Schaub 4:00 R12 REVERSE ENGINEERING THE BRAIN: AN ETHICAL ISSUE Emily Trea (emt58@pitt.edu) INTRODUCTION: THE USE OF STEM CELL RESEACH The human brain could be considered one of the many great wonders of the world. This organ is what allows humans to interpret the unpredictable world around us, make decisions based on these interpretations and act accordingly. This astounding ability to turn chemical reactions into thoughts and these thoughts into actions have amazed and stumped scientists to this day. Many of the chemical reactions are known but how thoughts and actions result from them are what mystify neurologists. The pursuit to fully understand how the brain works is known as reverse engineering [1]. The knowledge that could result from reverse engineering the human brain is extremely valuable and could help unlock numerous paths; one of these paths being advanced artificial intelligence. Engineers have been trying for years to create artificial intelligence that will allow technology to perform an operation based on its environment. Unfortunately, little success has been made in this field; current technological devices can only perform relatively simple tasks in controlled environments [2]. Experts who are trying to develop artificial intelligence are now looking to the brain for clues. The human brain has been performing homogeneous tasks in the real world for thousands of years so it only makes sense to take inspiration from it. Artificial intelligence that is modeled after the brain could result in an unlimited amount of benefits. The most obvious is luxury; advanced computers could be developed to cook or clean. Additionally, machines with artificial intelligence could take on the responsibility of dangerous jobs, such as mining or the disposal of toxic waste. More importantly, devices could be created that simulate parts of the brain; these simulators could give those who are missing certain traits, such as memory or mobility, the tools to reestablish these qualities [1]. This technology could help those who suffer from currently untreatable neurological disorders. In order to reach these goals, further achievements must be made in reverse engineering the brain. While there is research that looks at the brain and how it interacts as a whole, some researchers are investigating specific elements. There are a few institutions that are exploring the development of brain cells in a lab dish, known as in vitro, with the use of stem cells; recent publications have shown success in this field of research with the discovery of various neuronal traits that are associated with schizophrenia [3]. Stem cells allow scientists to recreate and study any part of the body because they have the ability to differentiate into any specialized cell [4]. There are currently two main techniques in stem cell research: embryonic or induced pluripotent stems cells University of Pittsburgh, Swanson School of Engineering 1 2014-09-30 (iPSC). iPSC differ from embryotic in that these cells are derived from adult somatic cells [4]. They are better than embryonic stem cells when it comes to ethical dilemmas because it does not require the destruction of embryos. Whichever technique is used, stem cell research can give experts intuition on how the brain comes to be and allow them to gain insight on how the brain organizes itself and neural connections form. However, this type of research is extremely controversial and can bring up many ethical issues, such as in the scenario that follows. THE SCENARIO The Institute for Neurological Discoveries is a research facility located in Pittsburgh that is focused on understanding the human brain. It has been around for years and is known globally for several breakthroughs in neuroscience. Their head researcher, Dr. Avery Brown has done amazing work; he has won countless awards and several Nobel Prizes. He is currently investigating the development of brain cells in vitro with the use of stem cells. I am currently a graduate student at The University of Pittsburgh studying Neuroscience and graduated last year from The University of Pittsburgh with a bachelor degree in Bioengineering and Neuroscience. Being my first year as a graduate student, you can image my surprise when I received an invitation from the Institute for Neurological Discoveries to work with Dr. Brown on his stem cell research. I was ecstatic and immediately accepted their innovation. The particular experiment that Dr. Brown asked me to work on involved the neurological disorder known as bipolar. Dr. Brown explained that by analyzing the development of a brain inflicted with bipolar disorder, we would be able to not only understand characteristics of such a brain, but we would better understand the regions of the brain that deal with emotions. He also informed me that we would be using iPS cells because the federal