[Robinson] 1 Andrew Robinson Dr. Shanthu ...

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[Robinson] 1 Andrew Robinson Dr. Shanthu Shantharam ISU STB 596X April 30th, 2017 An Argument for the Responsible Proliferation of Genetic Editing Research and Revision of Biotechnology Regulations Executive summary Learning about how to manage innovation in research and development in the seed biotechnology industry through enrolling in Iowa State University's Seed Technology and Business program's course 596X, investigating the latest trends in seed biotechnology through writing a term paper for the course, and attending the annual Everson Symposium in Ames, IA on April 12th and 13th 2017, provides the ability to make relevant comments on proposed revisions of the USDA APHIS's 7 CFR 340 regulation. Introduction Due to the historical and future global population growth trend (see fig. 1) demanding an equal ability to provide secure supply of food, fuel, and fiber for a predicted 9.7 billion people in 2050, recent developments in genetic editing with engineered nucleases, or GEEN, shows promise of helping the seed biotechnology industry keep pace with the demand of population growth.

Fig. 1. World population - historical data and future predictions Data from United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, custom data acquired via website. Using this recently discovered tool for the development of biological products, such as seeds, will require further investments of resources into research as the complexity of the most recently discovered genome editing technology known as CRISPR is not fully understood yet. (Paul and Qi 2016) Thus far, research has been completed to discover how genomes can be accurately, quickly and cheaply edited using the latest GEEN technologies, and other research indicates this method can actually strengthen biosafety and biosecurity.

[Robinson] 2 Only showing only positive research results can be perceived as an incomplete or slanted point of view, so possible insecurities in this newly discovered area of genetic editing have been considered. The fact that the entire CRISPR CAS system is not fully understood yet by the scientific community and discoveries are still being made indicates that more research and education is warranted. (Paul and Qi 2016) Once these massive research projects are completed, reviewed, and reproduced by scientific peers in multiple disciplines, a firm consensus can be reached to show that CRISPR is fully understood. Until now, responsible and transparent seed biotechnology organizations have submitted documents for six products using the USDA APHIS's Am I Regulated method to provide evidence that the proposed new GEEN products do not include any pests or weeds, and USDA APHIS has agreed that they are not considered regulated articles. (USDA APHIS 2017) A recent report, "Preparing for Future Products of Biotechnology", intended to aid upcoming policy making in biotechnology regulations provides three recommendations to update their regulations or they may never catch up fully to the inquiries and submissions of the various seed biotechnology organizations. (National Academies of Sciences, Engineering, and Medicine. 2017) One of these regulations that is currently being investigated is the USDA's APHIS division's 7 CFR part 340. A comparison of current and proposed section numbers and headings are in table 1. Table 1 USDA APHIS 2017 Current regulations at 7 CFR 340 listed next to Proposed Revision Current Section 340.0 340.1 340.2

340.3 340.4 340.5 340.6 340.7 340.8 340.9

Current Heading Restrictions on the introduction of regulated articles. Definitions. Groups of organisms which are or contain plant pests and exemptions. Notification for the introduction of certain regulated articles. Permits for the introduction of a regulated article. Petition to amend the list of organisms. Petition for determination of nonregulated status. Marking and Identity. Container requirements for the movement of regulated articles. Cost and Charges.

Proposed Section 340.0 340.1 340.2

Proposed Heading General restrictions and scope. Definitions. Taxa that are or contain plant pests.

340.3

Permits.

340.4

Regulatory status evaluation.

340.5

Record retention, compliance, and enforcement. Confidential Business Information Costs and charges.

