Conference and General Assembly of the IAP Hermanus, West Cape, South Africa

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1 Conference and General Assembly of the IAP Hermanus, West Cape, South Africa Roundtable Discussion on Science Advice in the International Arena with a Special Focus on Synthetic Biology Monday, 29 February 2016 The Importance of Transgenic Organisms in Validating and Underpinning Synthetic Biology Francisco G. Bolívar-Zapata Institute of Biotechnology National Autonomous University of Mexico & Chair of the Biotechnology Committee of the Mexican Academy of Sciences Abstract. The experience of using DNA synthesized by organic chemistry began with the construction of the first bacteria using genetic engineering, which permitted the production of transgenic or recombinant human insulin in On the basis of this experiment and capacity, DNA fragments synthesized by organic chemistry or by cloning DNA obtained from various organisms and edited with synthetic DNA, were used to create a wide variety of transgenic organisms. The initial aim was to determine the structure and organization of eukaryote genome, which made it possible to discover the existence of introns. Immediately afterwards, transgenic organisms or GMO as you know, has been developed for different purposes, particularly transgenic plants with bacterial genes that made it possible to resist insect pests in order to reduce the amount of chemical insecticide required. There is extensive, solidly supported scientific information (over two thousand publications) that has permitted the endorsement and use of these transgenics or GMO to address various issues and demands. Papers show that synthetic biology is ultimately based on chemically synthesized DNA and that many of the accusations against GMO will be leveled against organisms designed by synthetic biology. One must therefore seize the opportunity and highlight the enormous advantages (including the health and economic benefits) of transgenics and the overwhelming scientific evidence supporting the fact that they are harmless, low-risk organisms, to advance and meet different needs. This information and strategy must definitely be used to defend organisms designed by synthetic biology from attacks. 1

2 I am grateful to Professor Daya Reddy, President of the Academy of South Africa and Co-Chair of the InterAcademy Council, for the invitation to participate in this Panel on Synthetic Biology. 1. I am a researcher in the area of genetic engineering and biotechnology. I was part of a group in San Francisco, which in 1977, using genetic engineering techniques and DNA synthesized by organic chemistry that coded for human insulin, developed the first transgenic organisms that permitted the production of this recombinant (transgenic) hormone, identical to the human version, which is now sold in pharmacies worldwide to treat diabetes. Thanks to these methodologies, we are able to build transgenic organismscells containing genetic material from other sources, including chemically synthesized ones- and today we have over 100 drugs in pharmacies to address various health problems that would not exist without this methodology. 2. When I returned to Mexico to the National Autonomous University of Mexico (UNAM), a research center was created in 1982, which is now the Institute of Biotechnology (IBt), at the UNAM campus in Morelos. I had the distinction of being the founding director of both centers, with the mission to develop biotechnology including that of transgenics. We fulfilled our mandate and today, the IBt has an important history of generating leading-edge knowledge in various models and of using this knowledge to understand and address various problems and social demands through a major effort to achieve technological development and establish links with the industrial sector and the government. 3. From the outset, largely due to ignorance, partial visions and myths, but also as a result of economic and social interests, GMOs have been demonized in Mexico and the rest of the world. Attention has focused on the use of transgenic plants designed to significantly reduce the utilization of chemical insecticides to kill insects that feed on cultivars. It is commonly believed that transgenic plants are harmful to health and trigger cancer, which is a myth yet held to be true by many. Reality and solid scientific evidence overwhelmingly suggest the opposite. In the United States, where more than 95% of the corn and soybeans grown are transgenic, there has been a significant reduction in the use of 2

