SISR Big Pharma - International Spring 2017 by The Triple Helix at UChicago

ASU - Berkeley - Brown - Cambridge - CMU - Cornell - Georgia Tech - Georgetown - GWU - Harker - Harvard - JHU - NUS - OSU - UC Davis - UCSD - UChicago - Melbourne - Yale

FEATURED CHAPTERS University of Chicago Editor in Chief Annie Albright

Founder Fotis Chatzisaris

Managing Editor Aya Nimer

Editor in Chief Theodora Panagiotidou

Associate Editors Gregory Justice Alborz Omidian

Associate Editor Freideriki Tziora

Writers Nishant Aggarwal David Gao

UC Berkeley Cover Designer Jessica Zhuge

Aristotle University of Thessaloniki

Writers Filippos Karageorgos Georgia Katsioudi Konstantinos Kyriakidis Anna Mavromanoli Paschalina-Danai Sarra

Johns Hopkins University

University of Cambridge

Associate Editors Adam Wolin Walter Zhao Kathy Le

Associate Editors Patrick Lundgren Luke Braidwood Roshani Badgami Ed Carter

Editor in Chief Jocelyn Chang

Writer Sehej Parmar

Editor in Chief Justin Koh

Writer Arthur Neuberger

TABLE OF CONTENTS BIG IDEAS

On Drug Compound In-licensing as a Business-strategic Approach to Succesful Drug Development in the Biopharmaceutical Industry

Arthur Neuberger....................................................................................

Understanding and Assessing Research and Funding in the US

Sehej Parmar.............................................................................................

Drug Discovery: The Pre-Clinical Trial

David Gao.............................................................................................

Internet of Things and Big Data: The Coming Revolution in the Healthcare Industry

Nishant Aggarwal...............................................................................

From Pharmaceutical Patents to Generic Drugs

Paschalina-Danai Sarra.......................................................................

THE MORE YOU KNOW Psoriasis

On Sleep Deprivation

Konstantinos Kyriakidis.....................................................................

Georgia Katsioudi................................................................................

GOING FORWARD Targeted Cancer Therapy

Anna Mavromanoli.............................................................................

Wearable Kidneys

Filippos Karageorgos..........................................................................

Letter from the Editors Dear Reader, It is with great excitement that we bring you this special edition of the Science in Society Review, featuring articles that explore the scientific, economic, political, and humanitarian forces that shape the global pharmaceutical industry. Discourse on college campuses is now brighter, better, and louder than ever before. It is important that amidst the din of explosive ideas we find a quiet space for measured collaboration, listening, and constructive disagreement. And so, driven by a desire to bring students from some of the world’s best universities together to share and discuss and disagree and, importantly, record their thoughts on topics of global importance, we created The Triple Helix’s Cross-Chapter Editing Project. For the past six months, writers and editors at Aristotle University of Thessaloniki, the University of Cambridge, the University of Chicago, and Johns Hopkins University have collaborated on this collection of articles focusing on a single topic. It is our hope that this effort will encourage further collaborations between students willing to consider the “Big Problems” of our generation. In this vein, the name of the issue sitting in your hands “Big Pharma.” It is our hope that the articles presented herein will stimulate and challenge you to join our dialogue. -The Editors

Fotis Chatziaris

Aristotle University of Thessaloniki

Justin Koh

University of Cambridge

THE TRIPLE HELIX Spring 2017

Annie Albright

University of Chicago

Jocelyn Chang

Johns Hopkins University

BIG IDEAS

On Drug Compound In-licensing as a Businessstrategic Approach to Successful Drug Development in the Biopharmaceutical Industry Arthur Neuberger (Cambridge)

is characterized by large investments (typically several billion USD) into a drug development process that reveals high failure rates at all of its respective stages (Figure 1). Furthermore, since it takes on average more than a decade of clinical development until a pre-clinical drug candidate can eventually reach market launch, these exorbitant investments (on average over 900 million USD1) into an uncertain future need to be made over a long period of clinical development time. he pharmaceutical market

Fig. 1 The drug development pipeline.

From a business-strategic perspective, it is therefore most crucial to identify managerial strategies which increase the likelihood of success in clinical drug development. A common and critically debated strategy is the in-licensing of drug compounds that were developed by other companies. In a nutshell, this means that an in-licensing company â&#x20AC;&#x153;buysâ&#x20AC;? a drug compound (at a certain stage of the development process; see Figure 1) from its originating company, i.e. the rights to further develop and, if approved, to commercialize it. An overview of the various stages towards a successful licensing agreement are summarized in Figure 2. This article examines drug compound in-licensing as a business-strategic approach to successful drug development in the biopharmaceutical industry.

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Licensing agreement

The technology owner or rights holder is compensated, usually financially, for the grant of those rights.

The respective rights duties and obligations of the parties that will govern their legal relationship are set out.

The right to exploit the technology is granted by the technology owner or rights holder, to the technology transfer partner that will exploit the technology.

Fig. 2 Stages of a licensing agreement.9

Licensing is a common business-strategic approach in the drug developing industry. The latter is formed by small- to medium-sized biotech firms and large (traditional) pharmaceutical companies as well as biotech companies that once started as small firms and gained a certain size over time that allows them to compete on eye level with some of the “old pharma giants”. Typically, the latter two in-license drugs from the small- and medium-sized companies at any of the research and development (R&D) stages (pre-clinical, clinical I to III). Evidently, the price of the out-licensed drug highly correlates with the stage of the drug in this development process. It remains, however, to explain why some companies would have an incentive to out-license its drug candidate(s) at all. The out-licensing of drugs is a very common business strategy In comparison, the inamongst most biotech firms. Some licensing party will most of these firms are created with the sole purpose of developing a prom- certainly not have the ising drug candidate that can then same access to the kind of be sold on to a larger company. A great number of biotech firms information that is needed simply lack the resources for costly to assess the real, inherent clinical development and are hence forced to out-license the compound quality of the in-licensed to a larger partner.

drug candidate.

As for the acquiring company’s perspective, one evident situation that might encourage in-licensing could be one in which a drug developing company’s R&D pipeline is endangered of “drying out”, due to a significant fraction of failed in-house originated compounds (i.e. due to early-stage withdrawal from the R&D process). However, in-licensing is not at all exclusive to companies with endangered R&D pipelines, but is a prevalent business-strategic behaviour in the overall sector. As with buying used cars, the danger of “buying a pig in a poke” is an ever-present risk if knowledge between buyer and seller is not aligned. Whilst some companies are 6

