News Article | March 4, 2016
Getting a full readout of your entire genetic sequence promises to radically alter how we monitor our health, providing advanced warning of cancer and other diseases we may suffer and our chances of passing on those ailments. Clinical genetic testing firm Illumina is valued at nearly $23 billion, for example, while direct-to-consumer offering 23andMe is at about $1 billion. Meanwhile, the price for so-called whole genome sequencing has dropped to about $1,000. But such whole-genome sequencing currently over-promises in several ways. One of them is a false sense of what constitutes a "normal" genome with which to compare someone's results. (The U.S. government's National Institutes of Health provides a narrow, widely used model.) The promise is best if you're white, and drops off fast for other ethnicities, like people of African origin. That’s because we simply don't have easy access to enough reference genomes, from a big enough variety of people, to understand the range of normal. Nor is there much willingness for companies that analyze genomes to look at all the varieties that are out there. Geneticists aren't blind to this problem. In fact, it's been a big topic of discussion at the Future of Genomics conference, a gathering of top genetics experts and entrepreneurs in San Diego. One solution is to simply share existing databases of sequenced genomes (in anonymized form). "We have an enormous and rapidly increasing quantity of genomic information," said David Haussler, a researcher at the UC Santa Cruz Genomics Institute. "And where is that? It's held in silos all over the world." Haussler is a leader of a project called the Global Alliance for Genomics and Health. Instead of building a master database of genetic data, the alliance is modeling itself on the way that consumer online services and apps work: creating common application programming interfaces (APIs) so that anyone can plug into any database with the same software. (It's a biotech process like the one that, for example, allows you to access a cloud service like Dropbox from within an app like Slack). The Alliance is an open-source project, with all the code available on free programmer community GitHub. The project is not just an academic endeavor. Among the nearly 400 members from about 40 countries, it has recruited about 120 companies, ranging from traditional tech firms like Google and Microsoft to genetic testing firms like Color Genomics, which focuses on consumer breast cancer screening. Haussler says that companies are willing to give up some data in order to get info from others that makes their services better. "We collaborate on the interface, but we compete on the implementation," he said. "And we're getting creative products out of it." But not everyone goes for that argument. Myriad Genetics, for instance, tried to patent the genes that cause breast cancer. However, a 2013 Supreme Court case invalidated their patents on genes, which enabled the emergence of many competing firms. The Global Alliance for Genomics and Health has several projects, such as a deep dive on how the genes for breast cancer vary from patient to patient. (12,000 versions have been found so far.) Another effort, the Human Genome Variation Map, focuses on comparing the full genomes of people from around the world. Even the scarce data now commonly available shows just how varied normal DNA is. As an example, Haussler showed a spaghetti graph of squiggly lines—each representing the majority of genes that encode the human immune system. These variations are included in the U.S. government's reference genome (called GRCh38). One line is the reference that almost everyone uses, and the other seven are official variations. "Why those seven?" asked Haussler. "Because that's all we had. Is it a fair representation? No. Does anybody use them? No." One piece of good news is that getting more genetic samples may not require digging deeply into old databases that are hard to make compatible. It's enough to make sure that the new data is easily accessible, according to Haussler. "The amount of genome data we will create next year dwarfs all previous historical genome data," he said.