340.6 340.7

This regulation deals with lowering the risk of pests and weeds from spreading as genetic information from pests and weeds have been used in genetic engineering of seeds in the last roughly 29 years. (USDA APHIS 2017) As already decided six times by USDA APHIS, using

[Robinson] 3 GEEN's CRISPR technology does not include anything considered a pest when the null segregant is used as the product, which is what this regulation intends to control, so the use of just this technique to edit the genome of an organism would result in it that organism not being considered a regulated organism under the proposed regulation. If the intention of the proposed update to 7 CFR 340 is to spur innovation, lessen the burden carried by USDA APHIS, and allow resources to focus on unfamiliar and/or complex products as it states, this would strongly encourage development of seeds using GEEN technologies. Theme It is shown next that medical advancements and agricultural advancements have gone hand in hand in the past to increase global human population, and can be predicted to continue on in the same fashion. The USA has previously led the way in these areas and should continue on for the greater good of humanity as they are well equipped to do so through revising regulation in the biotechnology industry. It has been widely reported that he entire mass of humanity on planet earth must be ready to sustainably feed the population if the forecasted population increase (see fig. 1) comes to pass. (United Nations, 2015) The UN's Population Division produces this World Population Prospects every two years, and their last Prospect in 2015 shows that increasing life expectancy (see fig. 2) is one of the main drivers of the predicted population increase of 2.3 billion people by 2050, to bring it up to 9.7 billion.

Fig. 2. World life expectancy - historical data and future predictions Data from United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, custom data acquired via website. Top countries of predicted population growth are also considered: During 2015-2050, half of the world’s population growth is expected to be concentrated in nine countries: India, Nigeria, Pakistan, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania, United States of America (USA), Indonesia and Uganda, listed according to the size of their contribution to the total growth.(United Nations, 2015)

[Robinson] 4 Due to five of the nine countries that are predicted to experience the largest population growth being on the African continent in what is referred to as Sub-Saharan Africa or SSA, it is easy to see that there will need to be focus on the agricultural systems in place in that region. This region is not well equipped to handle population growth at this time, as a paper from FAO titled "How to Feed the World in 2050" reports. (Alexandratos, N. and Bruinsma, J, 2012) Third from last on the list of high population growth nations is the USA, a country that leads the world in biotechnology innovation. The USA has achieved top place in Scientific American's worldView annual scorecard since inception in 2009, so they would be considered already prepared to keep up with the demand from an increasing population and thus morally obligated to help other developing areas that are not so well equipped, such as SSA. (Scientific American, 2017) What has increased the worldwide life expectancy that drove up the world's human population to begin with? Evidence points to a combination of the green revolution and advances in medicine and disease prevention if one considers the findings of a 23 year long study funded by the Bill and Melinda Gates Foundation that contributed to the Global Burden of Disease study, or GBD. (Bill and Melinda Gates Foundation, 2015.) The findings of this study state the reason behind life expectancy rising is that developed countries have had advancements in medicines, therapies, and disease prevention, while developing countries have had success in the UN's Millennium Development Goals, specifically to reducing under five mortality (see fig. 3).

Fig. 3. World under five mortality – historical data and future predictions Data from United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, custom data acquired via website. Using data from the aforementioned UN's WPP website that provides interactive data, the findings of the study funded through the Bill and Melinda Gates Foundation on causes of death to contribute to the Global Burden of Disease shows strong convergence of evidence which forms a strong conclusion - The data provided in the prediction analysis on the UN's WPP website is based on solid historical data and corroborating evidence in the GBD study finds similar conclusions. This makes the WPP's data a reliable source to predict future global population trends.