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forced to out-license their most promising drug candidates, other companies might try to get rid of their least promising candidates. The latter scenario is however only possible if information asymmetries between buyer and seller exist. In this case, as with used cars, the seller, i.e. the out-licensor of a drug compound, is expected to know the subject of a licensing agreement’s real “quality.” In comparison, the in-licensing party will most certainly not have the same access to the kind of information that is needed to assess the real, inherent quality of the in-licensed drug candidate. These information asymmetries could result in a moral hazard behaviour according to which companies out-license bad drugs (“lemons”) to in-licensing companies. This is commonly referred to as a “lemons” problem in a market. Such a lemons problem in the pharmaceutical industry was originally proposed by Pisano2 using a theory-based analytical approach. However, considering the high failure rates which prevail throughout the entire drug development process (drugs candidates do fail in late stage clinical development more often than one might expect!),3 it is rather questionable whether even the out-licensing party has any reliable knowledge on the drug’s potential to treat a disease. In general, the following scenarios seem conceivable: If neither party has reliable information on the inherent quality of the subject of a license agreement, success rates of in-licensed drugs and those developed in-house by the in-licensing company should be rather similar. The same would be true if both parties can equally well assess the drug’s quality. One could even think of in-licensed drugs out-performing in-house originated ones, if the in-licensor is bad at development but skilled in assessing other companies’ drugs in development. If, however, the out-licensor is able to assess its drug quality whilst the in-licenser has limited access to such information, the out-licensor has a financial motivation to out-license its bad drugs (moral hazard), which would result in a lemons problem. A case where an in-licensor can assess the inherent quality better than the out-licensor seems rather irrational. The simple fact that a lot of companies in-license drugs at pre-clinical stages, i.e. when there is no reliable data on the clinical performance of the acquired compound (not to mention the fact that drugs do fail at considerable rates in phases II and III too) suggests that these companies at least believe in their ability to (1) screen for potent drug development targets and therewith to (2) outsmart the lemons problem. Academic literature examining the lemons problem in the (bio-)pharmaceutical industry has not been able to prove its existence: In a quantitative analysis using R&D data from the world’s top 50 pharmaceutical companies, DiMasi and colleagues4 find in fact higher success rates of in-licensed compounds in phase I (compared to phase I in-house developed drug candidates). Interestingly, success rates between in-licensed and in-house developed candidates are equal in late stage clinical development (phases II and III).4 Using a more comprehensive data-set, Danzon and colleagues find that drug candidates that small firms out-license to large companies and other small firms do as well as the average, with the exception of a lower chance to complete phase I if small firms out-license to medium-sized firms5. Other obtained differences in clinical phase completion success rates between in-house developed and in-licensed compounds (for medium-sized and large firms out-licensing to other medium-sized or large firms in phases I-III vs. in-house development) are either insignificant in comparison with the average success rates © 2017, The Triple Helix, Inc. All rights reserved.

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(majority of cases) or, if different, positive for in-licensed compounds as compared to in-house originated drugs.5 Considering the lack of supporting data, it is suggested that a lemons problem is not prevalent in the drug developing industry. Quite the contrary! It seems that in-licensing is a vital approach to maintain the productivity level of this thriving industry. In recent years, the role of big pharma has significantly evolved – away from drug discovery research towards clinical drug development, production and marketing of other companies’ drug candidates. In fact, recent studies6, 7 show that big pharma, in a direct comparison with biotech firms, is not as productive at drug development as biotech firms: per FDA-approved review for a new drug compound, pharma has to spend four times more R&D money (see Table 1). Moreover, drugs are nowadays more often originated by smaller and much more innovative biotech firms that have smaller yet more focused drug portfolios.8 Sector

R&D Expenses ($bn)

Biotech

1.63

Pharma

6.30

Table 1 Estimated allocated R&D expense per FDA-approved priority review for a new drug compound.7

The in-licensing of drug compounds from small- to medium-sized biotech firms therefore seems to be a success parameter in the pharmaceutical industry. These “foreign” drugs can be a valuable innovation source for companies that lost their ability to innovate. Whilst biotech firms can innovate more efficiently and effectively, using a much smaller budget, pharma has the greater competency to clinically develop and commercialise compounds (that other companies originated) using their rich resources and easier access to the global market. A somewhat provocative yet economically rational conclusion would suggest a clearer separation of roles based on the prevalent distribution of competencies and resources between pharma and biotech: biotech firms are clearly the leading innovators of novel drug technologies and should therefore focus entirely on pre-clinical and early clinical drug development rather than on gathering scarce financial resources for late stage clinical development. Big pharma on the other hand could reduce their in-house pre-clinical drug development and focus on funding (under the condition of in-licensing) the biotech sector’s drug development (pharma as focused investment banks). Such “division of labour” (based on different competencies) could have the potential to increase the number of new drug approvals per year, a change from which society would greatly benefit. References

Vernon JA, Golec JH, Dimasi JA. Drug development costs when financial risk is measured using the Fama-French three-factor model. Health Econ. 2010;19(8):1002–5.

Pisano GP. R&D Performance, Collaborative Arrangements and the Market for Know-How: A Test of the “Lemons” Hypothesis in Biotechnology. SSRN Electronic Journal. 1997.

Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat. Biotechnol. [Internet]. 2014;32(1):40–51. Available from: http://www.nature.com/nbt/journal/v32/n1/full/

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nbt.2786.html?WT.ec_id=NBT-201401 4

DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin. Pharmacol. Ther. [Internet]. 2010;87(3):272–7. Available from: http://www.scopus.com/inward/ record.url?eid=2-s2.0-77149155968&partnerID=tZOtx3y1

Danzon PM, Nicholson S, Pereira NS. Productivity in pharmaceutical-biotechnology R&D: The role of experience and alliances. Vol. 24, Journal of Health Economics. 2005. p. 317–39.

Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat. Rev. Drug Discov. [Internet]. 2011;10(6):428–38. Available from: http://dx.doi.org/10.1038/nrd3405

Drakeman DL. Benchmarking biotech and pharmaceutical product development. Nat. Biotechnol. [Internet]. 2014;32(7):621–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25004226

Danzon PM. Economics of the Pharmaceutical Industry. NBER Report [Internet]. 2006;23(6):14–7. Available from: http:// www.nber.org/reporter/fall06/danzon.html. Rahul Gulrajani. Pharmaceurical Licensing. SlideShare. 2011. Available from: http://www.slideshare.net/rahulgulrajani/ pharmaceutical-licensing.

BIG IDEAS

Understanding and Assessing Research and Funding in the US Sehej Parmar (Johns Hopkins)

Edited by Theodora Pangiotidou and Freideriki Tziora (Aristotle)

axpayers in the United States care about how the federal government uses their

money. Yet, not many know that our government funds nearly two-thirds of all science, biomedical, and engineering research. Further, in 2016 the federal budget was approved with bipartisan support to allow for significant increases in government spending on scientific research at the National Institute of Health (NIH), Center for Disease Control (CDC), Food and Drug Administration (FDA), National Science Foundation (NSF), National Center for Biotechnology Information (NCBI), National Aeronautics Space Administration (NASA) and the Department of Energy. Many government-funded organizations received funding increases, which gave researchers somewhat of a break from running after grant opportunities. However, Deepti Pradhan from the Huffington Post argues that despite the NIH having received its biggest raise in more than a decade, researchers only got cut a little slack because “…when adjusted for inflation the 2016 budget is actually 15 percent smaller than it was in 2006 ($28.6 billion).”6 The National Priorities Project also shows that despite the increase in funding, the portion of the government’s discretionary spending on science and health is still the same from 2015 to 2016: 3 percent in science and 5 percent in Medicare and health. All in all, adequate research funding is hard to come by these days. Dr. Tamkum, who works in the Anatomy/ Zoology building at Colorado State University, goes as far as to say “All of us spend more time than we should looking for money to run the research programs.”5 Thus, science research funding needs a smarter process for budget allocation. The job of the NIH, when it comes to allocating funds for research, is to ensure that American taxpayers’ money is being used resourcefully. Despite it being difficult at times, it is imperative that the NIH do a better job of determining which research projects © 2017, The Triple Helix, Inc. All rights reserved.