Scientists hail CRISPR/Cas9 as more accurate and efficient than other, now-traditional genetic engineering methods. As a result, CRISPR has generated worldwide debate about how it could accelerate the manipulation of plants, animals and even human beings at the molecular level. That some DNA modifications can be passed on to future generations raises particular concern. But the patent dispute, focusing on whether scientists at the Broad Institute of MIT and Harvard or those at University of California, Berkeley invented the technology, seems far from these ethical concerns. Each institution asserts that its scientists are the rightful inventors – and therefore the owners of the CRISPR/Cas9 patents. As proof, the scientists are submitting their published articles, laboratory notebooks and affidavits to the US Patent and Trademark Office, which will make a decision in the next few months. This decision will influence whose name will go down in the history books, and perhaps also who will receive a Nobel Prize. And it will determine which institution will make millions by licensing use of the patented invention to researchers at other universities and companies. But amid all the breathless anticipation, we've been ignoring two important lessons from the CRISPR/Cas9 patent dispute: patent systems no longer fit the realities of how science works, and patents give their owners significant control over the fate and shape of technologies. Do we need patents to stimulate innovation? The U.S. patent system was built on the idea that the promise of an exclusive right to commercialize a technology for a limited period of time provided an important innovation incentive. Even today, this argument is used to justify strong patent systems across the world. But as basic science and applied technology have become increasingly difficult to distinguish, and more university scientists are receiving patents on ground-breaking discoveries like CRISPR, the old rules no longer seem to make sense. The modern patent system was built with individual entrepreneurs and discrete machines in mind. But university-based science is usually incremental and collaborative, driven by the hopes of tenure, promotion, grant funding, respect among colleagues and, if extremely lucky, a major scientific discovery. Indeed, whichever emerging CRISPR history you read, you learn about a series of discoveries made by an international array of professors, postdoctoral fellows and students, driven by intellectual curiosities across multiple, seemingly disconnected topics. As they got involved, the Broad's Feng Zhang, Berkeley's Jennifer Doudna and the Max Planck Institute's Emmanuelle Charpentier, the scientists involved in the U.S. patent fight, were surely motivated by the excitement that they might get credit for a major biotechnology breakthrough. But to think that patents were a major motivator is a serious misunderstanding of how science works and what drives scientists. Most, if not all, of the patent revenues, after all, will go to their institutions and not to them personally. We have seen similar situations before in the world of biotechnology. When there are dozens of participants and multiple motivations, it's enormously difficult – if not simply incorrect – to identify one person or institution as deserving the credit. Furthermore, especially in cases where there is widespread scientific involvement, patents ultimately become more hindrance than help, forcing scientists already working in the field to apply for licenses in order simply to continue. For all these reasons, it's time to consider a more nuanced approach to patents in biotech, one that disentangles innovation and the public interest from profits. Power of patents, in absence of regulations The CRISPR dispute also highlights how patents influence the social and ethical consequences of a technology. We tend to focus on how patents assign credit, facilitate financial gain for their owners, and therefore shape the marketplace. But the control that patent offices award extends much further than that, particularly in the absence of regulations. As patent holders decide whether and how to license their technologies, they can determine the shape a particular field takes, the technologies that become available, who has access to them, and what kind of access they have. At present, despite CRISPR's potential to enable relatively simple human genetic engineering that could be passed down through generations and broad support for national and international laws to govern its development and use, there are no U.S. laws governing CRISPR research or technology. This lack of regulation means that whichever institution is eventually awarded the CRISPR patents will have enormous control over how the controversial technology develops. Its licensing decisions will essentially determine what kinds of research will take place in embryos, whether there will be limits on this research, and what kinds of human genetic engineering might become commercially available. Consider a similar situation, the now-famous case of biotechnology company Myriad Genetics' patents on the BRCA genes, which confer increased susceptibility for breast and ovarian cancer. In the mid-1990s, Myriad used its patents to establish a monopoly over BRCA gene testing in the United States. In the absence of regulations around genetic testing, the company's patents gave it control not only over who could offer BRCA gene testing but also how the technology was built and made available. This had important ethical and social implications. Myriad Genetics, which obviously had an interest in widespread use of its technology, essentially had the freedom to set standards about when and how BRCA gene testing would be made widely available, even in the face of significant uncertainties about the meaning of the test results and the treatment options available. And because it did not require that users seek testing through a genetics specialist, BRCA gene test users often had to wade through these complicated uncertainties on their own. (Years later, civil society groups launched an unprecedented court challenge that eventually led the U.S. Supreme Court to revoke these patents in 2013.) CRISPR's future use in one institution's hands Despite the enormous power the CRISPR patent holder will have in shaping the development and use of the new technology, we know little about how the Broad or Berkeley will handle it. Both institutions emphasize their commitments to the public interest, and particularly in licensing the technologies widely and cheaply to other nonprofit institutions. But neither has addressed these ethical questions. Will their licensing agreements include language that prevents the use of CRISPR for human gene editing, for instance? Or a requirement that licensees comply with National Institutes of Health guidelines that may emerge, even if those institutions do not use NIH funds? Both Doudna and Zhang have acknowledged the ethical challenges at stake and articulated their support for regulatory frameworks governing the use of CRISPR in people. But we don't know whether their institutions are thinking about how to develop systematic approaches to these issues in their licensing decisions. Particularly in the absence of a U.S. regulatory framework, the patent holder should address these ethical issues proactively and in a transparent manner. Consulting with ethicists, historians and social scientists who are experts in the topic can help developers understand who might stand to lose and win with CRISPR's development, how to avoid the eugenic mistakes of our past and how these ethical and social concerns are connected deeply to decisions about CRISPR patents and licenses. And in the future, we should seriously consider the importance of the patent system – almost by default – in shaping the moral dimensions of science and technology.
