Controlling our DNA: the legal implications of CRISPR-Cas9

Science, Technology, and the Law

Controlling our DNA: the legal implications of CRISPR-Cas9

In 1928, Alexander Fleming discovered that a mold had contaminated one of his petri dishes and killed the bacteria growing in it. This mold defeated previously fatal infections and created one of the largest paradigm shifts in medical history. Howard Markel, The real story behind penicillin, PBS.com (Sept. 27, 2013), http://www.pbs.org/newshour/rundown/the-real- story-behind-the-worlds-first-antibiotic. Today, medical science is on the cusp of another monumental shift. In 2012, scientists discovered a way to quickly and cheaply edit genetic code. Abigail Beall, Genetically-modified humans: what is CRISPR and how does it work?, WIRED (Feb 5, 2017), http://www.wired.co.uk/article/crispr-cas9-technique-explained. This technique, known as CRISPR-Cas9, is remarkable because the possibilities are potentially endless. See Id.

The enormous implications of altering the genetic code of all organisms from small bacterial cells to larger eukaryotic cells in animals and human beings has raised important questions about how this technology should be developed, regulated and applied. The nearly limitless potential for medical therapies has also spurred heated patent battles around the world that are still being litigated. Sections one and two will provide scientific explanation and the ethical and regulatory concerns that CRISPR has raised. Section three will describe the current landscape of the patent battles in the United States, Europe, and China.

What is CRISPR?

Like Fleming’s discovery of penicillin, CRISPR-Cas9 was discovered by studying a bacterial cell under assault. When a bacteria is infected by a virus, an enzyme within the cell strips some of the DNA from an attacking virus cell and stores a record of that virus in its own DNA in case it is re-infected. Paul Knoepfler, GMO Sapiens: The Life-Changing Science of Designer Babies 258 (2016). These records are passed down from one generation to the next, allowing subsequent generations to mount rapid immune responses to viruses encountered by ancestral bacteria. Id. CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeat, refers to the way bacteria and other microorganisms organize their genomes[1], and Cas is the name of the enzyme that bacteria use to splice the new DNA strips into their genome. Abigail Beall, Genetically-modified humans: what is CRISPR and how does it work?, Wired (Feb 5, 2017), http://www.wired.co.uk/article/crispr-cas9-technique-explained. Since discovering this immune response in bacteria, researchers have experimented with using an enzyme called Cas9 to splice in and edit out specific genes in animal and even human cells. Id.

The technology is already creating exciting research possibilities including new therapies for genetic conditions, cancers and HIV. David Cyranoski & Sara Reardon, Chinese scientists genetically modify human embryos, Nature.com (April 22, 2015), https://www.nature.com/news /chinese-scientists-genetically-modify-human-embryos-1.17378 . Last year, researchers at Sichuan University in China injected a cancer patient with white blood cells that had been CRISPR-modified to attack cancer cells. Id. The researchers intend to continue the therapy with two to three more injections, while monitoring the patient for adverse reactions. Id. In June 2016, the United States National Institute of Health approved a similar proposal by the University of Pennsylvania. Concurrently, the US Department of Agriculture approved the first CRISPR-edited plants. How are governments regulating CRISPR and New Breeding Technologies (NBTs)?, Genetic Literacy Project (2016), https://gmo.geneticliteracyproject.org/FAQ/how-are-govern ments-regulating-crispr-and-new-breeding-technologies-nbts.

While the medical and agricultural applications are exciting, CRISPR has also raised concerns about the potential for germline editing. Sarah Ashley Barnett, Comment, Regulating Human Germline Editing in Light of CRISPR, 51 U. Rich. L. Rev 553, 559 (2017). Early CRISPR research, like the cancer study at Sichuan, have focused on somatic cells. Somatic cells are all of the cells in the body that are not reproductive, and therefore changes to these cells are not passed onto the next generation. Id. at 553. Conversely, germline editing changes reproductive cells, meaning that any alterations will remain in the gene pool and be passed to each subsequent generation. Id. Because of the possibility of creating long-term genetic diseases, or eugenically removing unfavorable traits in unborn children, ethicists worry that germline editing creates ethical and safety concerns that require careful consideration. Edward Lanphier et al., Don’t edit the human germ line, Nature.com (Mar. 12, 2015), http://www.nature.com/news/ don-t-edit-the-human-germ-line-1.17111#/.