3 chemical insecticides, which has benefited farmers health and yielded significant economic benefits in the US by substantially decreasing the use of chemical insecticides. They have been grown since 1996 and there have been no solid scientific evidences, repeated tests independently carried out by various groups to prove that they harm either human or animal health or the environment! Quite the opposite. There have been opinions issued by experts, including a statement by 24 Nobel laureates and declarations by Academies of Sciences of many countries, and scientific societies that support their use. This is increasingly well supported by over 2,000 scientific references published independently in many places, supporting the low risk and safety of GMO and their products. We in Mexico, as the Biotechnology Committee of the Mexican Academy of Sciences (AMC), have also written books and recommendations in Spanish and English versions. Some are electronic versions and are available on the websites of the AMC and other institutions. We have continued to collect and systematize information for and against GMO, and will go on collecting it to inform society and its ruling authorities. In this respect, we wish to point out that all this information on the low risk and safety of GMO explains why regulatory agencies such as the FDA (Food and Drug Administration) in the US and the EFSA (European Food Safety Administration) in Europe have not withdrawn them from the market or prevented the consumption of transgenic cultivars and their products, which can now be purchased off the shelf. In Mexico, in keeping with the Law on the Biosecurity of GMO, COFEPRIS (the Federal Commission for Protection from Health Risks), with the support of the Executive Secretary of CIBIOGEM (Intersecretarial Commission on Biosafety of Genetically Modified Organisms) has allowed the registration of GM cultivars and, like the FDA, has not withdrawn the various transgenic products that are actually present in the market. All these data indicating the broad health and economic benefits of transgenics over nearly 30 years and the more than two thousand references to their low risk and safety, must be used to support the importance of organisms designed by synthetic biology, as I point out below. 4. In any case, I wish to stress that during this process of collecting information in favor of GMO, a great deal of information against it was also collected, much of which states that they cause damage to health and the environment. This was done to evaluate and, where appropriate, endorse and support the scientific validity of this information. Two books stand out among all this information. One by Steven Drucker (USA) Altered genes, 3

4 twisted truth and another, Transgenic corn in danger from transgenics (Mexico) coordinated by Dr. Elena Álvarez Buylla. Also of note are the articles published by Dr. G. Séralini s group in France. In our view and based, I insist, on the broad, solid scientific evidence in favor, including the opinions of expert committees from several organizations in many countries, the arguments mentioned in these publications do not contain sufficient, solid scientific evidence to support the conclusion that transgenic plants and their products cause damage to human or animal health or the environment. In fact, the study by Dr. G. Séralini is an example of the false conclusions and lack of scientific bases present in many of them. One of the articles of this group was withdrawn by the editor of the journal in which it was published since it suffered from several problems including a limited number of animals and the use of strains of cancer-prone mice! For all these reasons, we insist that agencies in various countries such as the FDA in the US, COFEPRIS in Mexico and ESFA in Europe, have not pulled GM products from the market, nor have they been disapproved by the WHO! However, in Mexico, these opinions with no solid scientific basis, have promoted the use of injunctions at the judicial level by various groups, including NGOs and Greenpeace, to prevent the planting of transgenic soybeans. Moreover, planting GM maize in Mexico has been forbidden for a number of years, although soybean may be planted in small areas. These actions have prevented farmers in Mexico from enjoying the economic and health benefits available to their counterparts in the US and certain countries in South America such as Brazil and Argentina, where the soybeans grown are genetically modified. All this information, both for and against, has been systematized and is available to the Academies, the public and governments. 5. There is unlikely to have unanimity on this issue of GMO because, in addition to issues at the health level, transnational corporations have a large interest in controlling the food market. Monsanto and other companies own transgenic seeds. Moreover, companies such as Bayer produce the chemical insecticides currently used by many countries farm workers. It is not in these companies interest to stop selling them. In Mexico, we have developed extraordinary GM varieties to cope with climate change and pollution, and we are not utilizing them. Important transgenic 4

