"Despite the projected growth in market applications andabundant investment capital, there is a danger that legal andethical concerns related to genetic research could put the brakeson gene editing technologies and product programs emanatingtherefrom."
There are thousands of diseases occurring in humans, animals,and plants caused by aberrant DNA sequences. Traditional smallmolecule and biologic therapies have only had minimal success intreating many of these diseases because they mitigate symptomswhile failing to address the underlying genetic causes. While humanunderstanding of genetic diseases has increased tremendously sincethe mapping of the human genome in the late 1990s, our ability totreat them effectively has been limited by our historical inabilityto alter genetic sequences.
The science of gene editing was born in the 1990s, as scientistsdeveloped tools such as zinc-finger nucleases (ZFNs) and TALEnucleases (TALENs) to study the genome and attempt to altersequences that caused disease. While these systems were anessential first step to demonstrate the potential of gene editing,their development was challenging in practice due to the complexityof engineering protein-DNA interactions.
Then, in 2011, Dr. Emmanuelle Charpentier, a French professor ofmicrobiology, genetics, and biochemistry, and Jennifer Doudna, anAmerican professor of biochemistry, pioneered a revolutionary newgene-editing technology called CRISPR/Cas9. Clustered Regularly InterspacedShort Palindromic Repeats (CRISPR) and Cas9 stands forCRISPR-associated protein 9. In 2020, the revolutionary work ofDrs. Charpentier and Doudna developing CRISPR/Cas9 were recognizedwith the Nobel Prize for Chemistry. The technology was also thesource of a long-running and high-profile patent battle between two groups ofscientsists.
CRISPR/Cas9 for gene editing came about from a naturallyoccurring viral defense mechanism in bacteria. The system ischeaper and easier to use than previous technologies. It deliversthe Cas9 nuclease complexed with a synthetic guide RNA (gRNA) intoa cell, cutting the 'cell's genome at the desired location,allowing existing genes to be removed and new ones added to aliving organism's genome. The technique is essential inbiotechnology and medicine as it provides for the genomes to beedited in vivo with extremely high precision, efficiently, and withcomparative ease. It can create new drugs, agricultural products,and genetically modified organisms or control pathogens and pests.More possibilities include the treatment of inherited geneticdiseases and diseases arising from somatic mutations such ascancer. However, its use in human germline genetic modification ishighly controversial.
The following diagram from CRISPR Therapeutics AG, a Swisscompany, illustrates how it functions:
In the 1990s, nanotechnology and gene editing were necessaryplot points for science fiction films. In 2020, developments likenano-sensors and CRISPR gene editing technology have moved thesetechnologies directly into the mainstream, opening a new frontierof novel market applications. According to The Business ResearchCompany, the global CRISPR technology market reached a value ofnearly $700 million in 2019, is expected to more than double in2020, and reach $6.7 billion by 2030. Market applications targetall forms of life, from animals to plants to humans.
Gene editing's primary market applications are for thetreatment of genetically-defined diseases. CRISPR/Cas9 gene editingpromises to enable the engineering of genomes of cell-basedtherapies and make them safer and available to a broader group ofpatients. Cell therapies have already begun to make a meaningfulimpact on specific diseases, and gene editing helps to acceleratethat progress across diverse disease areas, including oncology anddiabetes.
In the area of human therapy, millions of people worldwidesuffer from genetic conditions. Gene-editing technologies likeCRISPR-Cas9 have introduced a way to address the cause ofdebilitating illnesses like cystic fibrosis and create betterinterventions and therapies. They also have promising marketapplications for agriculture, food safety, supply, anddistribution. For example, grocery retailers are even looking athow gene editing could impact the products they sell. Scientistshave created gene-edited crops like non-browning mushrooms andmildew-resistant grapes - experiments that are part of an effort toprevent spoilage, which could ultimately change the way food issold.
Despite the inability to travel and conduct face-to-facemeetings, attend industry conferences or conduct business otherthan remotely or with social distance, the investment markets forventure, growth, and private equity capital, as well as corporateR&D budgets, have remained buoyant through 2020 to date.Indeed, the third quarter of 2020 was the second strongest quarterever for VC-backed companies, with 88 companies raising roundsworth $100 million or more according to the latest PwC/Moneytreereport. Healthcare startups raised over $8 billion in the quarterin the United States alone. Gene-editing company MammouthBiosciences raised a $45 million round of Series B capital in thesecond quarter of 2020. CRISPR Therapeutics AG raised more in thepublic markets in primary and secondary capital.