The international concerns over genetic alteration to the human genome have been growing for decades. James Kozubek, Crispr-Cas9 Is Impossible to Stop, 18 Geo. J. Int’l Aff. 112, 144 (2017). In 1997, thirty-five countries signed and ratified the Oviedo Convention, an international treaty limiting alterations to the human genome. Id. Currently, germline editing is prohibited in forty countries. “[T]his consensus is especially visible in western Europe, where fifteen of twenty-two countries prohibit germline editing” Lanphier, supra. The United States is an outlier among western countries because it has no laws directly banning germline editing. However, a provision in the 2016 federal budget prohibited federal funding for its research. Consolidated Appropriations Act of 2016, Pub. L. No. 114-113, § 749, 129 Stat. 2283 (2015).

Ethicists including Hank Greely of Stanford Law School and Barbara Evans of Houston Law Center, have argued in favor of addressing the issue through state and national regulations rather than through international treaties. James Kozubek, Crispr-Cas9 Is Impossible to Stop, 18 Geo. J. Int’l Aff. 112 (2017). They point out that there are currently no international regulatory agencies with the capacity to enforce legal and ethical use of genetic technologies. Id. They argue that enforcement should be handled by national regulatory agencies who already regulate drugs, biotechnology, and intellectual property licenses. Id. Others contend however that the current regulatory framework in the US is insufficient to handle these questions. Barnett, supra Comment, at 577. The two main authorities that regulate gene transfer technology are the Food and Drug Administration (FDA), and the Recombinant DNA Advisory Committee (RAC) at the National Institute of Health (NIH). Id. The FDA regulates experiments that involve “human subjects,” meaning that laboratory experiments on human reproductive cells outside of the body are beyond their scope. Id. The RAC only regulates organizations that receive NIH funding. Id.

Bioethical concerns and regulation

The development of increasingly effective tools for gene editing has sparked serious debate among scientists about the ethical implications of heritable changes to human genetic code. In March 2015, a group of scientists called for a moratorium on all germline editing research. Lanphier supra. In the article, they highlighted three of the major concerns facing bioethicists about germline editing: non-therapeutic uses of CRISPR like ‘designer babies,’ the difficulty of obtaining informed consent from prospective parents, and the risk of unintended mutations. Id.

Since the discovery of CRISPR, dire predictions of the advent of ‘designer babies’ have lit up the internet and headlined print media. Bioethicists worry that germline editing for therapeutic purposes, like the elimination of genetic disorders, could be a slippery slope leading to aesthetic and non-essential edits. Alex Salkever & Vivek Wadhwa, When Baby Genes Are for Sale, the Rich Will Pay, Fortune.com (Oct. 23, 2017), http://fortune.com/2017/10/23/designer- babies-inequality-crispr-gene-editing/. They warn of the potential exacerbation of existing social inequality if fertility clinics are able to offer genetic enhancements to prospective parents. Id. Wealthier parents would have the means to ensure their children not only the best education, but also the best memory or problem-solving genes. See id.

The issue of informed consent arises from the uncertain consequences that germline changes could have on future generations. The scientists who called for the moratorium contend that “the precise effects of genetic modification may be impossible to know until after birth,” and “[e]ven then, the potential problems may not surface for years.” Lanphier, supra. These scientists fear that uncertainty about the possible negative effects of germline editing on subsequent generations could make informed consent difficult, as prospective parents will need adequate information about the risks of embryonic editing to their child, grandchildren and great grandchildren. Id.

