CRISPR gene-editing becomes big business
Gene editing is starting to become truly "big business", according to this profile from New Yorker magazine. Patent litigation is ongoing to identify who owns the rights to the underlying technology. CRISPR, and venture-capital firms are investing millions to gain exposure to technology that has wide-ranging implications for not just human afflictions, but potentially crop blights and livestock disease too. Many are worried about its repercussions, however, Professor of Chemistry and of Molecular Biology at Berkeley and pioneer of CRISPR researcher, Jennfier Doudna, has been particularly outspoken about the potential for harm. She has called for a research moratorium in May of this year, following the publication of research from China, in which scientists used CRISPR to repair the gene responsible for betathalassemia. 

“And now we have our model,” Platt said, explaining that the mouse had just received an injection that carried three probes, each of which was programmed to carry a mutation that scientists believe is associated with lung cancer. “The cells will carry as many mutations as we want to study. That really is a revolutionary development.”

“In the past, this would have taken the field a decade, and would have required a consortium,” Platt said. “With CRISPR, it took me four months to do it by myself.” In September, Zhang published a report, in the journal Cell, describing yet another CRISPR protein, called Cpf1, that is smaller and easier to program than Cas9.

The lab employs a similar approach to studying autism. Recent experiments suggest that certain psychiatric conditions can be caused by just a few malfunctioning neurons out of the trillions in every brain. Studying the way neurons function within the brain is difficult. But by re-creating, in the lab, genetic mutations that others have linked to autism and schizophrenia Zhang’s team has been able to investigate faulty neurons that may play a role in those conditions.

As the price of sequencing plunges, cancer clinics throughout the United States have begun to study their patients’ tumors in greater detail. Tumors are almost never uniform; one may have five mutations or fifty, which means, essentially, that every cancer is a specific, personal disease. Until CRISPR became available, the wide genetic variations in cancer cells often made it hard to develop effective treatments.

“What I love most about the CRISPR process is that you can take any cancer-cell line, knock out every gene, and identify every one of the cell’s Achilles’ heels,” Eric Lander, the fifty-eight-year-old director of the Broad, told me recently. Lander, who was among the leaders of the Human Genome Project, said that he had never encountered a more promising research tool. “You can also use CRISPR to systematically study the ways that a cancer cell can escape from a treatment,” he said. “That should make it possible to build a comprehensive road map for cancer.”

Lander went on to say that each vulnerability of a tumor might be attacked by a single drug. But cancer cells elude drugs in many ways, and, to succeed, a therapy may need to block them all. That strategy has proved effective for infectious diseases like AIDS. “Remember the pessimism about H.I.V.,” he said, referring to the early years of the AIDS epidemic, when a diagnosis was essentially a death sentence. Eventually, virologists developed a series of drugs that interfere with the virus’s ability to replicate. The therapy became truly successful, however, only when those drugs, working together, could block the virus completely.

The same approach has proved successful in treating tuberculosis. Lander is convinced that it will also work for many cancers: “With triple-drug therapy,” for H.I.V., “we reached an inflection point: we were losing badly, and one day suddenly we were winning.”

He stood up and walked across the office toward his desk, then pointed at the wall and described his vision for the future of cancer treatment. “There will be an enormous chart,” he said. “Well, it will be electronic, and it will contain the therapeutic road map of every trick that cancer cells have—how they form, all the ways you can defeat them, and all the ways they can escape and defeat a treatment. And when we have that we win. Because every cancer cell starts naïve. It doesn’t know what we have waiting in the freezer for it. Infectious diseases are a different story; they share their knowledge as they spread. They learn from us as they move from person to person. But every person’s cancer starts naïve. And this is why we will beat it.”

Developing any technology as complex and widely used as CRISPR invariably involves contributions from many scientists. Patent fights over claims of discovery and licensing rights are common. Zhang, the Broad Institute, and M.I.T. are now embroiled in such a dispute with Jennifer Doudna and the University of California; she is a professor of chemistry and of molecular biology at Berkeley. By 2012, Doudna, along with Emmanuelle Charpentier, a medical microbiologist who studies pathogens at the Helmholtz Centre for Infection Research, in Germany, and their lab teams, demonstrated, for the first time, that CRISPR could edit purified DNA. Their paper was published that June. In January of 2013, though, Zhang and George Church, a professor of genetics at both Harvard Medical School and M.I.T., published the first studies demonstrating that CRISPR could be used to edit human cells. Today, patents are generally awarded to the first people to file—in this case, Doudna and Charpentier. But Zhang and the Broad argued that the earlier success with CRISPR had no bearing on whether the technique would work in the complex organisms that matter most to scientists looking for ways to treat and prevent diseases.

