Team:Penn/Perceptions

In order for synthetic biology to make valuable advances in medicine and biotechnology, progress must also be made on the bioethics front. Scientific progress solely for the sake of scientific progress is invaluable for increasing human knowledge, but as engineers, we must strive to make useful systems with the ultimate possibility of improving some aspect of life. This means that our engineered systems must comply with ethical and social norms. Although the development of new technologies in the laboratory is relatively independent of public opinion, the acceptance and integration of new technologies is largely dependent on public perception; a technology is useful only if it is used.

Scientific Risks

One of the biggest ethical concerns surrounding synthetic biology and genetically engineered bacteria centers on risk. Two major components of risk are biosafety, the impact of engineered organisms of human health and the environment and biosecurity, the potential for these engineered organisms to be used maliciously [1].

Biosafety

Almost all emerging biotechnologies carry an inherent risk to biosafety, especially at early and uncertain stages of development. This is especially true for synthetically engineered organisms. Because the field is so nascent, many of the developments by synthetic biologists are cutting edge. Biologists are still studying and discovering new information about the basic rules governing biology. Many of the gene networks and biological mechanisms used by synthetic biologists are still being studied, with fundamental advancements being made every day. With information constantly changing as well as the inherently nondeterministic behavior of many biological systems, it's very difficult to rationally design engineered organisms that act exactly as anticipated. The Registry of Standard Biological Parts attempts to address the issue of uncertainty by classifying and characterizing modular biological components. However, biology is not modular; different proteins and genes interact with each other in still unknown ways. While piece by piece assembly works extremely well for other forms of engineering (such as electrical or mechanical), this is because engineers designed all of these components from scratch and have a very good grasp on how each part works and how these parts interact with each other. Synthetic biologists are not yet at a point where they can build components completely from scratch that act exactly as anticipated; the core components (genes) are usually isolated from nature. While fusion-proteins can be designed using existing proteins, synthetic biologists cannot reliably synthesize a DNA sequence for a specific function. When building synthetic systems using a mix of natural parts, it's difficult to predict with complete accuracy how the system will react in varying conditions and with the surrounding environment or with the human body [2]. An organism engineered to produce a therapeutic and deliver it to a site in the body could unknowingly also be producing a toxin or other harmful metabolite and releasing it into the bloodstream, an outcome that may not be evident until it has an opportunity to cause significant harm.

Another biosafety hazard involves the risk of contamination. How will synthetic biologists ensure that any microorganism they engineer will stay where they want it to [3]. Bacteria and microorganisms are extremely mobile, able to travel between places through the very air we breathe. Pharmaceutical contamination of drinking water is already raising concerns [4]. Contamination by engineered microorganisms would be worse still, as these organisms have the ability to replicate and evolve and spread in ways that are difficult to anticipate. They may evolve to fill new niches or compete against natural organisms, altering ecosystems and biodiversity in unpredictable ways. Genetic pollution may also occur through horizontal gene transfer [2], giving natural organisms unexpected and potentially undesirable capabilities. Microorganisms are able exchange DNA with each other or uptake DNA from the environment. Leaked engineered bacteria could transfer resistance genes across species, similar to the StarLink corn controversy that surrounded genetically modified corn in 2000-2001. Aventis created a genetically modified corn called StarLink with Bacillus thuringiensis (Bt) derived insect resistance protein called Cry9c. Corn including this protein was restricted by the EPA to animal feed only due to potential for allergenicity, but traces of the Cry9c protein were found in human corn products due to genetic pollution of human feed, resulting in food recalls by the FDA and disruption of the food supply [5]. A similar gene transfer could occur in microbes; however, due to a shorter replication time, the suspect gene would spread much more quickly and a "bacteria recall" would be impossible to implement.

Biosecurity

While synthetic biology has the potential to greatly improve human life, it is also capable of producing harmful microorganisms, either by accident (discussed above) or on purpose. Synthetic biology could open the door for a new type of bioterrorist – one that could rationally design microbiological weapons for use on the public. While DNA sequences and research publications may be readily available, construction of an actual organism capable of acting as a biological weapon (for example, by reconstituting a virus) is both difficult and expensive. Though it is still a possibility and needs to be taken as a serious issue, the equipment necessary to synthesize full viral or bacterial genomes is expensive, furthermore, facilities that offer these services screen synthesis orders to ensure that the DNA being synthesized poses no threat to public safety. Lastly as the DNA sequence alone is not enough to create a bio-weapon, the synthesis of potential harmful DNA is not sufficient to pose a threat to public safety by itself [6].

