CRISPR Nobel Laureates and Their Gene-Editing Companies: From Breakthrough Science to Clinical Commercialization

On October 7, 2020, the Nobel Prize in Chemistry was announced. French biochemist Emmanuelle Charpentier and American biologist Jennifer Doudna were awarded this year’s prize for their contributions to the development of CRISPR, a next-generation gene-editing technology.

Emmanuelle Charpentier, born in 1968, is currently the Director of the Max Planck Unit for the Science of Pathogens and a Visiting Professor at Umeå University in Sweden. Jennifer Doudna, born in 1964, is currently a Professor in the Department of Chemical and Biomolecular Engineering at the University of California, Berkeley.

Doudna grew up in Hawaii, attended Pomona College and Harvard University, and later taught at the University of California, Berkeley. A structural biologist with a primary focus on RNA molecules, Doudna became interested in CRISPR with the aim of using X-ray diffraction to study its three-dimensional structure and elucidate how it recognizes viral DNA molecules.

In the spring of 2011, Professor Doudna from the University of California, Berkeley, traveled to Puerto Rico to attend the annual meeting of the American Society for Microbiology. During the conference, another female scientist, Charpentier, approached Doudna. Charpentier had discovered that a Cas protein, in conjunction with two RNA molecules, could recognize and cleave DNA. During their exchange, Charpentier sought Doudna’s expertise on several questions regarding RNA, and this conversation ultimately led to the inception of the CRISPR research project.

At that time, CRISPR had been discovered by multiple scientists, but its mechanism was not fully understood. Two female scientists began collaborating across their respective laboratories and ultimately demonstrated that the CRISPR/Cas9 system could serve as a next-generation gene-editing tool, publishing their findings in Science in 2012. Compared with previous techniques, this approach reduced the workload of gene editing to approximately 1/100 of the original level. However, early studies were conducted only in prokaryotic cells such as bacteria.

Recognizing the potential of CRISPR/Cas9, numerous laboratories began to follow suit. In early 2013, three labs successively demonstrated that the CRISPR/Cas9 system could efficiently edit the human genome. In addition to the Doudna team, Feng Zhang from the Broad Institute and George Church from Harvard Medical School published papers showing precise gene editing in eukaryotic cells. Zhang’s lab even demonstrated that multiple guide RNAs could be used simultaneously to perform highly efficient, multiplexed, and precise surgical operations on the genome.

George Church of Harvard Medical School and Feng Zhang of the Broad Institute have played pivotal roles in the study of TALEN proteins, serving as key drivers in the field of gene editing. Born in China and raised in the United States, Feng Zhang graduated from Harvard University in 2004 with a degree in Chemical Physics, earned his Ph.D. in Chemistry and Chemical Biology from Stanford University in 2009, and joined the Massachusetts Institute of Technology in 2011. Feng Zhang, a Chinese scientist with an extraordinary career trajectory, was involved in pioneering the field of optogenetics as early as 2005.

Experimental records submitted by Feng Zhang indicate that he began researching CRISPR/Cas9 technology in 2011, the same year Jennifer Doudna met Emmanuelle Charpentier. That year, Zhang attended a conference at the Broad Institute, where he heard a speaker casually mention the CRISPR immune system in bacteria. Zhang read all available literature on the subject. He placed particular emphasis on a 2010 paper by a Canadian biologist that highlighted the specific role of the Cas9 protein. By 2012, his experimental results had been validated. In January 2013, Zhang, as the corresponding author, and his student Le Cong, as the first author, published a paper in Science describing how to apply CRISPR gene-editing technology to plant, animal, and human cells.

Another ExpertGeorge ChurchGeorge Church has long been a renowned figure and a luminary in the field of biology. He joined Harvard Medical School as an Assistant Professor in 1986. A geneticist and chemist, he is celebrated for pioneering the fields of personal genomics and synthetic biology. In 1984, Church and Walter Gilbert published a method for direct genomic sequencing; some of the strategies outlined in that paper are still employed in next-generation sequencing technologies today. He currently serves as Professor of Genetics at Harvard University and Director of the Center for Genomic Research at Harvard Medical School. He also previously served as the postdoctoral mentor to Feng Zhang. In early 2013, Church’s paper demonstrating the application of the CRISPR system for genome editing in human cells was published in Science.