5 varieties have undoubtedly also been developed in other countries. We must use them, especially since the patents of transgenic seeds will run out in a few years time. We insist, there will never be unanimity on this issue. However, we also insist that the increasingly broad and convincing set of solid scientific evidence should allow us to move towards greater acceptance of the use and advantages of GMO. It is immoral that GMO and their products are being discredited and demonized with lies, on a planet with many needs and problems, when transgenics can contribute and play a sometimes unique role, as in the production of human proteins to address clinical problems. 6. Why has this issue elicited so much debate and interest? Because the potential for helping to solve problems and meet demands, as mentioned earlier, is enormous. However, scientific advances are not always well received, often because of a lack of awareness of their benefits and also because of the discrediting by certain groups, which realize that new knowledge and the associated technology imply changes. This is the case of the use of vaccines against infectious agents that have significantly reduced child mortality yet in some cases are rejected by uninformed parents who have tried to avoid these procedures, putting forward specious arguments and ignoring the risks involved for their children. There is increasingly less reluctance and greater consensus about the use and value of vaccines. A more recent case with less social consensus is climate change. There is a great deal of reluctance by powerful groups to accept the solid scientific evidence proving the existence of the problems caused by a warmer, polluted planet. As in the case of climate change, there will be no unanimity on the issue of GM, but we think that in some ways we have moved towards a greater consensus on the acceptance of the benefits of GMO. Nor is there is a consensus on the use of synthetic biology, as with climate change and GMOs, complex issues that must be studied and understood in an interdisciplinary way, and with the participation of leading experts from different institutions, including members of the academies. 7. As for synthetic biology and its relation to GMO, it is important to emphasize that the DNA synthesized by organic chemistry (synthetic) is 5

6 present and has been used as a tool in experimental biology and genetic engineering for a long time, most recently in the issue of editing DNA (CRISPR). In fact, as mentioned earlier, in 1977, human insulin, as mentioned, was successfully produced in bacteria by incorporating the synthetic genes that code for this protein in E. coli. Without this extraordinary capacity we have developed, we would not have more than 100 transgenic drugs to address various clinical problems and we would have failed to virtually eliminate, at least in the US, the use of chemical insecticides to benefit the health and economy of American farmers, where over 95% of the cultivars of soybean, corn and cotton are transgenic. As mentioned, the more than 2,000 solid scientific references and the opinions of Academies of Sciences, experts and leaders in favor of transgenic technology are overwhelming, as are their acceptance and approval by the FDA in the US, ESFA in Europe and COFEPRIS in Mexico, which continue to allow the production and use of GMO and their products, which are on the shelves today. This experience with GMO, including broad-ranging benefits, must support the decisions and recommendations made regarding the use of synthetic biology technology, since newly designed organisms that wholly or partially use synthetic DNA, such as GMO, are not unnatural organisms per se because they operate and would operate with the rules and tools of a living cell, sine qua non. Otherwise they will not exist! In fact, many new generation transgenics will be designed and built with the help of synthetic DNA gene editing and CRISPR techniques, as noted above. This will make it possible to redefine the design of GMO by inserting the new transgenic DNA or transgene into specific sites in the genome receptor target using the homologous DNA design of the host, particularly of the place where one wishes to insert it, flanking the transgene (and its possible expression system) allowing its insertion into the genomic specific target site. This will take place after it has been broken down by Cas9 enzyme or another CRISPR endonuclease, in the gene or locus of the target genome into which it is to be inserted. All this requires, as we know, the support of RNA molecule single chain guides to hybridize first at the target site, and then break it down, inactivate it and finally insert it into the specific locus, the transgene flanked by a region of homologous DNA from the target site that will permit its incorporation into the genome through homologous recombination. Since first generation transgenics on the market, particularly transgenic plants, did not use CRISPR technology, transgenes are randomly incorporated into different sites in the genome. 6