Intellectual Property and Ownership

Another important ethical issue is the relationship between synthetic biology, intellectual property, and ownership. Should someone be allowed to patent a gene? What about a synthetic network of genes that perform a specific function? Should these systems be patentable or copyrightable? Or should they be neither and left to the public domain? While genes are currently patentable under the same law that makes drugs patentable, there is ongoing debate and controversy as to whether this law, should change as technological progress continues to redefine the assumptions made by legislators and regulatory agencies [7]. Broad patents on entire genes can slow down the growth and stifle innovation in the field, preventing the production of potentially useful systems. Early entrants into synthetic biology are attempting to patent basic genetic components to get ahead of their competition. Copywriting genetic code is not clear cut either, as copyright law generally requires expressive choice, which is limited by the 4 DNA base pairs.

Putting the legal arguments aside, enforcing ownership of a gene or genetic system will be near impossible. Interested scientists can simply find the gene again in nature, or even in the engineered microorganism, and culture it themselves. Self-replicating bacteria that are distributed to the public and produce a therapeutic of choice could allow anyone interest to culture the organism themselves and have a potentially limitless supply of the drug. Simple PCR could allow direct access to the DNA "source code" for your own manipulations. This is much different than the current access to biologics or pharmaceuticals where only the final product, and not the means to produce for the product, is readily available. IP law will have to be very different to protect companies and provide incentives for the development of new biotechnologies while still promoting innovation and preventing the use of the patent system as a tool to monopolize and stifle competition.

Moral Issues

The use of bacterial-based therapeutics may open some moral discussion on humanity and augmentation. With standard drug-based therapies, the only way to make the effect of the drug "permanent" would be to constantly re-administer doses. With bacteria therapeutics, it would be possible for the microbe to anchor in the body and produce a constant supply of a molecule. The passiveness of the therapy may bring up discussion about augmentation. By injecting these bacteria into the body, the person becomes better than they were previously, and this could theoretically be engineered to be permanent. Once this happens, you have changed the person, and philosophical discussions on the limits of man and the definition of human will most likely have to occur discussing the morals of altering the person. With socioeconomic factors in play, bacterial augmentations may widen the gap between the haves and have-nots. While the possibility of this happening would be many years into the future, it is still something that should be kept in mind, especially when thinking about public perception of synthetic biology.

Solutions

The solutions to successfully integrate synthetic biology into society lie within the domains of regulation and control. Synthetic biology has the potential to do great good for humanity; it also has the potential to do great harm, whether intentionally or not. Therefore, measures must be put in place to ensure that the science is properly regulated and that synthetic organisms or systems are properly controlled.

To combat the issues of biosafety and biosecurity, controls need to be placed on the organisms themselves. "Kill switches" that cause the bacteria to die under anything other than ideal conditions are a popular method of controlling synthetically modified organisms. Modifying the lifespan of the bacteria finite will lower the risk of accidental contamination or genetic pollution. Additionally, regulation such as the FDA clinical trial process for drugs and biologics will need to be developed for engineered bacterial therapeutics. Scientists developing these treatments must be held to high standards, and should provide extensive research demonstrating not only that their microbe works, but that it doesn't react in unexpected ways or produce unwanted byproducts in various conditions.

Additional regulation must be enacted to ensure accountability and transparency among synthetic biologists. There should be accountability among labs. This may be difficult with the advent of the DIY "biohacker" cloning genes in their own private labs, but safety is of the utmost importance. Transparency and accountability helps prevent accidental leakage of microorganisms into the environment as well as careless or reckless science by unqualified people.

The Presidential Commission on the Study of Bioethical Issues outlined 18 recommendations that they believe the government and synthetic biologists should take as the science moves forward [6]. All of the recommendations apply to engineered bacterial therapeutics. To see the success of these microorganisms and to allow synthetic biology to reach its full potential, scientists and engineers will have to work hand in hand with businessmen and policy makers to support innovation, evaluate risks, and promote a regulated and transparent industry to a well educated public.

Hurdles in Public Perceptions of Bacterial Therapeutics

Even if an engineered bacterial therapeutic is developed, shown to be efficacious and safe, approved by relevant regulatory agencies, and launched, it will face hurdles in public and governmental perception. There is a reason why food products supplemented with bacterial cultures have been branded "probiotics"; there are clear negative associations with ingesting foreign bacteria. Unfortunately for projects like ours, there are also further negative associations with genetic engineering and synthetic biology.

Negative public opinion or low awareness can greatly hinder the progress of new technologies. Most notably, progress in stem cell research has been slowed by its initial negative public perception, which resulted in laws which outlawed or severely restricted this research in several countries. Although public opinion has recovered and 58% of the US population now approves of embryonic stem cell research [8], there is a long lag between changes in public opinion and changes in legislation, and progress has remained slow. To prevent synthetic bacterial therapeutics from following the same path, we must consider the potential public perception hurdles specific to synthetic biology and take action to minimize their impact.