Bayer, Humboldt Fund and Leaps are co-leading a $65 million Series A round for Metagenomi, abiotech startup launched by UC Berkeley scientists. Metagenomi,which will be run by Berkeley's Brian Thomas, is developing atoolbox of CRISPR- and non-CRISPR-based gene-editing systems beyondthe Cas9 protein. The goal is to apply machine learning to searchthrough the genomes of these microorganisms, finding new nucleasesthat can be used in gene therapies. Other investors in the Series Ainclude Sozo Ventures, Agent Capital, InCube Ventures and HOFCapital. Given the focus on new therapies and vaccines to treat thenovel coronavirus, we expect continued wind in the sails forgene-editing companies, particularly those with strong productportfolios that leverage the technology.
Despite the projected growth in market applications and abundantinvestment capital, there is a danger that legal and ethicalconcerns related to genetic research could put the brakes ongene-editing technologies and product programs emanating therefrom.The possibility of off-target effects, lack of informed consent forgermline therapy, and other ethical concerns could cause governmentregulators to put a stop on important research and developmentrequired to cure disease and regenerate human health.
Gene-editing companies can only make money by developingproducts that involve editing the human genome. The clinical andcommercial success of these product candidates depends on publicacceptance of gene-editing therapies for the treatment of humandiseases. Public attitudes could be influenced by claims that geneediting is unsafe, unethical, or immoral. Consequently, productscreated through gene editing may not gain the acceptance of thegovernment, the public, or the medical community. Adverse publicreaction to gene therapy, in general, could result in greatergovernment regulation and stricter labeling requirements ofgene-editing products. Stakeholders in government, third-partypayors, the medical community, and private industry must work tocreate standards that are both safe and comply with prevailingethical norms.
The most significant danger to growth in gene-editingtechnologies lies in ethical concerns about their application tohuman embryos or the human germline. In 2016, a group of scientistsedited the genome of human embryos to modify the gene forhemoglobin beta, the gene in which a mutation occurs in patientswith the inherited blood disorder beta thalassemia. Althoughconducted in non-viable embryos, it shocked the public thatscientists could be experimenting with human eggs, sperm, andembryos to alter human life at creation. Then, in 2018, abiophysics researcher in China created the first human geneticallyedited babies, twin girls, causing public outcry (and triggeringgovernment sanctioning of the researcher). In response, the WorldHealth Organization established a committee to advise on thecreation of standards for gene editing oversight and governancestandards on a global basis.
Some influential non-governmental agencies have called for amoratorium on gene editing, particularly as applied to altering thecreation or editing of human life. Other have set forth guidelineson how to use gene-editing technologies in therapeuticapplications. In the United States, the National Institute ofHealth has stated that it will not fund gene-editing studies inhuman embryos. A U.S. statute called "The Dickey-WickerAmendment" prohibits the use of federal funds for researchprojects that would create or destroy human life. Laws in theUnited Kingdom prohibit genetically modified embryos from beingimplanted into women. Still, embryos can be altered in researchlabs under license from the Human Fertilisation and EmbryologyAuthority.
Regulations must keep pace with the change that CRISPR-Cas9 hasbrought to research labs worldwide. Developing international guidelines could be a steptowards establishing cohesive national frameworks. The U.S.National Academy of Sciences recommended seven principles for thegovernance of human genome editing, including promoting well-being,transparency, due care, responsible science, respect for persons,fairness, and transnational co-operation. In the United Kingdom, anon-governmental organization formed in 1991 called The NuffieldCouncil has proposed two principles for the ethical acceptabilityof genome editing in the context of reproduction. First, theintervention intends to secure the welfare of the individual borndue to such technology. Second, social justice and solidarityprinciples are upheld, and the intervention should not result in anintensifying of social divides or marginalizing of disadvantagedgroups in society. In 2016, in application of the same, the CrickInstitute in London was approved to use CRISPR-Cas9 in humanembryos to study early development. In response to a cacophony ofconflicting national frameworks, the International Summit on HumanGene Editing was formed in 2015 by NGOs in the United States, theUnited Kingdom and China, and is working to harmonize regulationsglobal from both the ethical and safety perspectives. As CRISPRco-inventor Jennifer Doudna has written in a now infamous editorialin SCIENCE, "stakeholders must engage in thoughtfullycrafting regulations of the technology without stiflingit."
The COVID-19 pandemic has forced us to rely more on newtechnologies to keep us healthy, adapt to working from home, andmore. The pandemic makes us more reliant on innovative digital,biological, and physical solutions. It has created a united senseof urgency among the public and private industry (together withgovernment and academia) to be more creative about using technologyto regenerate health. With continued advances in computing power, networkarchitecture, communications bandwidths, artificial intelligence,machine learning, and gene editing, society will undoubtedly findmore cures for debilitating disease and succeed in regeneratinghuman health. As science advances, it inevitably intersects withlegal and ethical norms, both for individuals and civil society,and there are new externalities to consider. Legal and ethicalnorms will adapt, rebalancing the interests of each. The fourthindustrial revolution is accelerating, and hopefully towards curingdisease.
Originally published by IPWatchdog.com, November 24,2020.
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