[Robinson] 5 When the population increased in the past due to advances in disease prevention and cures and reduction in under five mortality, there was strong demand for food, driving agricultural systems to keep production up to the same level as population growth.(FAO Corporate Document Repository, 2002.) The green revolution is what helped the agricultural industry keep pace with population growth, and was led by Norman Borlaug. He is credited with improving agriculture by improving seed quality, promoting the use of fertilizers, chemicals, and irrigation, and also working with scientists and government representatives to educate them on the latest discoveries in agriculture. (World Food Prize, 2017) Simply improving agriculture would help extend life expectancy, as it would provide increased food security, but the other factor that increased world population through extending life expectancy was the medical science field and overall awareness of disease prevention. (Bill and Melinda Gates Foundation, 2015) Methodology What do these sound predictions of the increase in human population of the world by 2.3 billion people in 2050 that will then drive demand for food higher, combined with the inability of SSA, one of the largest population growth areas predicted, to provide proper food security, and the position of the USA as being the leader in biotechnology innovations have to do with arguing for increasing amounts of research and regulation of genetic editing? It has to do with the USA not only continuing to keep their agricultural production levels on pace with their demand as they are predicted to grow in population, but also for the USA to maintain their position as the top country in the world for biotechnology innovations so they can provide technology for developing countries to help world food security. There have been recent medical research studies concluded that show promise for using GEEN to continue the historical trend of raising life expectancy through solving genetic disorders. (Elsevier 2016) Along with a release from the USA's NAS suggesting the use of genetic editing is acceptable in humans as long as it is used for diseases that have significant impact on life expectancy that there is no known cure for, as long as the work is somatic in nature and would not be passed onto offspring. (National Academies of Sciences, Engineering, and Medicine, 2017. Human) This could extend life expectancy further, and possibly add to the population growth predictions. The historical pattern of world population growth and suggested causes of this growth being the medical cures and prevention of disease combined with the green revolution, indicates a strong demand for another revolution in agriculture and a need for someone who, like Norman Borlaug, can not only discover how to revolutionize agriculture, but who can work with scientists and government representatives to educate them on the latest discoveries in agriculture. This person or organization could help transfer technology to nations or regions that may need it the most, such as SSA. There is promise that GEEN may drive that sort of revolution in agriculture but the person or organization to lead this is yet to be determined. The winner of the 2017 World Food Prize will be decided later this year, but that winner could possibly be someone who has made the most progress in GEEN. The keynote speaker at the Everson Symposium, Ambassador Kenneth Quinn, the President of the World Food Prize, suggested this as a possibility and also that the next revolution in agriculture will be remembered as the "Gene Revolution". Discussion

[Robinson] 6 Increasing amounts of patent applications and research publications of GEEN in the last 5 years indicates that intense focus of the biotechnology industries' research and development based organizations have made useful discoveries. (Eglie et al, 2016) (Elsevier 2016) This increase in organisms ready for field trial studies will overwhelm the three government regulatory agencies tasked with providing evidence of food safety unless they update the regulations and possibly how they operate in general, according to conclusions in "Preparing for future products of Biotechnology". (National Academies of Science Preparing 2017) Findings of this effort to "modernize the U.S. regulatory system for biotechnology products" were presented at the Everson Symposium by Dr. Jeff Wolt, one of the committee members that worked on it. (Wolt, 2017 speech) This review, that is intended to be a guideline used by regulatory agencies, such as the USDA APHIS division when they propose updates to their regulations, included thorough analysis of potential future biotechnology products, the current state of the biotechnology regulations in the USA, the potential biosafety and biosecurity risks, and opportunities to advance the capabilities of the biotechnology regulatory system. It then provides six major conclusions and from those conclusions advises regulatory bodies to take three main recommendations into consideration. Recommendation one states that the EPA, FDA, USDA, and other agencies involved in regulation of future biotechnology products should increase scientific capabilities, tools, expertise, and horizon scanning in key areas of expected growth of biotechnology, including natural, regulatory, and social sciences. Recommendation two states that the EPA, FDA, USDA, and other relevant agencies should increase their investments in internal and external research and their use of pilot projects to advance understanding and use of ecological risk assessments and benefit analyses for future biotechnology products that are unfamiliar and complex and to prototype new approaches for iterative risk analyses that incorporate external peer review and public participation. Recommendation three finds that The National Science Foundation, the Department of Defense, the Department of Energy, the National Institute of Standards and Technology, and other agencies that fund biotechnology research that has the potential to lead to new biotechnology products should increase their investments in regulatory science and link research and education activities to regulatory science activities. Therefore, if the findings of this report are not taken into consideration and some of these regulations and regulatory bodies are not updated, it will stifle innovation in the seed biotechnology industry by discouraging the use of GEEN. The USA could then no longer be the leader in biotechnology innovations, and more importantly would hamper the world's ability to keep pace with the predicted growing population. If the regulatory agencies operations and/or regulations are updated, it will allow regulatory bodies to keep pace with the seed biotechnology industry's discoveries, and could actually increase innovation in the seed biotechnology industry to such an extent that it could overtake the pace of population growth. If this occurs, the USA will continue to be agile in responding to biotic and abiotic stressors as they are identified and

