Thursday, July 13, 2017

The Brave New World of Gene Editing

In the last few years, genetic testing has entered the commercial mainstream. Direct-to-consumer testing is now commonplace, performed by companies such as 23andMe (humans have twenty-three pairs of chromosomes). Much of the interest in such tests is based not only on the claim that they enable us to trace our ancestry, but also on the insight into our future health that they purport to provide. At the beginning of April, 23andMe received FDA approval to sell a do-it-yourself genetic test for ten diseases, including Parkinson’s and late-onset Alzheimer’s. You spit in a tube, send it off to the company, and after a few days you get your results. But as Steven Heine, a Canadian professor of social and cultural psychology who undertook several such tests on himself, explains in DNA Is Not Destiny, that is where the problems begin.

Some diseases are indeed entirely genetically determined—Huntington’s disease, Duchenne muscular dystrophy, and so on. If you have the faulty gene, you will eventually have the disease. Whether you want to be told by e-mail that you will develop a life-threatening disease is something you need to think hard about before doing the test. But for the vast majority of diseases, our future is not written in our genes, and the results of genetic tests can be misleading. (...)

More troublingly still, however imperfect its predictive value, the tsunami of human genetic information now pouring from DNA sequencers all over the planet raises the possibility that our DNA could be used against us. The Genetic Information Nondiscrimination Act of 2008 made it illegal for US medical insurance companies to discriminate on the basis of genetic information (although strikingly not for life insurance or long-term care). However, the health care reform legislation recently passed by the House (the American Health Care Act, known as Trumpcare) allows insurers to charge higher premiums for people with a preexisting condition. It is hard to imagine anything more preexisting than a gene that could or, even worse, will lead to your getting a particular disease; and under such a health system, insurance companies would have every incentive to find out the risks present in your DNA. If this component of the Republican health care reform becomes law, the courts may conclude that a genetic test qualifies as proof of a preexisting condition. If genes end up affecting health insurance payments, some people might choose not to take these tests.

But of even greater practical and moral significance is the second part of the revolution in genetics: our ability to modify or “edit” the DNA sequences of humans and other creatures. This technique, known as CRISPR (pronounced “crisper”), was first applied to human cells in 2013, and has already radically changed research in the life sciences. It works in pretty much every species in which it has been tried and is currently undergoing its first clinical trials. HIV, leukemia, and sickle-cell anemia will probably soon be treated using CRISPR.

In A Crack in Creation, one of the pioneers of this technique, the biochemist Jennifer Doudna of the University of California at Berkeley, together with her onetime student Samuel Sternberg, describes the science behind CRISPR and the history of its discovery. This guidebook to the CRISPR revolution gives equal weight to the science of CRISPR and the profound ethical questions it raises. The book is required reading for every concerned citizen—the material it covers should be discussed in schools, colleges, and universities throughout the country. Community and patient groups need to understand the implications of this technology and help decide how it should and should not be applied, while politicians must confront the dramatic challenges posed by gene editing.

The story of CRISPR is a case study in how scientific inquiry that is purely driven by curiosity can lead to major advances. Beginning in the 1980s, scientists noticed that parts of the genomes of microbes contained regular DNA sequences that were repeated and consisted of approximate palindromes. (In fact, in general only a few motifs are roughly repeated within each “palindrome.”) Eventually, these sequences were given the snappy acronym CRISPR—clustered regularly interspersed short palindromic repeats. A hint about their function emerged when it became clear that the bits of DNAfound in the spaces between the repeats—called spacer DNA—were not some random bacterial junk, but instead had come from viruses and had been integrated into the microbe’s genome.

These bits of DNA turned out to be very important in the life of the microbe. In 2002, scientists discovered that the CRISPR sequences activate a series of proteins—known as CRISPR-associated (or Cas) proteins—that can unravel and attack DNA. Then in 2007, it was shown that the CRISPR sequence and one particular protein (often referred to as CRISPR-Cas9) act together as a kind of immune system for microbes: if a particular virus’s DNA is incorporated into a microbe’s CRISPR sequences, the microbe can recognize an invasion by that virus and activate Cas proteins to snip it up.