Public acceptance of synthetic bacterial therapeutics is closely tied to public perception of synthetic biology in general. Since synthetic biology is still an emerging field, awareness is generally low but is increasing rapidly. According to a 2009 study by Hart Research Associates, roughly 48% of adults have never heard anything about synthetic biology, while 28% have heard "a little" about it, 22% have heard something about the field and 5% have heard a lot about the field [9]. Importantly, only 18% believed that the benefits of synthetic biology will outweigh the risks. Perceptions have since been influenced by the recent work of Venter, et al. in which they engineered bacteria from a "synthetic" chromosome [10]. This research propelled synthetic biology to the forefront of national discourse for the first time in 2010, resulting in widespread shifts in perception about synthetic biology and an increase in awareness. Discussions emerged about whether synthetic biologists were "playing God," which has had a negative impact on public opinion of the synthetic biology because this type of discourse has not been accompanied by public education on the reality of the field [11]. In addition, the distinction between genetic engineering and synthetic biology is often not well understood by the public, and the negative perceptions of genetically modified organisms (roughly half of the US population opposes GMOs [12]) can thus spill over to synthetic biology. Given this current opinion landscape, it is reasonable to assume that even if a synthetic bacterial therapeutic was shown to be safe and effective, it may encounter public resistance. The development of engineered bacterial therapeutics may also be hindered by an eventual decline in public interest in the field and parallel decreases in public and private funding. Since government research funding is largely dependent on public priorities, high interest and awareness of a field is generally beneficial to researchers in that field. Synthetic biology has recently been enjoying a rapid rise in awareness, which has been accompanied by a spike in research funding [13]. Some of this funding has already resulted in the development of novel proof-of-concept synthetic bacterial therapeutics [14,15] which may develop into new treatments with time. However, like many other fields before it (most notably nanotechnology), synthetic biology is likely to experience a drop in public interest in the near future.

Beating the Hype

The Gartner Hype Cycle [16] is a model which describes the public awareness of emerging technologies. It predicts that in the early onset of a new technology ("technology trigger"), expectations of its potential become inflated and the public gains considerable interest in it. This has arguably been occurring recently with synthetic biology, as evidenced by widespread claims that artificial life has been created and that the field can create designer organisms from scratch. These claims have greatly increased interest in the field, but in the near future the public will have to come to the realization that synthetic biology has limitations and is very far from actualizing many of the goals which have been presented to the public [11]. At this point of disillusionment, public interest will decrease, most likely accompanied by a decrease in research funding. In the case of nanotechnology, the initial excitement of the field throughout the 2000s has been subsiding, and federal funding for the field is also being decreased [17]. If synthetic biology follows this same path (Fig. 1), difficulties may arise in the development of engineered bacterial therapeutics. The very early stage of this type of research, combined with the long lead times for preclinical development and approval of therapeutics, and the fact that no such therapy has previously been approved will result in a very long timescale for the introduction of engineered bacterial therapeutics. This means that both near-term and long-term decreases in research funding for synthetic biology could significantly hinder their development.

It is clear that throughout all stages of research, engineered bacterial therapeutics will encounter hurdles in public perception including mixed opinions of synthetic biology, false impressions of the potential and dangers of the field, and potential decreases in interest and funding for the field. However, these hurdles can be overcome if several measures are taken by synthetic biologists (including iGEM teams), the lay public, the government and the media. Firstly, when iGEM teams, synthetic biologists, and the media describe advances in synthetic biology, we must strive for informational accuracy in our portrayals of the science. Phrases such as "creating life" and "playing god" detract from public opinion of the field. In response to this, the government has moved in the right direction by calling for an independent organization to fact-check the many claims made about synthetic biology which are disseminated to the public4. In parallel to such a strategy, improving public scientific literacy and education would decrease the likelihood that they accept such claims as truths. iGEM teams have contributed positively to this by engaging in outreach campaigns to the lay public, and the existence iGEM itself has greatly increased synthetic biology awareness and education among youth.

If the public is well-educated about synthetic biology and understands its immense potential in medicine, we believe that synthetic bacterial therapeutics will overcome perception and funding hurdles in the near future and eventually treat diseases in ways which were not possible before.

FDA Regulatory Barriers to Synthetic Bacterial Therapeutics

Many iGEM teams produce projects that they hope will one day be applied to human health, or in some cases, are actually designed to be consumed by human beings. Any project that has consumption or medical use as its ultimate goal would undergo scrutiny from a wide array of regulatory agencies. This process can take a great deal of time and money, and is a major consideration for any biotechnology startup, including ones that may arise as a result of an iGEM project. Here, we focus specifically on the US regulatory agencies, but many regulatory practices in other regions follow similar guidelines.

