Genetic scissors: at the cutting-edge of life

December 2020

By James Nurton, freelance writer

On October 7, 2020, the Nobel Prize in Chemistry was awarded to Professor Emmanuelle Charpentier, Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany, and Professor Jennifer A. Doudna, of the University of California, Berkeley, USA, “for a method of genome editing”. Their discovery of the CRISPR-Cas9 “genetic scissors” is one of the most important scientific developments so far this century. It has the ability to transform agriculture and medicine, and even cure inherited conditions such as Huntington’s disease, cystic fibrosis and certain types of cancer. But, as the researchers themselves have recognized, it also raises complex ethical, patent and policy issues, which are only just beginning to be explored.

Professor Jennifer A. Doudna (left) and Professor Emmanuelle Charpentier (right) have been jointly awarded the Nobel Prize in Chemistry for their discovery of the CRISPR-Cas9 “genetic scissors,” one of the most important scientific developments of the 21st century. (Photo: KEYSTONE/dpa/Alexander Heinl)

The collaboration between Professor Charpentier and Professor Doudna brought together their expertise in pathogenic bacteria and RNA interference, respectively. It began in 2011 and was, according to Professor Charpentier, “short and intense”, but its impact will be felt for many years. Their key achievement was identifying that CRISPR, a natural defense mechanism found in the DNA of bacteria, and Cas9, an enzyme, could be programmed to cut a DNA molecule at any point.

As Professor Claes Gustafsson, Chair of the Nobel Committee for Chemistry, explained in a paper published by the Royal Swedish Academy of Sciences pdf, “the development of this technology has enabled scientists to modify DNA sequences in a wide range of cells and organisms. Genomic manipulations are no longer an experimental bottleneck. Today, CRISPR-Cas9 technology is used widely in basic science, biotechnology and in the development of future therapeutics.”

Common terms

DNA: Deoxyribonucleic acid, a molecule present in all cells that carries genetic instructions.

RNA: Ribonucleic acid, a single-stranded molecule sometimes referred to as DNA’s “cousin.”

CRISPR: clustered regularly interspersed short palindromic repeats – arrays of repeated DNA sequences.

Cas: CRISPR-associated proteins that cleave virus DNA. There are 93 of them, one of which is Cas9.

TracrRNA: trans-activating CRISPR RNA, which enables long RNA created from a CRISPR sequence to mature into its active form.

A revolutionary tool to shape biological systems

“CRISPR-Cas9 pdf is a powerful tool that has made gene editing faster, more accurate, cheaper and easier to operate. It’s also a socially disruptive technology with many applications including to human medicine, agriculture and biofuels,” says Dr Kathy Liddell, Director of the Centre for Law, Medicine and Life Sciences at Cambridge University in the UK. As of October 2020, 115 clinical trials using human genome editing (HGE) technologies are underway, according to the World Health Organization HGE Registry, including for widespread genetic diseases such as sickle cell disease and beta thalassemia. In March 2020, the first CRISPR-Cas9 gene therapy was administered to someone suffering from a rare condition known as LCA10, which causes childhood blindness and for which no other treatment is currently available. In this instance, the therapy was used to remove a mutation in the gene (CEP290) which causes the condition.

But CRISPR-Cas9 has also resulted in some less favorable headlines, with a long (and as yet unresolved) patent battle and ethical debates about “designer babies”. Professor Jacob S. Sherkow of the College of Law, University of Illinois at Urbana-Champaign in the United States, says this reflects the fact that CRISPR-Cas9 is “the most important advance in biotechnology in the past 40 years.” “It allows scientists, researchers and developers to precisely edit the genome of a living cell. In other words, you can edit the software that makes us alive,” he adds.

Responsible development

The two Nobel Laureates realized the magnitude of their discovery early on. Professor Doudna has spoken about how, by 2014, she felt a growing responsibility to engage in the public ethical debates. In early 2020, she told the Financial Times: “We need to be thinking about these broader implications of a powerful technology and how to develop them responsibly.” She helped establish, and is currently President and Chair of the Governance Board at the Innovative Genomics Institute in Berkeley, California, USA. The Institute is committed to advancing public understanding, providing resources for the broader community and guiding the ethical use of genomic technologies.