The risk of a failed germline alteration also raise questions for the courts, which have limited liability for heritable defects caused by medical injury. See Enright v. Eli Lilly & Co., 570 N.E.2d 198 (N.Y. 1991) (holding that a drug manufacturer is liable when its product causes birth defects or stillbirths in infants whose mother took its product while pregnant, but not to the third generation. Noting the deterrence purposes of tort liability are maintained without risking overdeterrence and adverse effects on innovation). The courts will have to re-examine this question in light of the foreseeability of potential injury to the third, fourth, and fifth generations.

The concerned scientists argue that the dangers of editing the germline outweigh the potential benefits. They note that many of the benefits of genetic therapies can be accomplished without making heritable changes to the germline. These changes are riskier because early mistakes could have lasting consequences on future generations. See Lanphier, supra. In an experiment conducted last year by scientists at China’s Sun Yat-sen University, a small number of human cells were successfully edited using CRISPR. However, a much larger number were found to have “off target” mutations. David Cyranoski & Sara Reardon, Chinese scientists genetically modify human embryos, Nature.com (April 22, 2015), https://www.nature.com /news/chinese-scientists-genetically- modify-human-embryos-1.17378. The concerns over unintended mutations are magnified by a proliferation of “Do-It-Yourself” (DIY) gene editing kits. Stephanie M. Lee, This guy says he’s the first person to attempt editing his DNA with CRISPR, Buzzfeed News (Oct. 14, 2017), https://www.buzzfeed.com/stephaniemlee/this-biohacker- wants-to-edit-his-own-dna?utm_termveVPYykgd#.lrZ5ne62z. Josiah Zayner, a synthetic biologist and research fellow at NASA Ames Research Center, started an Indiegogo campaign that sold simple DIY kits for between $130 and $160 and, as of this writing, has raised over $71,000. Id. In laboratories and garages around the country, people are experimenting with gene editing with no oversight. Id. Zayner himself has made news recently by injecting himself with a CRISPR cocktail in a failed attempt to increase his muscle mass. Id. While Zayner’s attempt relied on an ill-conceived hypothesis, his DIY kits are feeding a growing movement of unregulated amateur genetic experimenters conducting CRISPR experiments in their garages. Id. As the supplier of this technology, Zayner may be liable in the event that one of his customer’s uses CRISPR in a negligent or even criminal way. He sells the technology over the internet with no way of knowing the experience level and intentions of his customers.

            As concerned bioethicists urge the scientific community to take a deliberate and careful approach to CRISPR research, Zayner’s campaign to proliferate the technology highlights the importance of instituting formal regulation of gene editing. If CRISPR technology remains largely unregulated, amateur geneticists will quickly drive the field of study away from solely therapeutic uses. Zayner has expressed interest in a world where intoxicated people can get CRISPR-powered body modifications instead of tattoos. Id. This type of unstructured experimentation is a recipe for serious genetic mishaps and misuses. Currently, these amateur CRISPR enthusiasts have mostly made beer glow; however, the low cost of equipment and ease of use has caused concern in the intelligence community. Antonio Regalado, Top U.S. Intelligence Official Calls Gene Edition a WMD Threat, MIT Technology Review (Feb. 9, 2016), https://www. technologyreview.com/s/600774/top-us-intelligence-official-calls-gene-editing-a-wmd-threat/ .

In February 2016, Director of National Intelligence James Clapper added gene editing to a list of weapons of mass destruction in the annual world threat assessment report. Id. Scientists have speculated that CRISPR could be used to make “killer mosquitos,” plagues to wipe out staple crops, or even a virus that damages the DNA of its carrier. Id. In September 2015, experts met in Warsaw to discuss the state of the Biological and Toxic Weapons Convention, a treaty banning the development of biological weapons which has been signed by the U.S., China, Russia, and 172 other countries. Id. The experts concluded that because developing bioweapons requires mastery of a wide range of technologies “for the foreseeable future, such applications are only within the grasp of states.” Id.

Intelligence experts remain concerned however that intentional creation of biological weapons is not the only way that this technology could be misused. Id. One of these experts is Daniel Gerstein, a senior policy analyst at RAND and a former undersecretary of the Department of Homeland Security. He says that “we are worried about people developing some sort of pathogen with robust capabilities, but we are also concerned about the chance of misutilization. We could have an accident occur with gene editing that is catastrophic, since the gene is the very essence of life.” Id.