The Food and Drug Administration (FDA) is the primary regulatory agency for medical devices and pharmaceutical compounds. Historically, the agency has guided and reviewed clinical trials for medications, as well as outlined standards for the testing and approval of medical devices. The rapid development of the biotechnology industry has also prompted the FDA to make further distinctions between "chemical small molecule entities," (SME) and "biologics," which are defined as "any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man." This definition has since been applied to products of the biotechnology industry, including future products based on the work of the 2012 Penn iGEM team. Essentially, the FDA makes a distinction between products that are manufactured in a well characterized fashion, such as traditional pharmaceuticals and recently some recombinant proteins, and products that are produced in processes which are more variable, such as the growth of viruses in bioreactors [18].

The FDA is divided into two large divisions, the Center for Drug Evaluation and Research (CDER), which is responsible for evaluating SME drugs, and the Center for Biologics Evaluation and Research (CBER), which is responsible for evaluating biologics. It is likely that any bacterial-based therapeutics, such as the ones developed by the 2012 Penn iGEM team would most likely fall under the jurisdiction of CBER.

Under such regulations, a bacterial-based therapeutic would be required to undergo the biologic licence application process (BLA). During this process, the FDA would review not only the safety and efficacy of a biologic, but also the process by which a biologic is produced. SME drugs are often produced through established industrial processes, and are therefore biologics are extremely sensitive to small variations during the production process, and are therefore more strictly regulated. The FDA BLA process can be divided into five distinct stages [19].

The first stage is the "Filing Determination & Review Planning Stage," where reviewers from the FDA determine if the BLA meets the minimum standards that the FDA has set for filing an BLA, the amount of review required for the specific needs of the BLA, and the primary areas of the BLA that reviewers must focus on. FDA officials convene to produce a timeline for the rest of the review process. This process can be considered a planning stage, where all BLAs that meet the FDA requirements advance to the next stage [19].

The second stage is known as the "Review Phase," where FDA officials not only review the merits of the application itself, but also distribute the application to outside investigators, who can provide their own evaluations of the BLA. During this process, FDA officials are in constant contact with the BLA applicant, who may be asked to provide additional information depending on the requirements of the reviewers [19].

The third stage is known as the "Advisory Committee Meeting Phase." This stage occurs when "the clinical study design used novel clinical or surrogate endpoints, the application raises significant issues on the safety and/or effectiveness of the drug or biologic, or the application raises significant public health questions on the role of the drug or biologic in the diagnosis, cure, mitigation, treatment, or prevention of a disease". In the case of bacterial therapeutics, due to lack of precedent, any BLA based on such technology would most likely undergo this third step [19].

The fourth stage is known as the "Action Phase." During this phase, the FDA officials, based on the information obtained during the "Review Phase," will outline a series of requirement for the final therapeutic product. In this phase, specific requirements for the labeling of the product, as well as the conclusions reached by the FDA officials is summarized [19].

The final stage of the BLA approval process is known as the "Post-Action Phase," where FDA officials analyze their performance during previous BLA evaluation stages, and improve upon them for future BLA applications [19].

The BLA approval process is time consuming and can discourage the commercialization of may biologics. However, this process also has several advantages. Firstly, while SMEs are much easier to approve, they also allow for Abbreviated New Drug Applications (ANDAs). The ANDA process allows for generic drug manufacturers to produce generic versions of SMEs after five years, a factor that significanly reduces the incentive for applicants to submit an appliation for a SME. However, no ANDA analog exists for BLAs. Therefore, if an BLA is approved, it would be extremely difficult for other companies to produce "generic" versions of the biologic, creating a larger incentive for applicants to undergo the BLA approval process.

References

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[9] (2009). Nanotechnology, synthetic biology, & public opinion. Washington, DC: Hart Research Associates.

[10] Gibson, D. G. et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science (New York, N.Y.) 329, 52–6 (2010). [11] Presidential Commission for the Study of Bioethical Issues, (2010). New directions: The ethics of synthetic biology and emerging technologies. Washington, DC: Hart Research Associates.

[12] (2006). Review of public opinion research. Washington, DC: The Mellman Group.

[13] (2010). Trends in synthetic biology research funding in the united states and europe. Washington, DC: Woodrow Wilson International Center for Scholars.

[14] Chen, Y. Y. & Smolke, C. D. From DNA to targeted therapeutics: bringing synthetic biology to the clinic. Science translational medicine 3, 106ps42 (2011).

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[16] Linden, A. (2003). Understanding gartner's hype cycles. Conshohocken: Gartner.

[17] Sargent, J. F. (2011). Federal research and development funding: Fy2011. Washington, DC: Congressional Research Service.

[18] Kathleen R. Kelleher, FDA Approval of Generic Biologics: Finding a Regulatory Pathway, 14 Mich. Telecomm. Tech. L. Rev. 245 (2007)available at http://www.mttlr.org/volfourteen/kelleher.pdf

[19] Wan, Elysa, Jeffrey Kopacz, and Kathleen Williams. Biological Licensing v. Drug Approval Processes: Comparison & Consequences. N.d. Legal Brief. Massachusetts, Boston