News Article | January 13, 2016
The U.S. government is finally on its way to closing one of the health sector's most controversial loopholes. Test kits that are sold to hospitals or directly to patients as medical devices are regulated by the Food and Drug Administration, but it does not oversee tests that are designed in a single laboratory with all the samples being sent there. These LDTs, or lab-developed tests, include Myriad Genetics' breast cancer risk test, the noninvasive prenatal tests for Down syndrome, and tests from the controversial startup Theranos, among others. Experts say that thousands of these medical diagnostic tests have never been scrutinized for accuracy and reliability. "There's never been any real regulation at the federal level of whether these lab tests are meaningful," Hank Greely, director of the Center for Law and the Biosciences at Stanford University, told Fast Company. Others say that the loophole is in the best interests of patients, particularly those with rare diseases. Cary Gunn, the president and CEO of San Diego-based diagnostics company Genalyte, says that many of the life-saving, innovative tests on the market start out as LDTs. Once physicians start to use the test, the test-makers will often move ahead with an expensive regulatory process. "For esoteric diseases like ALS, where it's difficult to justify the cost of a commercial filing, the tests almost always stay as LDTs," he added. But that loophole could close soon. In 2014, FDA released a draft guidance proposing how they'll regulate LDTs, and the House and the Senate are both considering new legislation. How did this category of tests evade regulation for decades? Historically, according to Greely, LDTs have been monitored by the College of American Pathologists—every clinical lab has a pathologist—as well as a statute called CLIA. This helps ensure that labs are treating samples appropriately and sending back the right results. Neither of these entities hold lab companies accountable for how they interpret the test results and diagnose diseases. Moreover, CLIA lacks the authority to mandate that lab-testing companies report adverse events, like side effects. Therefore, the public has no way of knowing if the product isn't working. This approach may have been sensible enough in past years when labs were small-scale and developing tests for very niche needs. But circumstances have changed. Nowadays, tests are becoming "more complicated, more strange, and more important," Greely explained. And the sheer number of lab tests has exploded with recent advances in human gene-sequencing. Some health experts are growing increasingly concerned that inaccurate test results could cause potential harm to patients, particularly those with cancer and other serious diseases. "If cancer patients and their physicians are to make life-changing decisions on the basis of diagnostic tests, they must be assured that such tests are reliable and provide clinically meaningful information," The Cancer Leadership Council, an advocacy group, wrote in a letter to the government last year. "It’s critical that when patients and their doctors use such a test, they know the results can be trusted," Calaneet Balas, chief executive of the Ovarian Cancer National Alliance, said in a statement in July of 2014. The FDA is also concerned about the risk of inaccurate tests. At the recent hearing, the FDA's Jeffrey Shuren stressed that the agency wanted to ensure that these tests "are accurate, reliable, and that they do, in fact, identify a disease." The agency has made it clear that it wants to regulate LDTs and protect patients. So why aren't LDT's regulated? "Politics," says Bradley Merrill Thompson, an attorney with the firm Epstein, Becker & Green who specializes in FDA law. "The lab industry has long been vocally complaining to any who will listen, and brandishing its political sword in the form of lobbying and threatened litigation." Indeed, resistance has been fierce for decades. A handful of Republican lawmakers spoke out against regulation of LDTs at the The Energy and Commerce's Subcommittee on Health in November, citing the lack of patient complaints. "My office isn't being overrun by calls from doctors and patients saying that there are some terrible LDTs out in the marketplace," said Congressman Joe Barton (R-TX). But the tide does seem to be turning against the critics of regulation. Theranos generated some public awareness of the issue last year when it voluntarily went to the FDA with the goal of getting its LDTs cleared for use. And the FDA has addressed its critics by promising a phased approach to regulation, which would focus on the highest-risk LDTs. "There has been talk of the industry softening its opposition," said Greely. "But predicting politics is never easy."