Ethical issues came to the fore in November 2018, when Chinese scientist He Jiankui announced that he had used CRISPR-Cas9 to create genetically edited twin girls. Other scientists condemned the research – including Professor Doudna, who immediately flew to Hong Kong (SAR) to investigate. He Jiankui was subsequently fired from his university, fined and imprisoned for three years.

Genomic manipulations are no longer an experimental bottleneck.

The case was very much an outlier: He Jiankui’s research was not regulated or published and not even scientifically credible (his claim that the genetically modified embryos would confer HIV immunity met with considerable skepticism). Professor Sherkow notes that the ethical debates about editing human embryos to avoid genetic illness or favor certain characteristics are not new, and have been present since the introduction of in vitro fertilization (IVF) in the 1970s. “Some concerns about CRISPR-Cas9 are greatly overblown. It’s not that different from what is being done now,” he observes.

Dr. Liddell agrees, saying: “In the UK, for example, we have a track record of broad, pragmatic deliberation on ethically contentious issues, such as IVF and prenatal screening. It’s important to scrutinize arguments about whether there are real harms to society or human values from heritable gene editing.” In many countries (including the UK) IVF research is regulated by a public authority so that new issues can be debated and resolved as they arise.

The role of the patent system

The ethical issues raised by CRISPR-Cas9 are not limited to human germline editing. In view of its potential to transform biological systems, there are also questions such as: Who decides how the technology can be used and by whom, and which uses are safe and socially acceptable? Which research should be prioritized? How to ensure fair access to life-changing therapies that may cost millions of dollars per treatment, particularly in health systems based on public payment? What is the social and economic impact of modifying the genes of crops or fuels on farmers and agricultural workers and what effect will such uses have on ecological systems?

Some of these questions inevitably concern the role of the patent system, which is designed to incentivize innovation for the benefit of society as a whole. Researchers have applied for thousands of patent applications involving CRISPR technology over the past decade, demonstrating the importance of patents in attracting and encouraging investment in research and technological development. As Professor Doudna herself has said: “There’s a huge layer of IP [intellectual property] that’s been developed. It will be interesting how that plays out in the future once we have products with value.” Standards body MPEG LA has even proposed creating a CRISPR-Cas9 joint licensing platform (or patent pool) to promote access to related patented technologies.

Story of the research

1953: Francis Crick and James Watson identify the molecular structure of DNA.

1987: Yoshizumi Ishino identifies repeated structures in prokaryotic DNA.

1993: Francisco Juan Martínez Mojica coins the term CRISPR.

2005: Mojica proposes that CRISPRs provide a defense against foreign DNA.

2008: Erik Sontheimer and Luciano Marrafinni identify the CRISPR mechanism as a gene-editing tool.

Spring 2011: Emmanuelle Charpentier, a microbiologist, and Jennifer Doudna, a biochemist, meet during a conference in Puerto Rico and discuss CRISPR-Cas9 for the first time.

June 2012: Professors Charpentier and Doudna and others publish their research in Science under the title A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity.

March 2013: The University of Vienna and University of California file a US patent application titled Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription (priority date 25 May 2012). Professors Charpentier and Doudna are among the inventors.

December 2012: Feng Zhang of the Broad Institute publishes a paper showing that CRISPR works in eukaryotic cells, and subsequently files US patents. A series of USPTO patent interference cases between UC Berkeley and the Broad Institute begin, with the latest decision published in September 2020.

October 2020: Professors Charpentier and Doudna are awarded the Nobel Prize in Chemistry “for the development of a method for genome editing.”