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will produce the most valuable results. The NIH roughly follows a series of five criteria to determine which projects should be funded. However, there are factors specifically in the second and fourth criteria that the NIH often overlooks or does not aptly adhere to. At the same time, the critiques of American citizens on scientific research must also be addressed. The second criterion of the NIH is that funded research must yield knowledge applicable to a broad range of biological questions and clinical problems. A consequence of this criterion is that not all government-funded research is primarily for application, but rather that a good portion is for basic research, namely research that is driven by a scientist’s curiosity aiming for the expansion of knowledge. Many Americans, however, often do not recognize the merit in funding basic research and criticize it as a misuse of resources for two reasons. Firstly, as a capitalist nation, many Americans do not see the commercial value of the knowledge that results from basic research. They tend to perceive valuable research as research that has a practical application, an opinion which devalues the essence of basic research. Secondly, basic research is publicized as counterproductive entertainment for scientists, mainly due to funded projects such as “Freeway Air Bad for Mouse Brain,” “Pressure produced When Penguins Pooh – Calculations on Avian Defecation,” and “Ovulatory Cycle Effects on Tip Earning by Lap Dancers: Economic Evidence for Human Estrus?” seemingly lacking in productive meaning. Such articles make it seem like the basic research being funded by the NIH is not of the highest scientific caliber.

The job of the NIH, when it comes to allocating funds for research, is to ensure that American taxpayers’ money is being used resourcefully. Nevertheless, the NIH acknowledges the value and long term benefits of basic research as reported in The Washington Post: “…half the NIH budget is spent on general scientific projects that can’t be classified by disease and might yield insights or tools useful in many areas.” History has proven that basic research has been fundamental in the advancement of scientific research and often ends up being applied in some area. For instance, the discovery of the structure of DNA has been applicable in many key genetic findings and precision medicine. Similarly, Thomas Brock finding on the bacteria Thermus aquaticus was integral for Katy Mullis to invent the Polymerase Chain Reaction (PCR). Time and time again basic research has proven to be valuable and the government should, for that matter, continue to invest a significant portion of their budget on it. At the same time, the NIH should make more of an effort to explain the importance of basic research to the people. A better understanding for why basic research projects are funded will cause the media to reduce mockery of researchers. After all, negative publicity of scientific research can significantly affect private funding. In compliance with criterion four, the NIH ranks diseases by their “burden of disease” in the U.S., meaning that diseases with a higher burden of disease will be funded more. First, an important question to consider is the following: by what parameters is the burden of disease assigned? Dr. Carrie Wolinetz, the NIH’s Associate Director for Science Policy, says that burden of disease is “the impact of 10

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a health condition as measured by mortality, morbidity, financial cost, and other indicators. Different diseases can impose vastly different kinds of burdens.”7 These different kinds of burdens can include symptoms such as premature death, chronic disability, mental health repercussions, contagiousness, resistance to drugs, and more. In Dr. Wolinetz’s words, “A thousand people with influenza is not equivalent to a thousand people with headaches.”7 Furthermore, the NIH also characterizes disease burden by time. For example, the potential disease burden of the Ebola epidemic in Africa would have been huge had it not been contained immediately. Further, the NIH uses other measures as well to quantify the burden of disease such as Disability Adjusted Life Years (DALYS) and number of deaths. Overall, by looking at the NIH’s Report on the NIH Funding vs. Global Burden of Disease, it is evident that in general the same diseases consistently cause the highest DALYS and deaths: the top 3 being cancer, heart disease, and lung disease. Also, when plotting DALYS and deaths against estimates of funding for various research, condition, and disease categories (RCDC), the graphs generally have a positive trend, meaning that the diseases with the highest DALYS and deaths or burden of disease are awarded the most funding. There are notable outliers to this trend that need to be addressed. Within the United States inequities in disease funding to disease burden is evident due to private funding, which is influenced by social factors. For example, the Washington Post states that, “Two diseases with a similar health burden [within the US], that is breast cancer and chronic liver disease, received wildly different levels of support: $763 million for the cancer best known for the iconic pink ribbon awareness efforts, versus $284 million for a disease commonly caused by alcohol abuse.”3 Just in this example, there are many social factors at play. First, there is the commercialization of breast cancer as a product. As the Washington Post points out, the iconic pink ribbon has become a brand that amasses many donations for the disease, while collecting profit and being positive advertisement for many companies such as the NFL, which makes it an attractive disease to fund. American values are at stake. Does providing more funding for chronic liver disease imply that alcohol abuse is socially acceptable? Or does that mean that chronic liver disease does not deserve the same research treatment as breast cancer? Lastly, the target group that identifies with breast cancer is much larger and more acknowledged than that of chronic liver cancer. The target group for breast cancer is mostly all women, and the fact that everyone in the world is either a woman or has a mother, sister, wife, or daughter makes the disease personal to a large population and evokes empathy for research funding. Meanwhile, the target group of chronic liver cancer is alcoholics and smokers, people who do not evoke a lot of empathy because alcohol consumption and smoking are intentional actions. Therefore, such social factors lead to more Americans funding breast cancer over chronic liver cancer, leading to inequity in funding. Another such example of inequity in private funding due to social factors is funding for sickle cell anemia. While it is the most common life-threatening genetic disease in the U.S. with over 100,000 Americans suffering from the painful life it entails, Daily Kos reports that “the funding and publicity of sickle cell disease lags drastically far behind that of virtually every other genetic illness.”10 In comparison to another life-shortening genetic illness, cystic fibrosis, which received $176 million in 2011, sickle cell anemia only received $1.1 million. This difference arises because the diseases target contrasting groups: cystic fibrosis primarily affects © 2017, The Triple Helix, Inc. All rights reserved.