government was funding his research and the contract specified that he only use iPS cells to avoid the controversy that could result by using embryonic cells. Before we could begin, a donor with dipolar disorder needed to volunteer a cell sample, such as skin cells. After months and months of searching, however, hope of finding a donor with a severe enough case of bipolar began to dwindle. After ten months with still no luck, the government sent us notice stating that they would pull our funding if Dr. Brown and I did not find a donor by the end of the year. Surprisingly, Dr. Brown informed me a few days after receiving the notice that he had personally found a donor. This was great news; we could now begin the project and are able to keep the federal funding. Dr. Brown then told Emily Trea me I did not need to come to the lab for the next two weeks, because he was going to reprogram the adult cells and did not require my assistants. I was a little disappointed because I wanted to see the procedure, but I did not want to be a burden. On the last day of the two weeks in which Dr. Brown was supposed to be reprogramming the cells, I made a visit to the facility to see what progress he made. When I arrived, Dr. Brown was not in the lab. I found this a little odd, but I figured he may have finished early. As I was leaving the institute, I noticed a delivery truck with the logo of a well-known embryotic stem cell distributor. I went over to the men hauling a container out of the back of the truck and asked them to whom the delivery was addressed. They told me Dr. Avery Brown put in the order two weeks ago for the embryonic stem cells of a patient that had severe bipolar disorder. I was shocked. Not only was Dr. Brown planning to use ethically questionable stem cells, but he was breaking the contract with the federal government and several ethical codes. I was unsure how to react to this so I consulted ethical codes and other related articles. When I first discovered that Dr. Brown decided to use embryonic stem cells in replacement of iPSC, I knew I had only two options: to confront him directly or ignore the issue. I decided immediately that I could not just report him without talking to him first because if I reported him, his reputation would be ruined and this research opportunity would slip out of my hands. So, with the two options I had narrowed down for myself, I researched the ethical codes and other related articles. In addition, NSPE code also sets forth that “engineers shall be guided in all their relations by the highest standards of honesty and integrity” and “shall advise their clients or employers when they believe a project will not be successful” [5]. Mr. Brown and I realize that the research may go fruitless due to our inability to find donors; according to this code, we should inform the federal government, who was supplying us with funds, that the success of the project was questionable. Dr. Brown deceitfully fixed the issue by obtaining unapproved embryotic stem cells because he knew we could possibly lose the funding for the project. I know this would be a great lose to both of us but we cannot go against ethical codes. Finally, the main ethical code that Dr. Brown violates has to do with the report of our findings. All of the codes I discovered that related to our research, which included NSPE, BMES and SfN, have canons against fabrication in published articles [5,6,7]. If someone were to discover that embryonic stem cells were used in place of iPSC then Dr. Brown would come under the fire of all three of these establishments for publishing false experimental data. I also discovered that, according to SfN, I would also be responsible for the falsification of the report because “all authors share responsibility for the scientific accuracy” [7]. Therefore, not only would Dr. Brown’s reputation be destroyed, but mine as well before I even become a professional. This would affect further research opportunities or even future career positions for both of us. These ethical guidelines helped me to lean toward confronting Dr. Brown because I did not want either of our reputations to be affected due to ethical code violations. The other articles I found on stem cell research also helped me to lean in this direction. VIOLATION IN ETHICS FACTS AND OPINIONS The three major relevant ethical codes I found belong to the National Society of Professional Engineers (NSPE), the Biomedical Engineering Society (BMES) and the Society for Neuroscience (SfN). The guidelines set forth by NSPE applies in this case because Dr. Brown and I are engineering stem cells. Being a cell and part of biology, the codes of ethics for BMES also apply. Lastly, the stem cells are being engineered to develop into brain cells and the goal of the research is to further understand the brain therefore proper conduct put forth