Rejections for US patents related to personalized medicine have spiked after recent Supreme Court decisions tightened the rules for such claims, an analysis of more than 39,000 patent applications reveals. The data, presented on 11 August at the Intellectual Property Scholars Conference in Stanford, California, address patent applications in eight categories that commonly include personalized-medicine patents. They show that following a key Supreme Court decision in 2012, the US Patent and Trademark Office (USPTO) was nearly four times more likely to deem subjects of such applications unpatentable — and applicants were less than half as likely to overcome those rejections. “The change in office actions was absolutely striking,” says Nicholson Price, who studies intellectual property at the University of Michigan Law School in Ann Arbor. “The data are very clear that the patent office has changed its behaviour.” Over the past decade, the Supreme Court has used a series of patent cases to clarify what the USPTO should consider patentable. Natural phenomena and abstract ideas, for example, are not patentable, according to section 101 of the US patent code, and the court has attempted to distinguish between these categories and true inventions. Two of those Supreme Court cases touched directly on the biomedical industry. In 2012, the Mayo Collaborative Services v. Prometheus Laboratories, Inc. decision struck down two patents on medical diagnostics, and in the 2013 Association for Molecular Pathology v. Myriad Genetics ruling, the court threw out patents on gene sequences used to assess cancer risk. In the wake of those decisions, many lawyers predicted that patents on inventions that are important to personalized medicine — particularly, diagnostic tests that could match individuals to a particular therapy — would be hard to come by, potentially driving away investors. Legal scholar Bernard Chao of the University of Denver in Colorado decided to find out just how big the impact has been. Chao sifted through around 85,000 records of USPTO actions taken on more than 39,000 patent applications, and sorted out those that had been rejected for not meeting the requirements of section 101. He found that last year, 22.5% of those office actions were rejections because of section 101, compared with only 5.5% in 2011, the year before the Mayo decision. Applicants were also less likely to overcome those rejections in the wake of the Mayo decision: before Mayo, 70.7% of the section 101 rejections were successfully overcome. After Mayo, that percentage dropped to 29.7%. But Chao notes that there are caveats to his analysis: the categories he examined omit some personalized-medicine patents and contain other kinds of patents as well. In the future, he hopes to take a closer look at individual patent applications, and to learn more about whether certain applications are more likely to get through than others. Those analyses will be key to finding out how patent applicants are adapting to the new requirements, says Price. “Patent attorneys are clever,” he says, and may have learned how to construct their patents to avoid conflict with the recent decisions. Others have documented a clear effect of the Supreme Court’s patent decisions on software patent applications. But some have cheered that change, Chao adds. Software patents are controversial, and some scholars have argued that such patents cause more harm to the industry than help it. Personalized-medicine patents, however, tend to get more support: “Personalized medicine is probably the poster child of what we think should be incentivized by patents.” Ultimately, it will be difficult to unravel what impact the patent decline is having on the personalized-medicine industry, cautions Arti Rai, a legal scholar at Duke University in Durham, North Carolina. The sector is facing challenges from several sides: the US Food and Drug Administration has proposed tougher regulations, and insurance companies have been reluctant to pay for new diagnostic tests. “Diagnostics start-ups are not in a good space right now, that’s clear,” Rai says. “But how much of that is due to Mayo is less clear.”