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Caucasians, a population with moderate to high socioeconomic status on average, while sickle cell disease primarily affects African-Americans, a population that has faced discrimination and inequality for centuries. Here we can see how the social construction of race plays an ugly role in scientific research, a place where race should not hold any conflict of interest. However, it is important to clarify that the funding inequity in both cases of chronic liver cancer and sickle cell anemia is not derived from the government but from the American people. Americans are the ones donating more readily to the National Breast Cancer Foundation than the American Liver Foundation and to the Cystic Fibrosis Foundation than the Sickle Cell Disease Association of America, possibly due to social bias and prejudices. Consequently, this discrepancy in private funding is another factor the NIH must address when deciding budget allocation. It is bad practice for the government to award two diseases of the same disease burden with equal funding when they are receiving wildly different quantities of private funding. This is not something the government is doing as of today. In 2015, despite the Cystic Fibrosis Foundation collecting more donations from private donors than the Sickle Cell Disease Association of America, the NIH still awarded cystic fibrosis with 5 million dollars more for research than sickle cell disease, only widening the gap. Instead, the NIH needs to be mindful of private funding when deciding allocation of funds, i.e. if two diseases have the same disease burden, their government and private funding in total should be roughly the same. There are some notable outliers to the trend of diseases being funded according to their burden of disease. These outliers are sensible and should be better understood by the American people. Such outliers prioritize the global eradication of diseases above disease burden. For example, Hepatitis C, which causes just under 5,000 US DALYS and approximately 400 US deaths a year receives one million dollars of funding, the same as Chronic Obstructive Pulmonary Disease (COPD), which causes over 4 million DALYS and approximately 250,000 US deaths. While the inequity in funding is clear, there is another factor to consider as outlined by Dr. Wolinetz. She says, “NIH will invest in research on certain diseases that are close to a cure.” This statement is emphatic because it alludes to the goal of global eradication of diseases as quickly as possible, and thus funding diseases where this goal is closer in sight. For example, Hepatitis C, a blood-borne disease, has an ample amount of research conducted on it as well as vaccinations and new drugs undergoing clinical trials. Meanwhile, COPD is nowhere near a cure to reverse the damage caused by the disease to the airways and lungs. And so, to accomplish the feat of disease eradication at a global level, the NIH is compelled to consider disease funding as a public health undertaking. Rather than just looking at data from America, it is integral that the NIH begins looking more closely at Global DALYS and Global deaths data. This takes adherence to criterion four of the NIH a step further. Diseases will be ranked by their “burden of disease” globally, meaning that diseases with a higher burden of disease at a global level will be funded more. However, even if the NIH is willing to take such measures, public health efforts are difficult to fund because it is important to remember that a large portion of government funding comes from taxes of Americans. A current topic of debate in America, especially after the election of President Trump and public consideration of his policy plans, is the allocation of the federal budget. The primary concern of the American people is within the country’s borders and they want to see their hard-earned tax money being put to 12

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good use. The health of the American people comes first, and domestic affairs take precedence over foreign aid. In fact, The Kaiser Family Foundation reports that, “While there are some partisan differences in attitudes towards U.S. global health spending, these differences are much smaller than other surveys have found on questions of domestic health care policy.”9 However, it is not that the American people don’t want to help, as “improving health in developing countries is one of many priorities the public sees as important for the President and Congress to address in world affairs.”9 On one hand, in the eyes of the American people, there are simply other issues that gain precedence, such as boosting the economy, creating jobs, and upgrading national security. In addition, the government must continue funding mandatory spending in social security, Medicare, and welfare. All these priorities pull the federal budget in different directions, and with an already considerable budget deficit, the government can only afford to pay so much attention to funding scientific research, much less to funding scientific research for global rather than national benefit.

Diseases will be ranked by their “burden of disease” globally, meaning that diseases with a higher burden of disease at a global level will be funded more. On the other hand, in the eyes of other developed countries, America is self-absorbed and ignorant of the burdens of diseases in developing nations. The International Debate Education Associations (IDEA) says that, “America puts billions more dollars in US-run international anti-AIDS initiatives, which have been seen by some as by-passing the Global Fund and undermining its work through conflicting policies.” America’s stinginess when it comes to foreign aid is not surprising as previous Kaiser Family Foundation surveys found that “…misperceptions persist about the size of U.S. foreign aid and how aid is directed. On average, Americans think 28 percent of the federal budget is spent on foreign aid, when it is about 1 percent.”9 This meager 1 percent makes a bad name for the U.S. in foreign relations and shows American’s ignorance in recognizing burdens of disease in developing countries. First there is the humane reason for why America should become more active in public health efforts. The fact that over 1.7 billion people in developing countries lose their lives to diarrhea, a perfectly curable disease, is a testament to need for attention toward the inequity in health care at a global scale. Yet, putting the human perspective aside, there is also the very real threat that epidemics in third world countries can grow into pandemics. Antibiotic resistance, Ebola, and Zika virus are appropriate examples when developed countries turn their backs to burdens of developing countries. Evidently, it is not only a concern of humanity for America to fund public health, but also of necessity as many pandemics can be stifled before they grow into a crisis. The problem, however, is that it is difficult to foresee the long-term implications of inefficiently funding public health efforts. NIH is pressured to fund more short term diseases such as Alzheimer’s disease, heart disease, and breast cancer that are closer to home. However, it is imperative that Americans better understand the effect of public health needs and smart funding for the NIH means spending a significant portion on global © 2017, The Triple Helix, Inc. All rights reserved.

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health. Overall, when it comes to allocating funds for scientific research, the job of the government is to ensure that American taxpayers’ money is going towards productive research. Although waters are muddy and it can be difficult to determine which projects will produce the most valuable results, there are a few parameters that need to be considered. Such parameters include basic research, disease burden, private funding, total eradication of disease, and public health as a bigger priority. As it is difficult for the NIH to attain more funding from the government due to the tight federal budget, there is a “calling for the NIH to do a better job evaluating the disease burden.”3 Furthermore, there is also a calling for the NIH to be more transparent in its allocation of funds as Dr. Carrie Wolinetz discloses that “…this [2013] is the first time that the NIH has put out its own analysis of the breakdown of research funding…a signal of transparency that many outside researchers applauded.”3 It is important that American citizens understand what is being funded and why. There is a cultural shift calling for the NIH to consider a more holistic picture when deciding burden of disease as well as a call for a more congenial, understanding relationship between the NIH and civilians.

References Breaking through government control of science. (2016, March 02). Retrieved from http://wcsj2013.org/breaking-government-control-science/

Discretionary Spending. (2014, March 19). Retrieved from https://www.nationalpriorities.org/analysis/2014/presidents-2015-budget-in-pictures/presidents-proposed-discretionary-spending-fy2015/

Johnson, C. Y. (2015, July 17). Why the diseases that cause the most harm don’t always get the most research money. Retrieved from https://www.washingtonpost.com/news/wonk/wp/2015/07/17/why-the-diseases-that-cause-the-most-harm-dontalways-get-the-most-research-money/

Kintisch, E. (2014, October 29). Should the Government Fund Only Science in the “National Interest”? Retrieved from http:// news.nationalgeographic.com/news/2014/10/141029-congress-science-investigation-research-funding/

Petrilli, B. (2014, May 01). The importance of research and research funding. Retrieved from http://collegian.com/2014/05/ the-importance-of-research-and-research-funding/

Pradhan, D. (2016, February 17). Scientific Research Needs More Funding, But Also Smarter Spending. Retrieved from http://www.huffingtonpost.com/footnote/scientific-research-needs_b_9244102.html

Rocky, S., & Wolinetz, C. (2015, June 19). Burden of Disease and NIH Funding Priorities. Retrieved from https://nexus. od.nih.gov/all/2015/06/19/burden-of-disease-and-nih-funding-priorities/

The USA should increase funding to fight disease in developing nations. (n.d.). Retrieved from http://www.europe.idebate. org/debatabase/debates/health/usa-should-increase-funding-fight-disease-developing-nations

Tucker, J. (2015, February 9). President’s 2016 Budget in Pictures. Retrieved from https://www.nationalpriorities.org/ analysis/2015/presidents-2016-budget-in-pictures/

2013 Survey of Americans on the U.S. Role in Global Health. (2013, November 7). Retrieved from http://kff.org/global-health-policy/poll-finding/2013-survey-of-americans-on-the-u-s-role-in-global-health/