[Robinson] 7 allow other nations who might look to the USA when they update regulations to take advantage of innovations created with GEEN. Derivations As advances in GEEN discoveries have been published since the findings of the "Preparing for future products of Biotechnology" was released, it would be advised to take those into consideration in addition to the six major conclusions and three recommendations the committee recommended. Some of the recent publications were recently presented at the same Everson Symposium that Dr. Wolt presented the conclusions and recommendations of the "Preparing for Future Products of Biotechnology". At the same symposium, Jeffry Sander, a research scientist at DuPont Pioneer showed the use of GEEN reduced the development of a new crop from 5 lifecycles down to 1 or 2. This has more recently been publicized by DuPont Pioneer on a new website developed to encourage learning by anyone in the general public at (DuPont Pioneer, 2017) This indicates up to an 80% decrease in the time it will take seed biotechnology organizations to produce an organism they deem worthy of field trials which could allow for increasing amounts of innovative discoveries to come to light. The very same day, an announcement from The Broad Institute was released showing ability of a recently understood class II of CRISPR gene editing enzyme, Cas13a (formerly known as C2c2) to provide inexpensive, portable, and accurate diagnosis of Zika virus. This diagnosis process was named SHERLOCK and the research paper was published the same day in Science Magazine. (Gootenberg, J et al, 2017.) This evidence lines up with conclusion 2.1 from the "Preparing for Future Products of Biotechnology" report, "The U.S. bioeconomy is growing rapidly; the scope, scale, complexity, and tempo of biotechnology products are increasing." Switching gears to highlight potential risks, gene editing was mentioned at last year's Worldwide Threat Assessment report, under the Weapons of Mass Destruction section. (Clapper 2016) This mention gives warrant for regulatory bodies to increase their capabilities for risk assessment of unfamiliar or complex products, and cooperate with other federal agencies such as the Department of Defense. These are consistent with recommendation two and three from the "Preparing for Future Biotechnology Products" report. As terrible as this may sound, the report indicates that it is new technology and not advanced enough to be turned into WMD yet. Advancements in biosafety and biosecurity have been reported using GEEN, and those types of advancements could be helpful to the Department of Defense in reducing the possible misuse of this technology. Biosafety efforts by Locus Biosciences have been announced but the research has not been made public. They are focusing on using CRISPR-Cas3 enzymes to produce a work around for antibiotic resistance, as those enzymes can destroy the DNA of an intended bacteria. Co-Founder of Locus Biosciences, Paul Garofolo, reported this in an interview with Sarah Burr on Techcrunch.com. (Buhr, S, 2016.)This possible discover could be linked to the seed biotechnology industry, as recently there has been research into microbial consortia and commercialization of microbial seed treatment. (O'Callahan 2016) (Unglesbee 2017) The biosecurity of the USA could be strengthened using GEEN, as reports of anti-CRISPR proteins, or a possible off switch to this method of GEEN, have been published. (Pawluk 2016) (Rauch 2017) These discoveries could lower the risk of unintended changes while researching GEEN, and with more research this might be turned into a biosecurity tool in case an open release GEEN product were to cause any unintended or unforeseen issues.