by SfN also comes into play. First of all, Dr. Brown was violating codes that involved my training. According to BMES, bioengineers must “honor the responsibility not only to train biomedical engineering students in proper professional conduct in performing research and publishing results, but also to model such conduct before them” [6]. Mr. Brown unknowingly violates this statement when I discover the delivery of embryonic stem cells. He showed me improper professional conduct by being dishonest with not only his assistant, myself, but his employer, the federal government. Before this research opportunity, I was not familiar with the controversy and ethical issues surrounding stem cell research. I discovered through an article I found titled “How Can Ethics Relate to Science? The Case of Stem Cell Research” by Ana Sofia Carvalho and João Ramalho-Santos that the issues mainly stem from the technique used. The use of embryonic stem cells are ethically questionable because this research requires the destruction of embryos [4]. Even he creator of the first human embryonic stem cell lines, Jamie Thomson, stated in a New York Times interview that “if human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough” [4]. This fact made me uncomfortable using embryonic stem cells in our research because it possibility means the loss of an unborn child. The next article I found, which was titled “Stem-Cell Doubletalk” by Wesley J. Smith, a Senior Fellow in Human Rights and Bioethics at the Discovery Institute, explained that iPSC was discovered in an effort to find a technique that did not restrict scientists due to ethical issues [8]. The THE SOLUTION 2 Emily Trea achievement was seen as a major breakthrough in not only stem cell research but in the field of science as a whole. The new technique was so important that the journal Science named iPSC the scientific “breakthrough of the year for 2008” [8]. This made me realize that the federal government would only fund our research if we used iPSC because they wanted to avoid upsetting the public or causing a disputation. I agree with this decision because iPSC allows us to continue our project without destroying an embryo. The last thing I found, however, was an article that described the drawbacks of iPSC. In an article on the website of Scientific American by Charles Q. Choi, it turns out embryonic stem cells are still considered the golden standard due to issues found with iPSC. According to some studies, the cells that are derived from iPSC have a “significantly higher rates of cell death” than those of cells derived from embryonic stem cells [9]. This means that using iPS cells may hinder some of our more extensive experiments due to premature aging; the cells may not divide into enough cells to do adequate research or the cells may die before the experiment is complete. Even if this is the case, I feel that the ethical issues that involve embryonic stem cells are more pressing than some of our experiments. A human life is more valuable than the information we may discover. If the results are extremely important, than a new method or improved iPSC should be designed. Finally, with the findings of my research, I decided I needed to confront Dr. Brown. I was going to speak to him in a nice, respectful manner and present to him my findings. I will simply explain that we can work harder at finding a donor and, as long as he returns the embryonic stem cells, I will not report this incident. could result from this type of research could be great; in addition to advances in reserve engineering the brain, neurologists and other specialists could gain insight on how to better treat certain neurological disorders. However, the controversy surrounding stem cell research can make it difficult to work with such technology. One of the leading scientists working in the program, Sherman Ku, states that embryonic stem cells are rare and nearly unobtainable due to the ethical debate that surrounds them. After reviewing the publications of the results found using iPSC, they decided to use this methodology instead because it will still allow for access to unique and relevant genetic backgrounds needed to do the study [13]. Therefore, the team can bypass road block associated with embryonic stem cells by using iPSC. Ku goes on to explain that by using the cells from patients of various diseases, iPSC can be generated that can provide a new technique in studying disease in vitro [13]. Issues with the research could come up, like in the scenario above, if the scientists are unable to find iPS cells that contain the correct genetic background. RECOMMENDATIONS FOR FUTURE ENGINEERS Ethically questionable situations are difficult. When one does arise, however, I think it must always be addressed; especially in the field of engineering where outcomes can be drastic. For example, if