This was a pretty big deal for microbiologists, but the excitement stems from the realization that the CRISPR-associated proteins could be used to alter any DNA to achieve a desired sequence. At the beginning in 2013, three groups of researchers, from the University of California at Berkeley (led by Jennifer Doudna), Harvard Medical School (led by George Church), and the Broad Institute of MIT and Harvard (led by Feng Zhang), independently showed that the CRISPR technique could be used to modify human cells. Gene editing was born.

The possibilities of CRISPR are immense. If you know a DNA sequence from a given organism, you can chop it up, delete it, and change it at will, much like what a word-processing program can do with texts. You can even use CRISPR to introduce additional control elements—for example to engineer a gene so that it is activated by light stimulation. In experimental organisms this can provide an extraordinary degree of control in studies of gene function, enabling scientists to explore the consequences of gene expression at a particular moment in the organism’s life or in a particular environment.

There appear to be few limits to how CRISPR might be used. One is technical: it can be difficult to deliver the specially constructed CRISPR DNA sequences to specific cells in order to change their genes. But a larger and more intractable concern is ethical: Where and when should this technology be used? In 2016, the power of gene editing and the relative ease of its application led James Clapper, President Obama’s director of national intelligence, to describe CRISPR as a weapon of mass destruction. Well-meaning biohackers are already selling kits over the Internet that enable anyone with high school biology to edit the genes of bacteria. The plotline of a techno-thriller may be writing itself in real time. (...)

The second half of A Crack in Creation deals with the profound ethical issues that are raised by gene editing. These pages are not dry or abstract—Doudna uses her own shifting positions on these questions as a way for the reader to explore different possibilities. However, she often offers no clear way forward, beyond the fairly obvious warning that we need to be careful. For example, Doudna was initially deeply opposed to any manipulation of the human genome that could be inherited by future generations—this is called germline manipulation, and is carried out on eggs or sperm, or on a single-cell embryo. (Genetic changes produced by all currently envisaged human uses of CRISPR, for example on blood cells, would not be passed to the patient’s children because these cells are not passed on.)

Although laws and guidelines differ among countries, for the moment implantation of genetically edited embryos is generally considered to be wrong, and in 2015 a nonbinding international moratorium on the manipulation of the human germline was reached at a meeting held in Washington by the National Academy of Sciences, the Institute of Medicine, the Royal Society of London, and the Chinese Academy of Sciences. Yet it seems inevitable that the world’s first CRISPR baby will be born sometime in the next decade, most likely as a result of a procedure that is intended to permanently remove genes that cause a particular disease. (...)

Like many scientists and the vast majority of the general public, Doudna remains hostile to changing the germline in an attempt to make humans smarter, more beautiful, or stronger, but she recognizes that it is extremely difficult to draw a line between remedial action and enhancement. Reassuringly, both A Crack in Creation and DNA Is Not Destiny show that these eugenic fantasies will not succeed—such characteristics are highly complex, and to the extent that they have a genetic component, it is encoded by a large number of genes each of which has a very small effect, and which interact in unknown ways. We are not on the verge of the creation of a CRISPR master race.

Nevertheless, Doudna does accept that there is a danger that the new technology will “transcribe our societies’ financial inequality into our genetic code,” as the rich will be able to use it to enhance their offspring while the poor will not. Unfortunately, her only solution is to suggest that we should start planning for international guidelines governing germline gene editing, with researchers and lawmakers (the public are not mentioned) encouraged to find “the right balance between regulation and freedom.”

by Matthew Cobb, NY Review of Books |  Read more:
Image: Anthony A. James/UC Irvine
[ed. Ever get the feeling that there's some kind of morbid inevitability to technological progress? I'm not sure what'll kill us first: nuclear warheads, climate change, gene editing, artificial intelligence, biological weapons, or politicians.]