King, Shaun. How race plays an ugly role in the drastic underfunding of sickle cell research and advocacy. (2015, May 05). Daily Kos. Retrieved from http://www.dailykos.com/stories/2015/5/5/1382655/-How-race-plays-an-ugly-role-in-thedrastic-underfunding-of-sickle-cell-research-and-advocacy

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THE MORE YOU KNOW

Psoriasis

Konstantinos Kyriakidis (Aristotle)

Edited by Roshani Badgami and Ed Carter (Cambridge)

of the world’s oldest documented diseases. Records of psoriatic patients can be found in texts as early as the bible, where the disease is called “tzaraath.”8 In the early 19th century dermatologists Robert Willan and Thomas Bateman divided psoriasis cases into two categories: (1) Leprosa Graecorum, when the disease presented with skin scales, and (2) Psora Leprosa, when the disease presented as eruptive psoriasis. Early nomenclature was misleading, because psoriasis is completely unrelated to leprosy; that is, it isn’t caused by Mycobacterium leprae.6 In the 1840s, Doctor Ferdinand von Hebra, founder of modern dermatology, eliminated the word “lepra” from the clinical description of psoriasis, thus distinguishing psoriasis from leprosy and defining it as a non-contagious disease. Later, in 1841, the disease was formally named psoriasis from the Greek word “psora,” meaning to itch. soriasis is one

Psoriasis is characterized by periods of active disease and remissions that may last years. In most patients, psoriasis appears either at the end of adolescence, around age 20, or around age 50. The disease often presents with an itching lesion. Plaque psoriasis, the most common form of psoriasis, is a common skin disease caused by a chronic inflammatory disorder characterized by red patches of skin, often covered by silvery scales. It begins as painless reddish spots, and, as the spots grow, they “flock,” or join. These spots commonly appear on the elbows, knees and scalp of the head. One painful side affect of the disease is psoriatic arthritis, which is characterized by inflammation and pain in the joints and usually occurs 10 or more years after the onset of psoriatic symptoms.7 The cause, or causes, of psoriasis are still unclear. We do know that psoriasis is associated with certain genes, some of which are the various alleles of histocompatibility genes. This allows physicians to estimate the probability of an individual developing psoriasis, but as not all individuals with the associated genes develop the disease there is most likely an environmental influence on development of psoriasis2. These environmental factors could include emotional stress, smoking, alcohol, obesity, and some infections diseases. Medications, including lithium, beta-blockers, quinolones and cortisone may affect the proper functioning of skin cells and result in rapid growth of cells in lesion areas, driving onset of active disease. Despite the lack of a cure, psoriatic patients can live fairly normal lives by following a regimented treatment plan. Psoriasis treatment can be very effective. Local steroid/anti-inflammatory ointments are used to address itching, and in the early stages of disease salicylic acid (aspirin), anthralin and some analogs of vitamin D (calcipotriene) can be used to tame outbreaks. In more advanced stages patients are sometimes prescribed immunosuppressants that work by reducing inflammation and by lowering the activity of the immune system. Unfortunately, some immunosuppressants when taken on a regular basis can have serious side effects: weakened immune system, weight gain, fatigue, mood swings, insomnia © 2017, The Triple Helix, Inc. All rights reserved.

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and acne. In the vast majority of cases psoriasis treatment has excellent results. In the past 100 years psoriasis has become largely manageable with treatment. Unfortunately, even in the 21st century patients with psoriasis experience stigma. In a recent National Psoriasis Foundation funded study, researchers showed healthy individuals pictures of various conditions such as psoriasis, acne, herpes labialis (which affects the mouth) and warts. Participants were asked questions about their reaction to the disease, and how they felt about people who have it. The results showed that the participant population had a surprisingly high engrained stigma against psoriasis. Luckily, according to the authors of a new National Psoriasis Foundation-funded study, psoriasis education could help dispel misinformation about psoriasis and reduce some of the stigma surrounding the disease. New medication, scientific insights, and better public understanding of their disease offer hope to psoriasis patients.5

References Disease-modifying Antirheumatic drug. (2017). Retrieved from Wikipedia: https://en.wikipedia.org/wiki/Disease-modifying_antirheumatic_drug

Guðjónsson, J.E., Valdimarsson, H. (2002). HLA-Cw6-Positive and HLA-Cw6-Negative Patients with Psoriasis Vulgaris have Distinct Clinical Features. Journal of Investigative Dermatology, 118(2), 362-365

Jaliman, D. (2015, April 16). Understanding Psoriasis -- the Basics. Retrieved from WebMD: http://www.webmd.com/ skin-problems-and-treatments/psoriasis/understanding-psoriasis-basics#1

Jaliman, D. (2015, December 10). What Is the Koebner Phenomenon? Retrieved from WebMD: http://www.webmd.com/ skin-problems-and-treatments/psoriasis/koebner-phenomenon#1

Leavitt, M. (2015, September 22). Overcoming the stigma of psoriasis. National Psoriasis Foundation. Retrieved from https:// www.psoriasis.org/advance/overcoming-stigma-psoriasis

McDermott, A. (2015, October 27) What’s the difference between Leprosy and Psoriasis? (blog). Retrieved from: http:// www.healthline.com/health/psoriasis/leprosy-vs-psoriasis

Tidy, C. (2016, January 18). Psoriatic Arthritis (blog). Retrieved from http://patient.info/health/psoriatic-arthritis-leaflet

Tzaraath. (2017, January 12). Retrieved from Wikipedia: https://en.wikipedia.org/wiki/Tzaraath

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BIG IDEAS

Drug Discovery: The Pre-Clinical Trial David Gao (Chicago)

that test new, innovative drugs offer hope in treating diseases like cancer and cardiovascular disease. However, these trials are criticized for their cost and failure rates where over 90 percent of clinical drugs fail to receive FDA approval.6 Outside of clinical trials, an entire other world of research exists and faces higher rates of failure, more expensive R&D costs, and longer approval processes. Drug discovery is a phase of research where scientists identify then test compounds on cells and animals prior to testing them on humans in clinical trials. If clinical trials are expected to have a steady supply of drugs, then this form of research needs more attention, increased organization between the academic and industry worlds, and increased detail to the quality of their drugs. linical trials

After identifying a disease’s biological basis, drug discovery researchers follow a fairly linear route of research. Scientists have begun implementing a “shotgun” approach, wherein thousands upon thousands of drug candidates are tested for a desired molecular response. The candidates are narrowed down with increasingly specific criteria, like acceptable toxicity levels, efficacy levels, effectiveness, and successes in animal models, until a handful of compounds are left. These compounds are called “lead compounds” and undergo an optimization process called “rational drug design.” Medicinal chemists design the drug while research scientists test it in the lab, sending it back to the chemists if they believe the results warrant a molecular edit. Once the drug is molecularly effective and proven to be safe in animal trials, it is sent for testing in human clinical trials. Such drugs fuel trials pipelines, yet are little emphasized. If drug Scientists have begun pipelines are to be strengthened, commercial and government implementing a ‘shotgun’ entities need to fund drug disapproach, wherein covery more extensively. The process takes an average of 81.2 thousands upon thousands months and $1.528 billion acof drug candidates are tested cording to a study released in 2016 by the Tufts Center for the for a desired molecular Study of Drug Development, where costs have more than response. doubled in the past two decades.4 Furthermore, although costs are increasing, pharmaceutical and government entities have been slow to respond. Of the four pharmaceutical companies with the highest market capitalizations (JNJ, ADR, PFE, and MRK), each spent an average of 1.8 times more on sales and marketing compared to R&D.5 For government entities like the National Institutes of Health (NIH), their drug discovery center, the National Center for Advancing Translational Sciences (NCATS) has a paltry 2% of the NIH’s budget yearly budget, compared to the National Cancer Institute’s 16%.1 More resources need to be efficiently allocated to drug discovery © 2017, The Triple Helix, Inc. All rights reserved.