The timeline of the scientists’ research disclosures is roughly as outlined above. So, why did a protracted patent dispute subsequently erupt? Although Jennifer Doudna of the University of California was the first to publicly disclose her findings on CRISPR/Cas9 and filed a patent application in May 2012, the Broad Institute, when submitting its patent application in 2013, utilized the expedited examination pathway by paying an additional $70 fee, thereby securing the CRISPR/Cas9 patent ahead of the University of California.

The University of California certainly could not stand by and let a patent with enormous commercial value slip away, and the ensuing patent dispute dragged on for several years. The United States followed a “first-to-invent” system for granting patents, rather than a “first-to-file” system. Consequently, both sides began presenting evidence of their research processes and documentation. Feng Zhang of the Broad Institute also submitted thousands of pages of materials to demonstrate that his research had begun in 2011, prior to the publication of Doudna’s paper in 2012.

Moreover, the Broad Institute submitted evidence demonstrating that Doudna’s early research was conducted in prokaryotic cells, and she has publicly stated on multiple occasions that gene editing in eukaryotic cells presents significant challenges. In contrast, Zhang Feng’s paper described gene editing performed in eukaryotic cells, achieving successful modifications in mice and even primates. Furthermore, the scope of his patent application specifically covers eukaryotic cells, underscoring the creativity and innovativeness of his invention, which is not merely a laboratory replication of Doudna’s work.

In February 2017, the Patent Trial and Appeal Board (PTAB) of the United States declared that the patent granted by the United States Patent and Trademark Office (USPTO) to the Broad Institute for CRISPR-based editing of eukaryotic genomes did not interfere with the relevant patents held by the University of California. In September 2018, the United States Court of Appeals for the Federal Circuit upheld the PTAB’s decision. The Broad Institute will continue to hold intellectual property rights for the use of CRISPR gene editing in eukaryotes, which represents the most lucrative application area of this technology.

However, U.S. patent rulings do not determine patent ownership in other jurisdictions. In many regions worldwide, including Europe and China, CRISPR patents have been granted to the University of California, Berkeley. A spokesperson for the Broad Institute stated that it hopes to strengthen collaboration with the University of California and reach an agreement to resolve the patent dispute, through either direct cooperation or via a patent pool.

The dispute over CRISPR patents lasted for seven years. During this period, the main research teams on both sides had already begun to capitalize on the commercial value of CRISPR, establishing companies to apply the technology in commercial sectors. Initially, Feng Zhang and his ally George Church sought to collaborate with Jennifer Doudna and others on patent matters. They co-founded Editas Medicine; however, shortly thereafter, the patent battle between Doudna and Zhang erupted. Doudna left Editas and founded Intellia Therapeutics. These companies have applied gene-editing technologies to address human diseases, developing novel therapies to tackle medical challenges that previously remained unsolved.

It was widely expected that CRISPR technology would win the Nobel Prize. It is regrettable that another key scientist, Feng Zhang, missed out on this year’s award. We hope that in the future, scientists in the CRISPR field will once again be awarded the Nobel Prize in Physiology or Medicine for their contributions to solving more human diseases.

The commercial application of gene editing primarily involves editing and modifying specific defective genes to address genetic disorders caused by genetic mutations or to enhance immunity against certain diseases. Most drug development efforts by biotechnology companies specializing in gene editing are still in the experimental stage.

Scientists must first identify specific gene targets associated with the disease. Next, gene-editing therapies undergo preclinical trials, including in vitro laboratory studies or animal testing. If the preclinical trials proceed successfully, the company applies for regulatory approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) to initiate clinical trials in humans.