Zhang was awarded the patent, but the University of California has requested an official reassessment, and a ruling has not yet been issued. Both he and Doudna described the suit to me as “a distraction” that they wished would go away. Both pledged to release all intellectual property to researchers without charge (and they have). But both are also involved in new companies that intend to develop CRISPR technology as therapies, as do many pharmaceutical firms and other profit-seeking enterprises.

Copy link to cartoon Copy link to cartoon Shop Shop

CRISPR research is becoming big business: venture-capital firms are competing with one another to invest millions, and any patent holder would have the right to impose licensing fees. Whoever wins stands to make a fortune. Other achievements are also at stake, possibly including a Nobel Prize. (Doudna’s supporters have described her as America’s next female Nobel Prize winner, and at times the publicity war seems a bit like the battles waged by movie studios during Academy Award season.) Last year, the National Science Foundation presented Zhang with its most prestigious award, saying that his fundamental research “moves us in the direction” of eliminating schizophrenia, autism, and other brain disorders. A few months later, Doudna and Charpentier received three million dollars each for the Breakthrough Prize, awarded each year for scientific achievement. The prize was established, in 2012, by several Silicon Valley billionaires who are seeking to make science a more attractive career path. The two women also appeared on Time’s annual list of the world’s hundred most influential people.

In fact, neither group was involved in the earliest identification of CRISPR or in the first studies to demonstrate how it works. In December, 1987, biologists at the Research Institute of Microbial Diseases, in Osaka, Japan, published the DNA sequence of a gene taken from the common intestinal bacterium E. coli. Those were early days in the genomic era, and thousands of labs around the world had embarked on similar attempts to map the genes of species ranging from fruit flies to humans. In an effort to better understand how this particular gene functioned, the Japanese scientists also sequenced some of the DNA that surrounded it. When they examined the data, they were surprised to see cellular structures that none of them recognized: they had no idea what to make of the strange phenomenon, but they took note of it, writing in the final sentence of their report, published in the Journal of Bacteriology, that the “biological significance of these sequences is not known.”

The mystery remained until 2005, when Francisco Mojica, a microbiologist at the University of Alicante, who had long sought to understand CRISPR, decided to compare its DNA with the DNA of tens of thousands of similar organisms. What he saw amazed him: every unknown sequence turned out to be a fragment of DNA from an invading virus.

The pace of research quickened. In 2007, Rodolphe Barrangou and Philippe Horvath, microbiologists then working for Danisco, the Danish food company, had noticed that some of its yogurt cultures were routinely destroyed by viruses and others were not. They decided to find out why. The scientists infected the microbe Streptococcus thermophilus, which is widely used to make yogurt, with two viruses. Most of the bacteria died, but those which survived had one property in common: they all contained CRISPR molecules to defend them.

“No single person discovers things anymore,” George Church told me when we met in his office at Harvard Medical School. “The whole patent battle is silly. There has been much research. And if anybody should be making a fuss about this I should be making a fuss. But I am not doing that, because I don’t think it matters. They are all nice people. They are all doing important work. It’s a tempest in a teapot.”

From the moment that manipulating genes became possible, many people, including some of those involved in the experiments, were horrified by the idea of scientists in lab coats rearranging the basic elements of life. In 1974, David Baltimore, the pioneering molecular biologist, who was then at M.I.T., and Paul Berg, of Stanford, both of whom went on to win a Nobel Prize for their research into the fundamentals of viral genetics, called for a moratorium on gene-editing research until scientists could develop safety principles for handling organisms that contained recombinant DNA. That meeting, which took place in 1975, at a conference center in Asilomar, California, has come to be regarded as biotechnology’s Constitutional Convention.