7 CRISPR technology therefore represents a substantial advance in the construction of safer, more refined second- and third- new generation genetically modified organisms. In addition, it is important to emphasize that due to genomics, proteomics and metabolomics capacities, the scientific community, the governments and the society in general, have achieved gigantic, incredible, fantastic and amazing information about the living cell. This information has been, is and will be utilized for the design of novel and incredible properties in the construction of genetically modified organisms, through genetic engineering, CRISPR techniques and synthetic biology. We should also point out that it is immoral and illegal to use GMO as biological weapons. This is borne out by the Law on the Biosecurity of GMO in Mexico and similar documents in many other countries. Indeed, we have insisted that organisms with these capacities cannot be endorsed, or even allowed to be designed or developed. In our view, these examples include the possible use of the gene encoding the botulism toxin that could be inserted into other organisms, including bacteria that exist in our gut. Another example we have opposed is the terminator gene, which certain multinational companies that produce genetically modified seeds attempted to introduce, which have the ability to prevent the growth of seeds carrying this genetic information in subsequent generations. Therefore, in our view, this is also a forbidden, illegal and immoral example, because the terminator genes could also be transferred to other species in soil. The same kind of arguments in their utilization as biological weapons used against GMO would also be leveled at organisms constructed through the use of DNA synthesized by organic chemistry (synthetic) synthetic biology. As in the case of GMO, using these types of organisms should be illegal and immoral if they are design as biological weapons. The above independently of the strategy of the creation of an organism that uses part of the genetic material of an existing cell (as in the first examples developed by Craig Venter) or by designing and building a living organism, using only DNA synthesized by organic chemistry. In both cases, in my view I would emphasize that living organisms will be developed by synthetic biology that will persist in nature insofar as they have the metabolic and other capacities to survive. Otherwise, they will not exist. 7

8 Organisms could be developed through synthetic biology to make substances that are not currently produced by living organisms. A simple example is a living being that could synthesized ampicillin (a substance currently not produced by any living being) from penicillin (a substance made by certain organisms), since ampicillin is currently commercially manufactured from penicillin through enzyme technology processes using the enzyme penicillin acylase, which is why ampicillin is currently a semisynthetic antibiotic. The genetic/enzymatic/metabolic capacity in the receiving and producing organism would be required to achieve this, since this would not be possible otherwise. However, it is feasible to imagine about this particular experiment, by incorporating the capacity to produce penicillin acylase into a penicillin-producing organism. Lastly, one would have to build the appropriate cellular capabilities in the organism designed by synthetic biology, regardless of whether the goal is to produce a new or existing substance in living organisms. The potential of synthetic biology is extraordinary, as outlined in the IAP Statement on Realising Global Potential in Synthetic Biology: Scientific Opportunities and Good Governance. There is an extraordinary set of possibilities one can think of, through new organisms with special properties designed to meet different needs and address local, regional and global issues. All these data indicating the broad health and economic benefits of transgenics over nearly 30 years and the more than two thousand references on their low risk and safety, must be used to conclusively prove the importance of organisms designed by synthetic biology. Also, in my view, and as mentioned in the IAP Statement stated above, we must ensure that fear and ignorance, and other interests and opinions with no real solid scientific basis, do not delay the use of this technology because of the extraordinary benefits GMO will provide and have already provided, which is the simplest case, I insist, of an organism that carries a fragment or segments of chemically synthetized genetic material. Just as transgenic products have been demonized by the media and groups with other interests such as Greenpeace, on the basis of scientific evidence and experts opinion, we must not allow this reaction to synthetic biology. Lastly, just as using GMOs as biological weapons is immoral and illegal, using organisms that could be designed and built using synthetic biology to serve as biological weapons should also be illegal and regarded as immoral. 8

9 We must therefore continue to evaluate new transgenic organisms and those produced by synthetic biology in the same way we evaluate GMO today. In Mexico we have a Law on Biosecurity for the evaluation and approval of GMO. It states, among other things, that these two processes should be conducted on a case-by-case basis, step by step, taking into account the precautionary principle, and basing the proposal on sound scientific evidence and arguments that indicate the reasons, justifications, benefits, advantages, opportunities and potential benefits of constructing GMO and the disadvantages of not doing so. In other countries, this is evaluated and validated by taking the aforementioned elements into account. Within this same context of the responsible use of organisms developed by synthetic biology, the IAP Statement indicates that Maintaining biosecurity entails challenges beyond those of biosecurity: for biosecurity, the core defense rests on the responsibility of the scientific community. Individual academies, IAP and IAC have produced relevant material advising on individual scientific responsibilities and institutional codes of conduct that helps to promote both biosecurity and biosafety. These guidelines should be disseminated widely. 9