As gene editing is still in its nascent stages, it is difficult to predict precise market growth figures. A report by Research and Markets states that the global gene editing market will grow at a compound annual growth rate (CAGR) of 17% to reach $10.7 billion by 2025. On the other hand, Grand View Research offers a less optimistic outlook, estimating that the global gene editing market will reach $8.1 billion by 2025.

In the long term, many diseases can be targeted with gene editing therapies. Furthermore, other non-genetic diseases, including certain types of cancer, can also be treated using gene editing therapies that modify the body’s immune cells to combat disease. Therefore, the market opportunities presented by gene editing are likely to far exceed the market size previously discussed.

The patent dispute over CRISPR stems from the unimaginable market potential of gene editing in the future, where patent licensing fees will generate substantial revenue for the parties involved. While these experts have been engaged in extensive patent litigation, they have simultaneously continued to commercialize the technology. Beyond securing patent licenses, accelerating the commercialization of the technology to develop gene therapy drugs represents another avenue for monetizing their innovations.

This article will review the core business operations, financing status, and R&D pipelines of the companies associated with the two research and development teams, examining their applications of gene editing in the commercial sector as well as their corporate development histories. We have identified a total of eight companies affiliated with these scientists, revealing extensive collaboration among scientists from different teams.

CRISPR Scientists and Their Companies

Established in: 2013

Founders: Feng Zhang, Jennifer Doudna (later withdrew), David Liu, George Church, J. Keith Joung

Company Stage: IPO listing on February 3, 2016

Market Capitalization: $1.776 billion

The founders of Editas Medicine demonstrate that the company has assembled nearly all the luminaries in the field of CRISPR gene editing. In addition to Feng Zhang, Jennifer Doudna, David Liu, and George Church, J. Keith Joung is also a pioneer of ZFN (zinc-finger nuclease) technology, the first generation of gene-editing tools. However, Doudna departed from the company shortly after its establishment.

The company’s mission is to translate its genome editing technology into a novel therapeutic approach for human diseases, enabling precise correction of disease-causing factors at the genetic level. The company has filed numerous patent applications and holds intellectual property rights to foundational genome editing technologies, which will allow it to convert early-stage discoveries into viable human therapeutics.

Prior to its Nasdaq listing, Editas Medicine secured three rounds of financing. The Series A round was completed in 2013, raising $43 million from investors including Third Rock Ventures, Polaris Partners, Partners Innovation Fund, and Flagship Pioneering.

The second round of financing occurred in May 2015, with Juno Therapeutics making an exclusive investment of $47 million. Concurrently, Juno entered into an agreement with Editas Medicine to leverage the latter’s CRISPR technology for the joint development of cancer immunotherapies, including CAR-T and TCR therapies. This collaboration is projected to generate total revenues of $737 million for Editas.

In August 2015, Editas raised $120 million in financing from investors including Microsoft co-founder Bill Gates, Google, Deerfield Management, and Khosla Ventures.

Currently, Editas’ gene therapy drug development is still in its early stages, with a primary focus on gene therapies for inherited eye diseases, the treatment of rare genetic disorders, and even efforts to increase crop yields. In January 2018, co-founder Feng Zhang published an article in Nature demonstrating that CRISPR/Cas9 editing technology successfully restored hearing in mouse models of human hereditary deafness.

In January this year, Editas published another paper in Nature Medicine. The company’s candidate genome-editing therapeutic, EDIT-101, removes the aberrant splice donor site generated by the IVS26 mutation in the CEP290 gene, thereby restoring normal CEP290 expression and treating Leber congenital amaurosis type 10 (LCA10), a severe retinal dystrophy caused by CEP290 gene mutations.

EDIT-101 is a drug developed by Editas in collaboration with Allergan in 2017, for which Editas received a $25 million milestone payment from Allergan. On December 1, 2018, the FDA accepted the company’s Investigational New Drug (IND) application for EDIT-101, permitting clinical trials to evaluate the use of CRISPR gene-editing technology for treating patients with Leber Congenital Amaurosis type 10 (LCA10). Editas completed dosing of the first patient in March 2020, making EDIT-101 the first in vivo CRISPR therapeutic administered to patients.

