up any and all DNA molecules with the target sequence.
Once DNA is snipped up, there are ways to repair it using a different sequence, including a version of the gene that does not produce disease. Presto: gene editing and a path to designer genes.
Rewriting genes has the potential to cure many genetic illnesses. People suffering from sickle-cell disease, for instance, have just a single mutated “letter” in the DNA coding for their haemoglobin.
It shouldn’t be hard for Crispr to replace that letter in embryos or bone marrow, curing the millions who suffer from this devastating malady.
But that’s just one of myriad possible edits. Crispr can in principle cure any disease caused by one or a few mutations: not just sickle-cell but Huntington’s disease, cystic fibrosis, muscular dystrophy or colour blindness. We could cure Aids patients by editing out the HIV viruses that hide in their DNA.
By editing early embryos, we could reduce the incidence of genetically influenced diseases such as Alzheimer’s and some types of breast cancer.
We could make cosmetic changes in our children, altering their hair and eye colour or even, in principle, their height, weight, body shape and intelligence.
None of this has been tried in people, but since Crispr works well in human cell cultures, it seems just a matter of time.
Turning to other species, we could genetically engineer either pigs or people so we could transplant pig organs into humans without activating our immune response.
We’ve used Crispr to make virus-resistant farm animals, and we can now engineer insecticide-making genes into the DNA of crops, eliminating the need for dangerous sprays. As the book title implies, Crispr allows us to bypass or undo evolution without relying on the hit-or-miss methods of selective breeding.
But of course DNA editing also raises ethical issues, and these occupy the final quarter of the book. Doudna worries about the return of Nazi-style eugenics and even had a dream about Hitler asking her for Crispr technology.
Should we engage only in “somatic” gene editing: changing genes in affected tissues where they can’t be passed on to the next generation?
Or should we also do “germline” editing, changing early embryos in a way that could be transmitted to future generations? While that conjures up the bad old days of eugenics, it is in fact the only way to repair most “disease genes”.
But if we do that, should we stick to fixing genes that would debilitate the offspring, as with sickle-cell disease, or should we also change genes that merely raise the possibility of illness: those that could produce high cholesterol or heart disease?
Things get even more slippery. Should we edit the embryos of deaf parents to produce deaf offspring, so that their children can participate in “deaf culture”? And – the ultimate taboo – genetic enhancement: Should we give our children a leg up in looks or intelligence? That, after all, will provide genetic advantages only to those who can afford the technology.
Finally, how do we keep the technology out of the hands of bioterrorists? Cheap and simple Crispr kits are now sold on the internet, allowing anyone to edit the genes of bacteria. The nightmarish prospect of engineered diseases looms.
While it’s good to consider all these questions before the technology is widely available, Doudna and Sternberg come to few conclusions, and their extended vacillating is the book’s sole flaw.
Alongside the ethical quandaries come commercial ones. There is a great deal of money to be made through the licensing of Crispr technology.
We have already seen a protracted patent battle between Doudna’s employer, the University of California, and Harvard/mit’s Broad Institute, home to Feng Zhang, who was largely responsible for converting Crispr from a device for editing bacterial genes into a lab-friendly tool that works in human cells. There is a lot at stake. – The Washington Post
Coyne is professor emeritus in the Department of Ecology and Evolution at the University of Chicago.