When is $100 million not $100 million? When it’s a proxy, maybe even something akin to a bet.
The nice, round figure is the target initial public offering value for Editas Medicine, a biotechnology firm with a mission of using gene editing to treat disease. The company has already raised more than $160 million from investors, and initial evaluations of the IPO said it was almost certain to be exceeded when the stock started trading publicly.
But Editas could face a big problem. The company has hitched its fortunes to CRISPR,1 a revolutionary gene-editing technology embroiled in concerns over ethics and, most immediately, a patent dispute. Editas licensed the technology in 2014 from the patent holder, scientists from the Broad Institute of MIT and Harvard, as part of its research into genomic medicine, including cancer immunotherapies. But earlier this month, the U.S. Patent and Trademark Office accepted a challenge to the Broad Institute group’s patent from the University of California, which is backing a rival group of scientists. Without licensing from the eventual winner of the patent fight, Editas and other companies investing in commercial CRISPR research could be blocked from marketing products based on the intellectual property in question, putting at risk hundreds of millions of dollars in investment.
CRISPR holds the promise to transform the human species in ways yet unknown and it has quickly gone from being written about only in scientific journals to receiving global media coverage. It is sometimes called the Microsoft Word of gene editing for its relative low cost and ease of use for researchers. It uses Cas9, a protein derived from bacteria, and a tailored guide RNA sequence to cut and splice material from or into the DNA helix. “Companies will apply this tech to a range of inventions as sophisticated as pharmaceutical research and as mundane as industrial technologies like yogurt creation,” said Robin Feldman, a patent law expert at the University of California Hastings College of the Law. As a result, “the value of licensing within the field of CRISPR/Cas9 is phenomenally high,” she said. CRISPR-derived treatments for conditions including HIV are the closest to becoming a reality, by far. But the technology’s applications in germline editing, which can change a patient’s — or an embryo’s — DNA permanently to cure a genetic disease, for example, or to select for brown eyes, may become the huge industry moneymakers.
CRISPR’s ability to rewrite the helix and allow the human species to make self-directed (and perhaps misdirected) genetic leaps has drawn a mix of devotees and detractors, but it’s one of the hottest investments in a sector that’s experiencing something of a gold rush. In 2015, the biotechnology industry ranked second only to software in total investment dollars among sectors tracked by Thomson Reuters, with $1.5 billion flowing to biotech in the fourth quarter alone. Between 1995 and 2015, the U.S. biotechnology industry brought in more than $81 billion in financing. Most of the money is going to established companies and technologies; that said, hundreds of millions of dollars are being poured into seeking commercial applications for CRISPR, and yet more into research and licensing here and abroad.
It’s impossible to know the exact financial potential for CRISPR and related technologies, but the earnings from past biotech successes illustrate why the sector is such an attractive investment category, even at such high risk. The first successful live birth from in vitro fertilization — then called a “test-tube baby” — took place in 1978. As of 2012, IVF was a $9.3 billion global industry; analysts predict the market may grow by an average of 7 percent annually over the next five years, at a time when many global investment indices are performing poorly. A May 2015 report estimated the genome editing industry to be worth $3.5 billion by 2019.
Scientists from Montana State University, which has a robust gene-editing research program, assessed investments in CRISPR for a paper published in the journal Current Opinion in Virology in June. “In total, companies with an interest in using Cas9 for applications related to gene therapy have raised over $600 million in venture capital and public markets since the beginning of 2013,” they found. Companies with significant investment dollars in CRISPR research include Horizon Discovery Group, Caribou Biosciences, CRISPR Therapeutics and Intellia Therapeutics.
Many of these investments are now in jeopardy because every company that wants to take a product to market based on CRISPR/Cas9 is legally obligated to pay a licensing fee to the patent holder and the patent is in dispute. Companies like Editas eager to reap the potential rewards of the technology are taking a chance and moving forward with licenses from either the Harvard/MIT group or the University of California one, while others are waiting to see which giant wins the fight.2 (Editas declined to comment, citing the quiet period before its IPO.)
A change in patent law is part of what’s complicating the math and strategy driving CRISPR investments. In March 2013, the U.S. patent system switched from a “first to invent” to a “first to file” system, following the passage of the America Invents Act. A day earlier, the University of California filed a patent application for CRISPR based on the intellectual property of scientists Jennifer Doudna and Emmanuelle Charpentier. But a team from the Broad Institute of MIT and Harvard, led by bioengineer Feng Zhang, fast-tracked a rival application, asking to be evaluated under the old “first to invent” standard, and got approval first. Doudna’s team is challenging the patent, saying that it was not only first to file but also first to invent. There’s still a chance the parties will negotiate a settlement, but Doudna acknowledged at a conference last month that she had “no idea” when the patent issue would be resolved, adding that “these things often take quite a long time.”
The patent fight over CRISPR is like a high-stakes poker game with a dose of caveat emptor for investors. “Investors in biotech darn well know that this is fraught with investment danger,” said Paul Leiman, who teaches the business law of biotechnology at Johns Hopkins University’s Carey Business School.