Another Editas project that quickly entered clinical testing is a CRISPR therapy for β-thalassemia and sickle cell disease (SCD). Although CRISPR Therapeutics gained an early advantage in this field, Editas believes its gene-editing approach is superior to that of its competitors because it more effectively preserves the function of hematopoietic stem cells. EDIT-301, as a candidate gene-edited cell therapy, has been granted Rare Pediatric Disease (RPD) designation by the U.S. FDA and is currently being developed for the treatment of sickle cell disease.

The CAR-T and T-cell receptor (TCR) therapies developed by Editas and Juno are still in the early stages of research, with no clinical trial plans announced yet.

Established in: 2017

Founders: Feng Zhang, David R. Liu, J. Keith Joung, John Evans

Company Stage: IPO

Market Cap: $1.502 billion

Compared with Editas, the founding team of Beam Therapeutics, established in 2017, includes Feng Zhang, David Liu, and J. Keith Joung, along with John Evans, who previously served as an investment manager at Agios. Beam Therapeutics is dedicated to leveraging gene-editing technology to perform precise single-base-pair edits in DNA and RNA for the treatment of genetic diseases.

More than half of the gene errors associated with genetic diseases are caused by single-base changes among the billions of bases that make up the genome. Currently, Beam Therapeutics’ gene-editing technology enables precise editing of individual bases (A, G, C, T) within genes, allowing for the knockout or insertion of specific genes without cutting DNA or RNA strands. This novel gene-editing approach developed by Beam Therapeutics holds promise for the prevention and cure of genetic disorders.

Prior to this, Beam Therapeutics secured $87 million in Series A financing on May 14, 2018. On March 6, 2019, Beam Therapeutics completed a $135 million Series B financing round. New investors in this round included Redmile Group, LLC, Cormorant Asset Management, Google GV, Altitude Life Science Ventures, and other undisclosed investors. Existing investors F-Prime Capital and ARCH Venture Partners also participated in this round. On February 6, 2020, Beam went public on the Nasdaq.

Established: 2016

Founders: David Scott, David Walt, Feng Zhang, Winston Yan

Company Stage: Unknown Round

Total Funding: $15.6 million

Compared with the other two companies co-founded by Feng Zhang, Arbor Biotechnologies is less well-known, with very little related news coverage. Information about the company was initially disclosed in filings with the U.S. Securities and Exchange Commission (SEC). Founders David Scott and Winston Yan are both former doctoral students of Feng Zhang. In an interview, the two founders discussed their work and study experiences in Feng Zhang’s laboratory, describing it as a place full of vitality, creativity, and intellectual freedom. In June 2017, Arbor Biotechnologies completed a $15.6 million Series A financing round led by investors including ARCH Venture Partners and Faridan Ventures.

Based on the introduction, Arbor’s vision is to build a novel protein discovery platform that integrates artificial intelligence, genomic sequencing, gene synthesis, and high-throughput screening technologies. By deeply mining the natural genetic diversity of peptides and proteins, the company aims to identify novel molecules for improving human health.

In fact, the company’s inaugural achievement was also CRISPR-related. Leveraging this platform, the co-founders of Arbor Biotechnologies discovered the Cas13d protein. Although belonging to the Cas13 family, Cas13d is smaller in size than other members, endowing it with greater potential for practical applications. Researchers have demonstrated its promise for RNA regulation and high-sensitivity diagnostics. This January, Vertex Pharmaceuticals entered into a collaboration agreement with Arbor Biotechnologies to develop novel CRISPR endonucleases aimed at advancing gene-editing therapies for cystic fibrosis and four other genetic disorders.