Who will own it?

The battle of who will own the right to CRISPR is currently being fought in U.S. courts, and in patent offices worldwide. Research teams around the world began studying the CRISPR/Cas9 system, but a partnership between Jennifer Doudna, Ph.D. of UC Berkeley and Emmanuelle Charpentier, Ph.D. of the University of Vienna have been credited with the first laboratory uses of CRISPR-Cas9 to modify genes in whole bacterial cells. John Rennie, Emmanuelle Charpentier, Ph.D. And Jennifer Doudna, Ph.D., Dr. Paul Janssen Award for Biomedical Research (2016), https://www.pauljanssenaward.com/blogs/emmanuelle- charpentier-phd-and-jennifer-doudna-phd. Six months after Doudna and Charpentier published their findings, the Broad Institute at MIT and Harvard University built on their accomplishment by using the technology on larger, more complex eukaryotic cells. Sharon Begley, University of California appeals CRISPR patent setback, Statnews.com (Apr. 13, 2017), https://www.statnews .com/2017/04/13/crispr-patent-uc-appeal/ (hereinafter “Begley, CRISPR”).

While Doudna and Charpentier filed their application first, the Broad Institute expedited its patent application process and was approved first. Ryan Cross, CRISPR patent dispute ends well for Broad Institute. Berkeley says: Not so fast, C&En (Feb. 20, 2017), https://cen.acs.org/articles /95/i8/CRISPR-patent-dispute-ends-well.html. Fen Zhang, Ph.D. of the Broad Institute was granted 12 patents for the use of CRISPR-Cas9 technology in eukaryotic cells, such as animal and plant cells. Id. UC Berkeley and the University of Vienna brought a suit for patent interference arguing that the Broad Institute patent was a natural extension from their own invention on bacterial cells. Broad Inst., Inc. v. Univ. Cal., No. 106,048 (DK), 2017 WL 657415 (Patent Tr. & App. Bd. Feb. 15, 2017). The U.S. Patent Trial and Appeal Board (PTAB) sided with Broad and Harvard, and ruled that the patents cover different technologies and that there is no interference between the Broad patent claims and the Berkeley patent claims. Id.

This decision was a significant victory for Broad and a major setback for Berkeley and Vienna, who were left with a patent that many experts believe to be less valuable intellectual property. Begley, CRISPR. Berkeley and Vienna have appealed the decision before the U.S. Court of Appeals for the Federal Circuit, and the Broad Institute replied in October setting up the second round of oral arguments in early 2018. Heidi Ledford, Bitter CRISPR patent war intensifies, Nature.com (Oct. 26, 2017), https://www.nature.com/news/bitter-crispr-patent-war -intensifies-1.22892. The US Patent and Trademark Office has not yet issued Berkeley a patent for the use of CRISPR in all cell types. However, the race for international patents is still heating up. Companies formed by scientists from Berkeley and Vienna have founded several companies, which have signed a global cross-consent and invention management agreement. CRISPR Companies Ink IP Collaboration with Charpentier-UC Patent Holders, Genetic Engineering & Biotechnology News (Dec. 16, 2016), https://www.genengnews. com/gen-news-highlights/crispr-companies-ink-ip-collaboration-with-charpentier-uc-patent-holders/81253574 . The agreement coordinates efforts to prosecute patent violations, shares prosecution costs, and provides consents from all owners for existing and future licenses. Id.