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to sustain a productive pipeline. Moreover, further collaboration in drug discovery research needs to be encouraged. The issue stems from a lack of collaboration between the government, academic institutions, and pharmaceutical companies. Whereas academic institutions have the brightest minds, pharmaceutical companies have the most funding, technology, and access to molecular databases and assays for their screens2. Collaboration is also less likely to occur if one group is already researching it, as commercial and publication rights complicate the research process. Legal issues play a role too where whoever owns the drug would de-incentivize collaboration by demanding publication rights to any work and research conducted on the drug. And even if a research group at a university were willing to share the physical drug compound, the act of data sharing incites legal issues between company and institutional lawyers that can delay research up to months at a time. Finally, research needs to emphasize the quality of the drug itself so that clinical trials are more likely to succeed. Researchers can improve the quality of drugs they send to clinical trial by investigating further their lead compoundsâ&#x20AC;&#x2122; pharmacology, animal model results, and off-target issues.3 Emphasizing funding, collaboration, and quality can save more lives and dollars in drug innovation. Clinical trials after all need a solid foundation whereby greater public scrutiny on drug discovery could accelerate drug research like never before.

References Budget. (2016, April 04). Retrieved January 25, 2017, from https://www.nih.gov/about-nih/what-we-do/budget

Closing the Global Health Innovation Gap: A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases (Rep.). (2007). Retrieved from http://www.bvgh.org/Portals/0/Reports/2007_closing_the_global_health_innovation_gap.pdf

Dahlin, J. L., Inglese, J., & Walters, M. A. (2015). Mitigating risk in academic preclinical drug discovery. Nature Reviews Drug Discovery, 14(4), 279-294. doi:10.1038/nrd4578

Dimasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, 47, 20-33. doi:10.1016/j.jhealeco.2016.01.012

Swanson, A. (2015, February 11). Big pharmaceutical companies are spending far more on marketing than research. The Washington Post. Retrieved from https://www.washingtonpost.com/news/wonk/wp/2015/02/11/big-pharmaceutical-companies-are-spending-far-more-on-marketing-than-research/?utm_term=.651f49d9fe41

Thomas, D., Burns, J., Audette, J., Carroll, A., Dow-Hygelund, C., & Hay, M. (2016, June). Clinical Development Success Rates 2006-2015. Retrieved from https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%20 2006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf

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GOING FORWARD

Targeted Cancer Therapy

Anna Mavromanoli (Aristotle)

Edited by Greg Justice (Chicago)

are increasingly being used in treatments as part of a multidisciplinary approach to handling cancer. Research in targeted therapy has resulted in more effective drugs which improve patient survival rates, even providing hope for those whose diseases were previously thought to be incurable. A patent is an exclusive property right to an intangible creation of the human mind. Patents are granted by a sovereign state to the inventor of a novel invention, and the lifetime of a patent varies according to the country and product it concerns. If the United States Patent and Trademark Office (USPTO) issues a patent on an item lasting 20 years, then only the owner of the patent has the right to use or sell the item during this 20-year period. Of course, these protections only apply if the patentee has applied for and received recognition of the rights to his/her intellectual property. argetted therapies

Traditional chemotherapy kills any rapidly dividing cell. Targeted therapies (which refer to a broad range of new drugs and approaches) are fundamentally different because they selectively attack cancer cells. This makes them considerably less toxic. Targeted therapies are often cytostatic, meaning that they aim to prevent cancer cells from dividing, as opposed to chemotherapy, whose goal is to kill the cells. These treatments are very much a modern approach to cancer treatment, and reflect our modern understanding of how cancer works. Many mutations play a role in oncogenetic pathways. Oncogenes RAS and MYC are responsible for normal cell growth and division. Tumor suppressor genes such as TP53 act, in essence, as â&#x20AC;&#x153;brakesâ&#x20AC;? for cell division. DNA repair genes such as BRCA1 and BRCA2 are responsible for repairing mutations. Production and upregulation of oncogenes, defects in or downregulation of tumor suppressor genes, and downregulation or dysregulation of repair genes can all contribute to uncontrolled cell growth and cancer. These DNA mutations may be insertions or deletions of nucleotides, such as the insertion in EGFR exon 20 causing non-small cell lung cancer, gene amplifications, as is the case in her2 positive breast cancer, or translocations, such as the reciprocal translocation of genetic material between chromosomes 9 and 22 involved in chronic myeloid leukemia development. These mutations may be inherited or due to environmental factors originating from exposure to radiation, food, working environment, smoking, alcohol consumption, and chronic infection by viruses and bacteria. Epigenetic modification can play an important role and can have tremendous effects on gene expression and cell behavior. These are just some of many mechanisms that can contribute to carcinogenesis, or development of cancer. What all of these mechanisms have in common is that they result in the loss of control over cell division or growth, and this is what is taken into account when developing targeted therapies. Targeted drugs may be enzyme inhibitors which induce apoptosis in cancerous cells, or angiogenesis inhibitors, which prevent the tumor from obtaining sufficient oxygen and nutrients. Enzyme ÂŠ 2017, The Triple Helix, Inc. All rights reserved.

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inhibitors aim to stop the growth of cancerous masses, for instance by inhibiting tyrosine kinases or the mTOR pathway. Tumor cell proliferation may be inhibited by targeting the growth factors which take part in the process of multiplying cells. Antiangiogenic factors can be administered to restrict the tumors resource access, while blocking of glycolysis interferes in the cancerous cells’ metabolism. PARP inhibitors block cells’ ability to repair themselves, leaving cancer cells to die due to accumulated defects over multiple generations. In theory, individual drugs can be developed to target virtually any of the steps involved in cancer progression. As with any clinical therapy, the targeted approach has its drawbacks. Most tumors contain many mutations, and some are heterogeneous, meaning that the tumor contains several clonal variants of the original cancerous cell, each ‘line’ carrying a different set of mutations. This heterogeneity may complicate an otherwise straightforward approach to therapy because tumor cell variation causes differences in response to drug treatment. In the worst case scenario, a heterogeneous tumor could respond to targeted therapy by eliminating one “line,” allowing another and more aggressive clone to take its place. This issue partly explains the propensity of patients being treated by current targeted therapies to relapse, and is a significant issue in treating cancers with different subclones and mutations. This issue is one of many in the development of new drugs, but ever since targeted therapies have reached the clinical trial stage of development, results have been surprisingly positive. Some targeted drugs seem to be so efficient that they may reach the market before phase three trials have concluded. This bodes well for the field as a whole; however, future development is not without important concerns. Adverse effects of many targeted therapies including their interactions with other drugs and resistance to therapy have yet to be explored. That said, in modern cancer treatment, combining multiple approaches can often provide the most benefit for the patient, and this will undoubtedly be true for targeted therapies. As targeted therapies become a standard approach to cancer care, they may be combined with chemotherapy, surgery, radiotherapy or immunotherapy. This multidisciplinary approach for the cancer patient aims to improve overall survival and quality of life. As more effective targeted therapies hit the market, they will become an increasingly important part of an integrated approach to cancer treatment.