Established in: 2018

Founders: Feng Zhang, Jim Collins

Company Stage: Series A

Financing Amount: $35 million

Sherlock Biosciences has just been founded and secured $35 million in financing. In April 2017, the team led by CRISPR pioneer Feng Zhang first described SHERLOCK in a paper as a rapid, low-cost, and highly sensitive diagnostic tool based on CRISPR technology. A core technology of Sherlock Biosciences is SHERLOCK, which has been licensed from the Broad Institute of MIT and Harvard. Professor Feng Zhang is also a co-founder of Sherlock Biosciences and serves as Chair of its Scientific Advisory Board.

Year Established: 2011

Founders: James Berger, Jennifer A. Doudna, Martin Jinek, Rachel E. Haurwitz

Company Stage: Series B

Total Financing: $74.6 million

Caribou Biosciences was founded in 2011 with the aim of consolidating the CRISPR/Cas9 intellectual property generated by the Doudna Laboratory at the University of California, Berkeley. Caribou has been dedicated to commercially licensing Doudna’s intellectual property and selling it as a research and development toolkit to other companies for various applications in human and veterinary medicine, agriculture, and industrial processes.

Doudna is one of Caribou’s two scientific advisors; the other is Martin Jinek, a former member of Doudna’s laboratory, co-author of the landmark 2012 CRISPR paper, and collaborator with Doudna and Charpentier. Caribou also helped establish another CRISPR gene-editing company, Intellia Therapeutics. Prior to its initial public offering (IPO), Caribou completed four rounds of financing—two Series A rounds and two Series B rounds—raising a total of $74.6 million.

However, Caribou is also attempting to transform itself from a “platform” company—a technology platform that helps other companies develop drugs and other products—into a product-focused company. This shift mirrors the transformation many biotechnology firms are undertaking as they enter the pharmaceutical industry, aiming to pursue higher-profit but also higher-risk business opportunities.

Recently, in a speech at the University of California, San Francisco, company founder Doudna outlined a timeline for Caribou’s transformation: completing an Investigational New Drug (IND) application in the near term and initiating clinical trials within 18 months.

Established in: 2014

Founders: Andy May, Derrick Rossi, Erik Sontheimer, Jennifer A. Doudna, Luciano Marraffini, Nessan Bermingham, Rachel E. Haurwitz, Rodolphe Barrangou

Company Stage: IPO on May 6, 2016

Market Capitalization: $756 million

Intellia Therapeutics holds a license to Caribou Biosciences’ CRISPR intellectual property, with Doudna serving as a co-founder. Intellia Therapeutics primarily focuses on the application of gene editing for disease treatment. Strictly speaking, Intellia was jointly established by Caribou Biosciences and Atlas Venture. Caribou Biosciences licensed its technology to Intellia, making it the exclusive licensee for human therapeutic applications. Additionally, Novartis obtained a five-year, non-exclusive license from Intellia for the use of CRISPR technology in in vivo therapies.

Atlas Venture and Novartis invested $15 million in Intellia Therapeutics’ Series A financing round. In 2015, Intellia secured $70 million in Series B funding from eight institutional investors. Subsequently, on May 6, 2016, Intellia went public on the NASDAQ, and its current market capitalization stands at $756 million.

Caribou licensed its CRISPR/Cas9 technology to Intellia for therapeutic use in humans. However, in a regulatory filing dated October 31 of last year, Intellia disclosed that it had entered into arbitration with Caribou two weeks earlier, alleging that Caribou had breached the 2014 licensing agreement. The two companies have engaged in a dispute over patent licensing, and Intellia has listed Caribou as one of its competitors in gene editing.

In Intellia’s pipeline, the diseases primarily targeted by in vivo therapies include transthyretin amyloidosis, alpha-1 antitrypsin deficiency, and hepatitis B virus infection, while ex vivo therapies mainly focus on hematopoietic stem cell transplantation and CAR-T cell therapy. All of these programs are currently in early-stage development, and the current development stage of the CAR-T program in collaboration with Novartis has not been publicly disclosed.