Patent battles ensue

Professors Charpentier and Doudna filed their first application in the United States in 2013, and this has been extended to many other countries via the Patent Cooperation Treaty (published as WO/2013/176772). Since 2015, UC Berkeley and the University of Vienna (the patent applicants) have been locked in patent interference proceedings before the United States Patent and Trademark Office (USPTO) against the Broad Institute in the United States to determine the validity of their application. There have also been disputes between these parties in other jurisdictions. They are not over yet – which, as Professor Sherkow says, raises the prospect of further battles being fought in the courtroom. “One of the big questions is why these disputes have not been resolved, and who is reluctant to settle. The stakes are very high, and we could yet see a full trial about who was the first to invent “single guide RNA”, with testimony from the various scientists involved,” he says.

So far, and perhaps surprisingly, the patent disputes have concerned issues about breadth and priority, rather than patentable subject matter. As Professor Duncan Matthews, Director of the Queen Mary Intellectual Property Research Institute at Queen Mary University of London, UK, says, the patent system is “part of the overall governance of technologies” such as CRISPR-Cas9. In particular, many patent laws have morality or ordre public exclusions from patentable subject matter. These are defined in national patent law and addressed in a document produced by the WIPO Standing Committee on Patents (last updated in April 2020) pdf. “I think patent examiners at the European Patent Office, where they are required to apply a morality exception, have done a good job by not rejecting applications outright but instead allowing claims to compositions or vector systems (delivery methods) for genome editing. They are applying the law as it is stated,” says Professor Matthews, who has convened an expert group on patents and genome editing to study the topic. “In other patent systems, it is perhaps too early to say [how the exclusions will be interpreted] and we haven’t yet seen disputes about the exceptions concerning morality or products of nature.”

We need to be thinking about these broader implications of a powerful technology and how to develop them responsibly.

Jennifer A. Doudna

Patents as a technology governance mechanism

Professor Matthews believes more work should be done on whether patent offices would allow genome inventions to be patented: “Until now, patents have been largely absent from the debate about human genome editing. I was pleased to be invited recently to give evidence before the WHO Expert Advisory Committee, which is considering patents as part of the governance of human genome editing.” The international WHO expert panel was established in December 2018, and published a statement on governance and oversight in July 2019.

Professor Matthews points out that the patent system could be a means of preventing rogue research: “Patents could be used responsibly to block unregulated use through a system of ethical licensing.”

The discovery by Professsors Charpentier and Doudna revealed that a DNA molecule could be ‘cut’ at any point by CRISPR, a natural defense mechanism present in the DNA of bacteria, and Cas9, an enzyme. (Photo: © Johan Jarnestad/The Royal Swedish Academy of Sciences)

A bold future

While the details of gene editing may seem complex to the uninitiated, scientists speak of the relative simplicity of the CRISPR-Cas9 tool, which has made it available to researchers across the globe in a wide range of fields. “Academic research into CRISPR has taken off in the past few years,” despite the well-publicized patent battles, says Professor Sherkow. “The limit of CRISPR is the human imagination,” he notes.

The Nobel Laureates have contributed greatly to this research, each of them being named on dozens of patent applications. Professor Charpentier has licensed IP to the biotech companies CRISPR Therapeutics and ERS Genomics while Professor Doudna has co-founded Caribou Biosciences, Intellia Therapeutics and Mammoth Biosciences. “This is the first time that two women have shared a Nobel Prize in Chemistry and they will be an inspiration, especially to girls around the world who are interested in science,” says Dr. Liddell.

The limit of CRISPR is the human imagination.

Jacob S. Sherkow

Their work has inspired hundreds of other researchers who have published papers on the use of CRISPR-Cas9 in many organisms. Scientists are also investigating the potential of other CRISPR-associated systems such as Cas12a and Cas13, including to test for and treat COVID-19. Some of this research uses powerful artificial intelligence tools including machine learning and deep learning to improve predictability and reduce off-target effects. Less than 10 years since the landmark collaboration between Professors Charpentier and Doudna, enormous strides have already been made – but it looks like many more achievements are just around the corner.

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