References Mak, I., Evaniew, N., Ghert, M. (2014). Lost in translation: animal models and clinical trials in cancer treatment. American Journal of Translational Research. 6(2): 114–118.

Omuro, MPA., Faivre, S., & Raymond, E. (2007). Lessons learned in the development of targeted therapy for malignant gliomas. Molecular Cancer Therapeutics. 6(7):1909–19.

Targeted Cancer Therapies. (2014, April 25). NIH National Cancer Institute.

Target Cancer Therapy. American Cancer Society.

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BIG IDEAS

Internet of Things and Big Data: The Coming Revolution in the Healthcare Industry Nishant Aggarwal (Chicago)

ankind has always strived to achieve even greater levels of health. Since the

1960s, the average lifespan has increased by 15 years. An aging population and newer diseases have created a demand for innovative healthcare practices, but only very recently has the needed technology to reimagine the production and distribution of the various facets of this industry been developed. And just as almost all other industries are incorporating big data and the internet of things, so is the world of healthcare. We are seeing a complete re-imagination of the ways in which healthcare products are being researched, produced, and delivered, and this shift will ultimately lead to the creation of a new medical value chain. Goodbye Paper and Person, Hello Cloud The physician-patient interaction model is becoming increasingly digitized. While records of a patient’s health history are currently paper-based and different between individual doctors and hospitals, advances are being made which will lead to a central repository of vital health statistics and records. Electronic Health Records (EHRs) will store patient data in an encrypted cloud, uploaded by physicians and smart-wears and this data will be accessible in real time by all entities authorized by the patient. Similarly, responsibilities for such minute tasks as food delivery, inter-hospital travel, etc. will shift from expensive human nurses to humanoid robots. The Japanese robotics firm Kokoro has already tested Actroid-F, a humanoid robot with moving eyes, mouth, head, and neck that can serve as a receptionist and a surveyor. Sensors and Data Technologies such as Fitbit, smart pill bottles, and smartphone apps have enabled us to digitize health tracking. Fractured body parts can be exercised at distance with real-time physician guidance using Myo, a gesture control armband, and heart rates and ECGs can be tracked and shared virtually with Zio, a connected cardiac monitoring system. In fact, many firms have started to offer bandages with integrated sensors that detect skin pH levels and signal the user if a cut is getting infected. All in all, we have embraced sensors and have started trusting automatic systems with our health, blurring the lines between healthcare and lifestyle. The Internet of Pharma With the advances in smart health technology and wearables, and a rapid popularization of big data analysis, pharmaceutical companies have long realized that selling traditional medicines is not enough for growth or competitiveness, and that they need to integrate technology with pharmaceuticals. This movement, called “beyond the pill,” takes a cue from the fact that pills are often not enough for optimal health outcomes and that there is an emerging market in new technology with a scope for great corporate profits. As a result, firms have started offering microcapsules with localized delivery capability, such as the one developed at West Virginia University which deliver drugs directly to the site of complication, thus reducing the reliance on blood travel. Many firms are also heavily investing in nano-bots, inexpensive, tiny, precise surgical instruments able © 2017, The Triple Helix, Inc. All rights reserved.

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to perform minor surgeries, take photos, and deliver radiation, etc. inside the human body. In fact, the pharmaceutical industry is molding 3D printing to its ways by not only printing low cost surgical instruments, but also drugs themselves by spreading layers of the drugs on top of one another until the right dose is reached, as Aprecia recently did with its epilepsy drug Spritam. This method also allows firms to quickly and inexpensively modify composition based on real-time patient feedback. As healthcare 3D printing develops, a whole ecosystem of consultancies has started to grow. Firms like VisMed3D offer everything between dental fabrication, legal model printing, medical device printing to simulation and testing services. Big Pharma not only offers tablets, but also advancement treatments that actively engage with patients through feedback and patient data. From Curative to Preventative Medicine The implications of EHRs are tremendous. Not only will patients be able to keep a complete and accessible record to which they can easily refer to receive proper treatment, but they will also be able to question and understand their diagnosis. AI systems will be able analyze patient health data, offer real-time advice to patients, and warn them of future symptoms through pattern recognition. Currently, a person is treated after he/she has developed an ailment. However, with these advancements, any anomaly in vital organs and fluids will be immediately caught and compared to similar cases, leading to the identification of a disease before it develops further. The consistent and reliable access to healthcare data will lead to reduced diagnostic errors and inexpensive early symptom advice systems that will transform medicine from a curative process to a preventative one. Patients at the Center Currently, healthcare works with a top-down approach where pharmaceutical companies develop drugs in isolated labs using static data, and physicians offer advice and diagnoses using general pattern matching. Thus, patients and providers are vertically integrated. However, with the generation and collection of big data and its use by corporations and physicians to offer improved products and services in real time, patients and providers will become horizontally integrated. Patients will become part of a dynamic relationship in which the two parties build upon the success of each other, where the patient provides data and the physician analyzes it to offer a solution. The rate at which medicine will be improved will increase due to the easier application of response information and the accumulation of larger datasets. In essence, patients will be offered tailored solutions developed with their information, leacing the capacity for further improvement. A democratization of medicine For far too long has medicine been either the domain of the experts and/or within the reach of the wealthy, where the recent increases in drug costs show that this problem is not just a matter of history but the present as well. Currently, a large percentage of most healthcare bills come from services (i.e. room & board, laboratory, CT scans, etc.) easily amounting to thousands of dollars. A major contributor to this steep price is the high cost of personnel who not only command a steep wage, but also require other benefits such as health coverage, paid leaves, etc. However, with the mechanization of such minute tasks as food delivery, inter-hospital travel, etc. and the shift from expensive human nurses to humanoid robots, hospitals will be able to minimize costs while improving. Whether hospitals will pass down savings to the consumer remains to be seen but it is highly expected that even without a passing down of benefits, an increased margin will give hospitals the liberty to offer improved services and 22

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invest in better resources. One of the biggest beneficiaries of sensors and 3D printed drugs will be patients in remote and under-developed locations. With the power of self-diagnosis and electronic-consultation, they will be able to avoid distant, expensive and often tiring physician visits. The capacity to print drugs will remove the burden of markups of the prices of specialized drugs and the ability to question diagnoses and check percent improvement in health will allow patients to quantitatively review physicians and base their decision on not only the qualifications of a doctor, but also the effectiveness of his work. With providers competing for dollar votes and increasingly open source research platforms, patients will see the price of health care decrease as innovation increases.