But biotech companies may still benefit from the research into CRISPR no matter what happens in the patent fight. In some cases, they can develop subsidiary technologies or products and market them even without owning or licensing the original intellectual property. For example, Myriad Genetics helped discover two variants of the breast-cancer-causing gene BRCA in the mid-1990s and tried to patent them. Myriad faced a challenge and lost at the Supreme Court (the justices ruled ruled unanimously in 2013 that isolating existing human genes was not patentable). But the company’s business is now largely based on intellectual property related to the BRCA discovery but not affected by the court’s decision: a proprietary database mapping outcomes and associated risks for BRCA carriers. Some of the firms investing in CRISPR research may likewise use the technology to inform other proprietary work rather than seek to use it directly.
The stakes in the patent case, and regarding CRISPR and gene editing more broadly, are not all financial. There are larger questions of whether gene editing will be used to combat disease (somatic treatments) or also used to permanently alter heritable traits (germline editing). The technology’s potential applications for the latter can start to sound like echoes of eugenics. In a November New Yorker article, Doudna revealed that she had a nightmare in which Hitler approached her asking to use the technology.
Eugenics is widely known as one of the specious justifications of the Holocaust, but science has often been used to promote normative judgments about “desirable” offspring, including in the long history of forced sterilizations in the U.S. (In one recent example, an investigation by the Center for Investigative Reporting found that from 2006 to 2010, doctors working on contract for the California Department of Corrections and Rehabilitation sterilized nearly 150 female inmates, violating the system’s own regulations.) At a recent conference on human gene editing, a panel of ethicists wondered what human traits would be tagged for elimination by scientists using CRISPR or similar technologies. For example, if scientists found a way to eliminate Asperger’s syndrome, would embryos be “corrected” in spite of evidence that Asperger’s may contribute to cognitive biodiversity?
“When it comes to children, most people, it’s safe to say, would choose characteristics that would give them an advantage,” said Marcy Darnovsky, executive director of the Center for Genetics and Society, a think tank that researches the ethical and societal implications of genetic technology and advocates for a moratorium on germline experimentation. “You might say that advantage is highest for tall, light-skinned, male people with a certain type of intelligence … and there we are back in the 20th-century eugenics world.” Darnovsky also worries about a possible “Gattaca scenario of haves and have nots.” That, in her estimation, would happen if germline editing became something that the wealthy could access routinely but few others could afford.
These ethical questions and how scientists and governments choose to answer them will inform what companies are able to do with CRISPR and how much money they can make. In addition to the patent fight, there’s the question of regulation, which will play out differently in different nations, even as bioengineering firms and investors seek to become global multinationals. For example, during its last budget approval process, Congress effectively banned the editing of human embryos. A 2014 study of 39 nations found that 25 — including many in Europe, plus Canada, Australia, Mexico and Brazil — had banned germline editing by law.
In March, a host of scientists called for a moratorium on germline experiments. Within weeks, a group of Chinese scientists reported that they had edited non-viable human embryos — a step considered so ethically questionable that the journals Science and Nature would not publish the findings. In response, the National Academy of Sciences and the National Academy of Medicine convened an International Summit on Human Gene Editing to discuss the road ahead.
Dana Carroll, a pioneering molecular biologist at the University of Utah, is excited by the promise of CRISPR but realistic about the medical, ethical and market-based challenges that it creates. Somatic therapies “don’t seem so much like playing God,” he said. Yet, “it’s very likely that some people somewhere are going to go ahead with human germline genome editing,” he said. “So we can talk about moratoria, we can talk about bans, but it’s easy enough [to use CRISPR] that there are people somewhere who are going to forge ahead with the technology.”
Perhaps, given the mix of scientific curiosity and human nature, we should be prepared for the possibility that anything that can be done with this technology will be done — legally or extralegally, said Joi Ito, who is director of the MIT Media Lab and tracks developments in bioengineering and other technologies. “If history is any guide, things like germline editing, non-medical somatic editing (basics like hair or skin color but eventually extending into editing our fundamental personalities and physical capabilities) are inevitable,” he said in an email. “So rather than calling for broad-based bans it’s important to get out in front and proactively work on standards and guidelines with a broad set of stakeholders.” Those stakeholders include investors, but also the public and government entities.
“When a technology is so revolutionary and so simple to use, it can’t be bottled up,” said Feldman of UC Hastings. “Science will move forward and not on the Patent and Trademark Office’s timeline.” She sees the government’s move to consider Doudna’s patent challenge as a major shift for CRISPR and gene-editing technologies — and the companies eager to license them. “But at the end of the day, the train’s going to move forward anyway.”
Anne Li contributed reporting.
CORRECTION (Jan. 28, 12:18 p.m.): An earlier version of this story incorrectly described a 2013 Supreme Court ruling on gene patents. The court prohibited patents on human genes, not on human genomes. (A genome is a full set of thousands of genes.)