a civil engineer cuts corners, and a eeeeetgtefbridge is not properly built as a result, lives could be at stake. In the scenario above, the outcome doesn’t directly affect the lives of others, therefore, it is less dramatic, but it is still crucial. Regardless of the degree of severity, ethical issues should never be ignored. If you find yourself in a similar circumstance, consult codes of ethics that relate to your profession and articles that contain facts and opinions of experts in the field. Most importantly, consider all possible consequences and choose wisely. INSPIRATION: BASIS FOR THE SCENARIO The inspiration for the scenario above came from the Allen Institute for Brain Science. According to Matthew Herper, a journalist for Forbes, the organization is a “medical Manhattan Project” [10]. The Allen Institute for Brain Science is a research facility mainly focused on developing technology that will allow scientists to understand how the human brain works [10]. In other words, researchers here are working to reverse-engineer the brain. Some of the most current projects being worked on are cell typing neural coding and in vitro human cell types, the last of which caught my eye [11]. The team of researchers working with in vitro cell typing are looking to discover “how and when” brain cells become different types of cells by investing their development in a dish [11]. Carol L. Thompson, the Scientific Program Manager for the in vitro Human Cell Types Program, explains that the purpose of the project is to understand the “molecular and genetic networks that govern brain development and neuropsychiatric disease” through the use of human stem cell technology [12]. The knowledge that REFERENCES [1] (2012). “Reverse-engineering the Brain.” National Academy of Engineering. (website). [2] R. Sanz, C. Hernández, J.Gómez-Ramirez. (2011). “Intro.” From Brains to the Machines of the Future. (print article). DOI 10.1007/978-1-4614-0164-3_1 p. 1-2 [3] Y. Wang. (2014). “Yanling Wang, M.D., Ph.D.: Manager, In Vitro Human Cell Types.” Allen Institute for Brain Science. (website) https://www.alleninstitute.org/ourinstitute/our-team/profiles/yanling-wang/ [4] A.S. Carvalho, J. Ramalho-Santos. (2012) “How Can Ethics Relate to Science? The Case of Stem Cell Research.” European Journal of Human Genetics. (online article). DOI:10.1038/ejhg.2012.232 p. 2-4 3 Emily Trea [5] (2007). “Code of Ethics for Engineers.” National Society of Professional Engineers. (online article). [6] (2004). “Biomedical Engineering Society Code of Ethics.” Biomedical Engineering Society. (online article) [7] (2010). “SfN Ethis Policy.” Society for Neuroscience. (website). http://www.sfn.org/Member-Center/ProfessionalConduct/SfN-Ethics-Policy [8] W.J. Smith. (2009). “Stem-Cell Doubletalk.” The Weekly Standard. (online blog) http://www.weeklystandard.com/Content/Public/Articles/00 0/000/016/263fnapt.asp [9] C.Q. Choi. (2010). “Cell-Off: Induced Pluripotent Stem Cell Fall Short Of Potential Found in Embryonic Version.” Scientific American. (online article). http://www.scientificamerican.com/article/cell-inducedpluripotent/ [10] M. Herper. (2012). “Inside Paul Allen’s Quest to Reverse Engineer the Brain.” Forbes. (online article). [11] (2014). “Research Science” Allen Institute for Brain Science (website). https://www.alleninstitute.org/ourresearch/research-science/ [12] C. L. Thomson. (2014). “Carol L. Thompson, Ph.D.: Scientific Program Manager.” Allen Institute for Brain Science. (website). https://www.alleninstitute.org/ourinstitute/our-team/profiles/carol-l-thompson/ [13] S. Ku. (2014). “Sherman Ku, Ph.D.: Scientist 1.” Allen Institute for Brain Science. (website). https://www.alleninstitute.org/our-institute/ourteam/profiles/sherman-ku/ you to my roommate, Emily Zapinski and my good friend, Faith Thaler for helping me discover resources and staying focused. ADDITIONAL SOURCES “Ethical and Policy Problems in Synthetic Biology: EBISC.” Online Ethics Center. (website). http://www.onlineethics.org/Resources/Cases/27581.aspx “Ethics Case Studies in Biodesign.” Stanford Biodesign. (website). http://biodesign.stanford.edu/bdn/ethicscases/13patientrecrui tment.jsp “I’d Rather Be Fishing.” National Institute for Engineering Ethics. (print article). ACKNOWLEDGEMENTS I would first like to thank my tenth grade psychology teacher, Ms. Hamiltion, for introducing me to the wonders of the brain. Without her interesting teaching techniques and general positive demeanor, I may have never developed an interest in the human brain. Additionally, I must thank the Allen Institute for Brain Science for inspiring me to write about in vitro research. I would also like to thank the director of the Freshman Engineering Writing Program, Beth Newborg and my writing instructor, Bill Kirchner for helping me develop a writing technique for this paper. Lastly, thank 4