Roughly a hundred and fifty participants, most of them scientists, gathered to discuss ways to limit the risks of accidentally releasing genetically modified organisms. At the time, the possibility of creating “designer babies”—a prospect that, no matter how unlikely, is attached to almost everything written or said about CRISPR—was too remote to consider. Nevertheless, the technology seemed frightening. In Cambridge, home to both M.I.T. and Harvard, the city council nearly banned such research altogether. The work went on, but decoding sequences of DNA wasn’t easy. “In 1974, thirty base pairs”—thirty rungs on the helical ladder of the six billion nucleotides that make up our DNA—“was a good year’s work,” George Church told me. Now the same work would take seconds.

At least for the foreseeable future, CRISPR’s greatest impact will lie in its ability to help scientists rapidly rewrite the genomes of animal and plant species. In laboratories, agricultural companies have already begun to use CRISPR to edit soybeans, rice, and potatoes in an effort to make them more nutritious and more resistant to drought. Scientists might even be able to edit allergens out of foods like peanuts.

Normally, it takes years for genetic changes to spread through a population. That is because, during sexual reproduction, each of the two versions of any gene has only a fifty per cent chance of being inherited. But a “gene drive”—which is named for its ability to propel genes through populations over many generations—manages to override the traditional rules of genetics. A mutation made by CRISPR on one chromosome can copy itself in every generation, so that nearly all descendants would inherit the change. A mutation engineered into a mosquito that would block the parasite responsible for malaria, for instance, could be driven through a large population of mosquitoes within a year or two. If the mutation reduced the number of eggs produced by that mosquito, the population could be wiped out, along with any malaria parasites it carried.

Kevin Esvelt, an evolutionary biologist at Harvard, was the first to demonstrate how gene drives and CRISPR could combine to alter the traits of wild populations. Recently, he has begun to study the possibility of using the technology to eliminate Lyme disease by rewriting the genes of mice in the wild. Lyme disease is caused by a bacterium and transmitted by ticks, and more than eighty-five per cent of the time they become infected after biting a mouse. Once exposed, however, some mice naturally acquire resistance or immunity. “My idea is to take the existing genes that confer resistance to Lyme and make sure that all mice have the most effective version,’’ Esvelt said. To do that, scientists could encode the most protective genes next to the CRISPR system and force them to be passed on together. Esvelt stressed that such an approach would become possible only after much more research and a lengthy series of public discussions on the risks and benefits of the process.

Copy link to cartoon Copy link to cartoon Shop Shop

The promise of CRISPR research becomes more evident almost every month. Recently, Church reported that he had edited sixty-two genes simultaneously in a pig cell. The technique, if it proves accurate and easy to repeat, could help alleviate the constant shortage of organ donors in the U.S. For years, scientists have tried to find a way to use pig organs for transplants, but a pig’s DNA is filled with retroviruses that have been shown in labs to infect human cells. Church and his colleagues discovered that those viruses share a common genetic sequence. He deployed CRISPR to their exact locations and snipped them out of the genome. In the most successful of the experiments, the CRISPR system deleted all sixty-two of the retroviruses embedded in the pig’s DNA. Church then mixed those edited cells with human cells in the laboratory, and none became infected.

While cRISPR will clearly make it possible to alter our DNA, serious risks remain. Jennifer Doudna has been among the most vocal of those calling for caution on what she sees as the inevitable march toward editing human genes. “It’s going to happen,” she told me the first time we met, in her office at Berkeley. “As a research tool, CRISPR could hardly be more valuable—but we are far from the day when it should be used in a clinical setting.” Doudna was a principal author of a letter published in Science this spring calling for a temporary research moratorium. She and others have organized a conference to discuss the ethics of editing DNA, a sort of Asilomar redux. The conference, to be attended by more than two hundred scientists—from the U.S., England, and China, among other countries—will take place during the first week of December at the National Academy of Sciences, in Washington.

Until April, the ethical debate over the uses of CRISPR technology in humans was largely theoretical. Then a group at Sun Yat-sen University, in southern China, attempted to repair, in eighty-six human embryos, the gene responsible for betathalassemia, a rare but often fatal blood disorder. If those disease genes, and genes that cause conditions like cystic fibrosis, could be modified successfully in a fertilized egg, the alteration could not only protect a single individual but eventually eliminate the malady from that person’s hereditary lineage. Given enough time, the changes would affect all of humanity. The response to the experiment was largely one of fear and outrage. The Times carried the story under the headline “Chinese Scientists Edit Genes of Human Embryos, Raising Concerns.”