In June, 2017, Intellia Therapeutics, co-founded by Dr. Doudna, was granted a broad patent by China’s State Intellectual Property Office (SIPO). Intellia, Holder of Rights to UC’s CRISPR Technology, to Win China Patent, Genetic Engineering & Biotechnology News (June 19, 2017), https://www.genengnews.com/gen-news-highlights/intellia-holder-of-rights-to-ucs- crispr-technology-to-win-china-patent/81254529 . The patent covered both bacterial cells and eukaryotic cells. Id. Intellia’s CEO, Nessan Bermingham praised the decision as “further global recognition that Jennifer Doudna, Emmanuelle Charpentier, and their team are the pioneers in the application of CRISPR/Cas9 in all cell types.” Id. Also in June, the European Patent Office (EPO) awarded a broad CRISPR technology patent to Charpentier, the University of Berkeley and the University of Vienna. Alex Philippidis, MilliporeSigma to Be Granted European Patent for CRISPR Technology, Genetic Engineering & Biotechnology News (Aug. 7, 2017), https://www.genengnews.com/gen-news-highlights/milliporesigma-to-be-granted-european- patent-for-crispr-technology/81254776 . In July, Collectis, a french biotech company, was granted a European patent for the use of CRISPR in T-cells. Jonathan Wosen, Collectis Granted T Cell CRISPR Patent in Europe, Genetic Engineering & Biotechnology News (July 25, 2017), https://www.genengnews.com/gen-news-highlights/cellectis-granted-t-cell-crispr-patent- in-europe/81254707 . The American life science business MilliporeSigma was granted an Australian patent in June, and announced in August that it had just been approved for a European patent for its CRISPR genomic integration method. Philippidis, supra. Jacob Sherkow, an associate professor at the Innovation Center for Law and Technology at NYU who has closely followed the patent fight, saw the European MilliporeSigma patent as potentially foreclosing a European patent to the Broad Institute. Id. The Broad Institute and DuPont Pioneer announced in October that they will be granting non-exclusive licenses to any organizations doing commercial agricultural research and development. Broad, DuPont Pioneer Partner to Provide Non-Exclusive Licenses to CRISPR IP (Oct. 18, 2007), https://www.genomeweb.com /business-news/broad-dupont-pioneer-partner-provide-non-exclusive-licenses-crispr-ip .

The ongoing battle for ownership of the technology has created significant uncertainty in the research community. Both sides have delegated licensing responsibility to surrogate companies who have begun granting licenses for CRISPR laboratory research, however neither side has certain control over future licenses. Jacob Sherkow, How Much is a CRISPR Patent License Worth?, Forbes (Feb. 21, 2017), https://www.forbes.com/sites/jacob sherkow/ 2017/02/21/how-much-is-a-crispr-patent-license-worth/#12d635a46b77. The combined patents for this technology will be the building blocks for twenty-first century medicine and is expected to be one of the most valuable biotechnologies ever developed by a research institution. Id. It is possible that Berkeley and Vienna will be awarded a U.S. patent for the bacterial cells, while Broad remains in possession of the more valuable patent for animal and plant cells. In this case, research teams will likely have to buy licenses from two sources to conduct CRISPR research in America.

Conclusion

The race to study genetic editing techniques and to develop new applications is just getting started. Research teams around the world are applying for patents and licenses to use CRISPR technology to take on cancer, HIV, and Alzheimer’s. As the applications begin to treat and cure diseases, the market demand for CRISPR-powered products will grow. After each success, society will likely become increasingly comfortable using gene editing for both therapeutic purposes and eventually nontherapeutic uses. It is important to heed the warnings of the scientific community to develop legal and ethical parameters before the technology is developed. Concerned scientists are calling for a more deliberative approach, encouraging the international community to “slow down, ask difficult questions beyond the science, and make conscious and well-considered decision[s].” See Katrine S. Bosley et al., Supplementary Comments, CRISPR Germline Engineering–The Community Speaks, 33 NATURE BIOTECH. 478-86 (2015), http:// www.nature.com/nbt/journal/v33/n5/extref/nbt.3227-S1.pdf. The responsibility of ensuring that this technology is not abused will fall on researchers and clinicians, but it will also fall on courts and legislatures. The United States will have to commit to developing a regulatory regime that is flexible enough to allow American companies to compete with the international market, while strict enough to prevent unintended societal and medical consequences.

 

 

 

 

 

 

 

 

 

 

 

 

[1] A genome is a full set of DNA, including all genes.