[Robinson] 8 Conclusions With the predicted global human population levels expected to rise, and the link between medical cures and disease prevention, along with agricultural systems improvements as the driver of this previous rise, a conclusion can be easily drawn that new medical advances using GEEN could drive further population growth, requiring agricultural systems to keep up production to avoid lowering the worlds food security. The USA is in the unique position as both a predicted top nine global human population growth country and the top nation for production of biotechnology innovations, and must act to revise regulations in biotechnology or severe lapses in biosecurity and biosafety could occur. The current regulation that is up for revision is open for public comment, the USDA APHIS department's proposed biotechnology regulation revision to 7 CFR part 340. With the findings of the "Preparing for Future Products of Biotechnology" in mind, along with the mention of gene editing under the Weapons of Mass Destruction section of last years Worldwide Threat Assessment report, the following comments have been readied for submittal on the USDA APHIS department's website: Regarding the proposed new definition of genetically engineered organisms – The precedent of six GEEN products having been determined to not be regulated articles/organisms is consistent with this new definition and thus it would improve the efficiency of the USDA APHIS department and improve this department's ability to focus on unfamiliar or complex product submissions, consistent with recommendation two of the "Preparing for Future Products of Biotechnology" report. Regarding PMPIs and the four options considered to revise regulation of them, option one is preferred, to remain consistent with all three recommendations of the "Preparing for Future Products of Biotechnology" report. Regarding PIP small-scale field testing regulation being shifted to the EPA, the logic presented makes sense however the transition to the EPA should possibly include consideration from recommendation two of the "Preparing for Future Products of Biotechnology" report if unfamiliar and complex PIP products are requested to be grown in small-scale field testing. Regarding the synchronous decisions with the EPA when herbicide resistant crops and subsequent herbicides are developed, it would be a good idea for the USDA APHIS department to coordinate with the EPA to release the decisions synchronously. The options discussed make sense when keeping recommendation two of the "Preparing for Future Products of Biotechnology" in mind, as synchronous decisions on crops and herbicides would clearly be complex. The EPA and USDA should examine a pilot project of the type described in recommendation two and ensure peer review and public participation are included. Regarding the request for public comment on the first of two instances that APHIS determines a GE plant to be a regulated organism, posting the list of combinations that can lead to an organism being considered a regulated organism, and also posting the list of combinations that are considered not to lead to an organism being considered a regulated organism on APHIS's website is considered to be a good idea as it shows transparency to the public and could also lead to smaller developers ability to focus their work on innovations already considered safe. Overall, the proposed revision to the USDA APHIS 7 CFR 340 regulations is consistent with the findings of the "Preparing for Future Products of Biotechnology" report. Using the current knowledge of the USDA APHIS department to reduce focus on familiar plants and increasing risk assessments and benefit analysis on products that are unfamiliar or complex will help decrease risk of plant pests or weedy plants from being released unintentionally. APHIS's

[Robinson] 9 Am I Regulated system is similar to the single point of entry mentioned in conclusion 6-6 and could be altered to turn into this single point of entry in the future. Revision of regulations similar to 7 CFR 340 should be investigated and regulatory bodies should be open to revisions like this more often in the future as long as they involve public comment and take into considerations the outputs of reports such as the "Preparing for Future Products of Biotechnology." By doing these things, the USA would remain as the top innovative biotechnology nation in the world, and those innovations could assist developing nations when necessary and this would contribute to enhancing global food security.

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[Robinson] 10 http://www.cell.com/cell/fulltext/S0092-8674(16)31589-6 , DOI: 10.1016/j.cell.2016.11.017 Rauch, B et al. 2017. Inhibition of CRISPR-Cas9 with Bacteriophage Proteins. Cell. Volume 168, Issues 1-2, p150–158 Scientific American. 2017. WorldVIEWGuide. http://www.saworldview.com/scorecard/worldviewguide/. Accessed 30 April 2017. Unglesbee, E. 2017. Betting Big on Microbes. DTN/The Progressive Farmer. https://www.dtnpf.com/agriculture/web/ag/news/crops/article/2017/01/11/monsanto-addmicrobial-seed-new-2017-2. Accessed 30 April 2017. United Nations. 2015. World Population Prospects, the 2015 Revision. Department of Economic and Social Affairs Population Division. https://esa.un.org/unpd/wpp/. Accessed 30 April 2017. United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Key Findings and Advance Tables. Working Paper No. ESA/P/WP.241. USDA APHIS. 2017. Regulated Article Letters of Inquiry. https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/am-iregulated/regulated_article_letters_of_inquiry/regulated_article_letters_of_inquiry. Accessed 30 April 2017. Wolt, Jeff. "Outcomes of the National Academies Report." Everson Symposium. Iowa State University. Seed Science Center, Ames, IA. 13 April 2017. Speech. World Food Prize. 2017. About Norman Borlaug. https://www.worldfoodprize.org/index.cfm?nodeID=87448&audienceID=1. Accessed 30 April 2017.