Milk-producing skin glands evolve during the Late Triassic period in a group of egg-laying proto-dinosaurs called cynodonts. Instead of sweat or scent, these early mammaries produce a simple milk to supplement the diet of hatchlings. Over time, these glands grouped together under nipples and began responding to sex hormones such as oestrogen. A medical text from ancient Egypt contains the first known reference to breast cancer. It describes 48 surgical problems, including “bulging tumours on the breast”. The unknown author describes “swellings on [the] breast, large, spreading and hard: touching them is like touching a ball of bandages”. It would be some time before surgeons could offer anything beyond a diagnosis. The author's take on treatment: “there is nothing”. During a 2015 excavation of the Egyptian necropolis Qubbet el-Hawa near Aswan, a team led by Egyptologists and anthropologists from the University of Jaén in Spain discovered a coffin with remarkable contents: bones of a woman, showing the tell-tale deformations of metastatic breast cancer (pictured). She died some 4,200 years ago, making her the first known victim of the disease. Doctors begin to embrace the possibilities — and limitations — of surgery for breast cancer. In eleventh-century Moorish Spain, the noted surgeon Abu al-Qasim al-Zahrawi writes that breast cancer could be cured when “complete removal [of the tumour] is possible, and especially when in the early stage and small. But when it is of long standing and large, you should leave it alone. I myself have never been able to cure such, nor have I seen anyone else succeed before me”. French surgeon Barthélémy Cabrol suggests that advanced breast cancer could be cured by removing the underlying chest muscles along with the breast. Others will attempt variations on this idea for centuries, with often dismal results. Emil Grubbe, an electronics enthusiast and medical student at the Hahnemann Medical College in Chicago, Illinois, assembles one of the earliest X-ray devices. A colleague remarks on the radiation burns on Grubbe's hands and suggests that X-rays might be used against unhealthy tissue. The first recorded instance of radiation oncology occurs later that year when Grubbe's machine is used to irradiate a breast carcinoma in a woman named Rose Lee. She reportedly received several hour-long treatments and died shortly thereafter. Robert Egan starts to develop effective mammography, an X-ray examination that can detect breast tumours that are too small to be felt. By the 1970s, mammography has become a popular screening test for women. The National Surgical Adjuvant Breast and Bowel Project shows that surgery combined with chemotherapy works better against breast cancer than surgery alone. Combined treatments become the standard of care. The oestrogen-blocking drug tamoxifen (pictured) is approved in the United States as a treatment for advanced metastatic breast cancer. Today, tamoxifen is one of many hormone-blocking drugs used worldwide to treat — and in some cases prevent — certain types of breast cancer. Mary-Claire King and colleagues ( et al. Science 250, 1684–1689; 1990) use samples of DNA from families with a history of breast cancer to establish a link between mutations in a tumour-suppressing gene she names BRCA1 and an elevated risk of breast and ovarian cancer. The discovery changed thinking about genetic influences on cancer. Further research showed that mutations in another gene, BRCA2, could also increase cancer risk. Today, some women who test positive for these mutations — including actress Angelina Jolie (pictured) — choose to have their breasts removed to reduce their cancer risk. The US Nurses' Health Study reveals that hormone replacement therapy (HRT) increases the risk of developing breast cancer. At the time, HRT was popular both to treat and prevent menopausal symptoms among post-menopausal women. Today, HRT is no longer routinely recommended for long-term use in post-menopausal women. Charles Perou and colleagues ( et al. Nature 406, 747–752; 2000) show that breast cancers can be grouped into clinical subtypes on the basis of mutations in their DNA. Analysis of tumour-cell DNA enables doctors to choose treatments that are more likely to be effective. The subtype of 'triple-receptor-negative' breast cancer is particularly difficult to treat because these cancers do not respond to signals from any of the breast growth hormones: oestrogen, progesterone and human epidermal growth factor 2. Two large studies show that people with breast cancer live just as long after small lumpectomy surgery combined with radiation as they do after radical mastectomy. Further studies show that only a narrow 2-millimetre 'clean margin' of healthy tissue needs to be removed along with the cancer in a lumpectomy. The US Preventive Services Task Force recommends that women should be offered a mammogram first at age 50, and then every other year after — a departure from previous advice to start annual screening at age 40. The change sparks debate about the balance between the harm of unnecessary treatment and the risk of undiagnosed cancers. In the case Association for Molecular Pathology v. Myriad Genetics, the US Supreme Court overturns molecular-diagnostics company Myriad's patents on the genetic codes of BRCA1 and BRCA2. The court's decision states that “a naturally occurring DNA segment is a product of nature and not patent eligible”, although tests to find specific harmful mutations are still considered patentable. In 2015, breast-cancer survival rates are at their highest ever. More than 6 million people worldwide are still alive 5 years after being diagnosed with breast cancer, although survival rates continue to lag in areas without reliable access to advanced medicine. Breast cancers are now treated with tailored combinations of surgery, chemotherapy and radiation, and continued research is making treatments more precise and minimizing side effects.