Established in: June 2017

Founders: Ashley Tehranchi, Janice Chen, Jennifer A. Doudna, Lucas Harrington, Trevor Martin

Company Stage: Series A

Total Funding: $24.6 million

Mammoth Biosciences, founded in June 2017, does not employ CRISPR gene-editing technology for therapeutic or drug development purposes, but rather for medical diagnostics. Its goal is to create point-of-care diagnostic tools capable of detecting a wide range of diseases, suitable for use in both hospitals and homes. In April 2018, Mammoth launched its first product based on CRISPR technology licensed from the Doudna Laboratory.

Mammoth is developing a platform capable of detecting any biomarker containing DNA or RNA using different enzymes: Cas12 and Cas13. According to news released on March 18, the company has added a new CRISPR enzyme, Cas14, to its “CRISPR diagnostic kit” through the University of California, Berkeley. The company’s founders believe that each CRISPR-Cas protein offers distinct advantages in various applications and can target different diseases, with Cas14 being particularly useful for infectious diseases, oncology, and genetic mutations.

Established: 2013

Founders: Chad Cowan, Craig Mello, Daniel Anderson, Emmanuelle Charpentier, Matthew Porteus, Rodger Novak, Shaun Foy

Company Stage: IPO on October 19, 2016

Market Capitalization: $6.155 billion

CRISPR Therapeutics’ name directly reflects its focus on CRISPR gene editing, and its founders include Emmanuelle Charpentier. The company is dedicated to developing revolutionary therapies using its proprietary CRISPR/Cas9 gene-editing platform, with patent licenses obtained from the University of California, Berkeley.

In February 2019, CRISPR Therapeutics announced that it had applied CRISPR gene-editing technology in the first-ever human clinical trial for therapeutic purposes, marking a milestone advancement toward the genuine application of gene editing in disease treatment.

According to CRISPR Therapeutics and its partner Vertex Pharmaceuticals Inc., the subject of this clinical trial is a patient with thalassemia. After collecting the patient’s blood cells, their DNA was edited ex vivo using CRISPR/Cas9 technology, and the modified cells were then returned to the patient via stem cell transplantation. CRISPR Therapeutics is also developing gene-editing therapies for sickle cell disease, with the first treatment expected to be completed by mid-year.

Established in: 2014

Founders: George Church, Luhan Yang

Company Stage: Series B

Financing Amount: $140 million

eGenesis was co-founded in 2014 by Harvard University genetics pioneer George Church and his Chinese student scientist Luhan Yang, focusing on applying gene-editing-based xenotransplantation technology to clinical medicine.

In March 2017, eGenesis announced that it had secured $38 million in Series A financing. The round was led by Biomatics Capital and ARCH Venture Partners, with participation from Khosla Ventures, Alta Partners, Alexandria Venture Investments, Berggruen Holdings North America, Uprising, and Fan Ventures. Additionally, Daniel S. Lynch joined eGenesis as Executive Chairman.On November 7, 2019, eGenesis announced that it had secured $100 million in Series B financing. The round was led by Fresenius Medical Care Ventures (FMCV), with participation from Leaps by Bayer, Wellington Partners, and the company’s existing investors, including Arch Venture Partners, Biomatics Capital, Alta Partners, and Khosla Ventures.

eGenesis leverages its proprietary CRISPR gene-editing platform to enable the cultivation of human healthy cells or tissue organs in pigs. Currently, this technology remains in its early stages.

“Although there are still certain technical challenges at present, we believe that our technology can help patients in need of organ transplants escape the threat of death,” said Luhan Yang, Chief Scientist and Co-Founder. “Following this financing round, we will continue our technological research. We hope that our technology can bring new hope to patients requiring organ transplants, enabling the translation of xenotransplantation into clinical practice through safe and effective methods.”

Partial content compiled from:

VCBeat: “From Patent Disputes to Commercial Rivalries: A Review of the Gene-Editing Business Strategies Deployed by CRISPR Pioneers”