Just as almost all other industries are incorporating big data and the internet of things, so is the world of healthcare. No More Volume Rewards Healthcare companies, especially big pharma, will gradually stop getting rewards for volume. With the technologization of healthcare and medicine, companies will need to not only deliver products, but also outcomes. People will soon have the ability to not only see whether they are completely cured but will also be able to quantify incremental improvements over time. They will have the ability to tap into their EHRs and see exactly how much their blood toxicity has increased or decreased and how much testosterone was in their blood at a given time. As such, the importance will not only be whether a patient survives cancer, but also how much his cancer has decreased and how quickly. There will also be a performance-based pricing structure for medicines, medical devices, and medical services based on their effectiveness. The priority will be on the delivery of outcomes and not on simple products. Changing Roles of Governments and Insurers For a long time, governments have played an important role in healthcare. Medicaid, NHS, etc. are all publicly funded programs that provide the populace with healthcare services. However, smart healthcare means a direct financial participation from the people. As a result, consumers will directly pay for healthcare instead of relying on the insurance agent or the government office. With an increased direct interaction between the consumers and corporations, the governmentâ&#x20AC;&#x2122;s role will thus shift from that of the payer to that of a regulator. It will no longer be paying for services, but working to enact fair practice laws, prevent price gouging, and maintain sufficiently low entry costs. This, in turn, will mean that consumers will have more options for healthcare as they are no longer restricted by the providers supported by their insurance companies. The overall price for various drugs and services will also decrease as firms face increased competition that fuels a need for innovation to attract customers, as opposed to simply managing to win a physician or insurance contract. News Jobs and Roles Electronic health records, sensors, and wearables all rely on data and data analysis. Hence, with their increased acceptance, there will be a massive trove of data at corporationsâ&#x20AC;&#x2122; disposal. However, big data is often very difficult to parse through and understand, especially when there are multiple variÂŠ 2017, The Triple Helix, Inc. All rights reserved.

THE TRIPLE HELIX Spring 2017

ables. As a result, there will be an increased need for medical data analysts and digital advisors. Medical data analysts will be trained in not only making sense of vast amounts of data but also making ethical decisions, such as data privacy and manipulation. Digital advisors will work directly with patients and provide real-time advice. They will not replace traditional doctors and physicians, but will take over primary response tasks by analyzing a patient’s medical history and interacting one-on-one with patients. These analysts and advisors will come with a diverse set of qualifications, backgrounds, and experiences; it is expected that boot-camps and two-year certificate courses will become a commonplace training mechanism. The creation of this medical value chain may seem simple in theory, however many challenges arise from smart healthcare. Firstly, for smart healthcare to properly function and give meaningful results, data has to be communicated seamlessly. A smart pill should be able to integrate with an ECG. Similarly, a customer’s medical history and his/her financial records should be analyzable in tandem. For this to happen, data needs to be centrally stored in a global repository using a single framework or collected from many sources, normalized into a consistent structure and distributed among unique entities such as physicians, patients, sensors all using different platforms. Who oversees this repository? What happens in case of national conflicts? What happens to national or regional patent systems? Secondly, given the private and sensitive nature of medical data, data privacy laws will need to be carefully thought out and implemented. Who owns a patient’s data and to what extent can that be used? Can physicians track terminally depressed patients and send help if they are in grave danger? Lastly, change is often bitter. People are risk averse and generally tend to view new technologies and processes with high skepticism. Given the very personal nature of this change, what will be the result of a political backlash? Will providers adopt a common transparency framework or will research continue to be shielded from public audit? These questions will need to be carefully assessed as we digitize an industry critical to the function of humankind.

References About Biodesign & 3D Printing. (n.d.). Retrieved January 20, 2017, from http://vismed3d.com/about-3d-printing/

Bo, L., & Yulong, L. (2017). Internet of Things Drives Supply Chain Innovation: A Research Framework. International Journal Of Organizational Innovation, 9(3), 71-92.

Chen, Y., Lee, G. M., Shu, L., & Crespi, N. (2016). Industrial Internet of Things-Based Collaborative Sensing Intelligence: Framework and Research Challenges. Sensors (Basel, Switzerland), 16(2), 215. http://doi.org/10.3390/s16020215

Dimitrov, D. V. (2016). Medical Internet of Things and Big Data in Healthcare. Healthcare Informatics Research, 22(3), 156–163. http://doi.org/10.4258/hir.2016.22.3.156

Harpham, B. (2015, September 08). How the Internet of Things is changing healthcare and transportation. Retrieved Nov. & dec., 2016, from http://www.cio.com/article/2981481/healthcare/how-the-internet-of-things-is-changing-healthcareand-transportation.html

Landro, L. (2016, December 12). Lessons From The Informed Patient. Retrieved January 05, 2017, from http://www.wsj. com/articles/lessons-from-the-informed-patient-1481563548

Longmire, M. (2015, December 17). Beyond the Pill: Data Is the New Drug. Retrieved December 15, 2016, from http://www. recode.net/2015/12/17/11621560/beyond-the-pill-data-is-the-new-drug

Mukhopadhyay, S. C. (2014). Internet of things: Challenges and opportunities. Cham: Springer.

Turcu, C. E., & Turcu, C. O. (2013). Internet of Things as Key Enabler for Sustainable Healthcare Delivery. Procedia - Social and Behavioral Sciences, 73, 251-256. doi:10.1016/j.sbspro.2013.02.049

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BIG IDEAS

From Pharmaceutical Patents to Generic Drugs Paschalina-Danai Sarra (Aristotle)

Edited by Adam Wolin and Walter Zhao (Johns Hopkins)

possesses immense power and influence. While the day-to-day responsibility of a pharmaceutical company is the discovery, development and marketing of new drugs and treatments, they also play a more esoteric role in investment into ideas. These ideas frequently lead to innovation and intellectual property, resulting in patents. Therefore, it is important to begin our discussion by analyzing the patent system. he pharmaceutical industry

A patent is an exclusive property right to an intangible creation of the human mind. Patents are granted by a sovereign state to the inventor of a novel invention, and the lifetime of a patent varies according to the country and product it concerns. If the United States Patent and Trademark Office (USPTO) issues a patent on an item lasting 20 years, then only the owner of the patent has the right to use or sell the item during this 20-year period. Of course, these protections only apply if the patentee has applied for and received recognition of the rights to his/ her intellectual property. The procedure for obtaining a patent and the type of intellectual property the patent protects varies between industries. In the pharmaceutical, chemical and biotechnological industries, patents usually cover a drug or product itself, not the manufacturing process used to produce it. Because the manufacturing processes for these drugs are easily replicable and copied, patent protection is more important in the biochemical and drug industries than others. Once patented, new drugs which has been developed for patients with a specific disease are initially sold under a brand name to be prescribed by clinicians. At this stage, the compound or chemical is called a brand-name drug. Per the patent protection system, only the pharmaceutical company that owns the patent on the brand-name drug has the right to produce and sell it. Once the patent expires, this restriction is lifted and the drug can be manufactured and sold by other competitors. These competitor-produced compounds are called generic drugs and often can be found sitting behind pharmacy windows next to the brand-name version. So how does the generic drug differ from the brand-name one, if at all? Per the Food and Drug Administration (FDA), the generic version of a drug must be equivalent to the branded one in the composition of active ingredients and in strength, dosage, condition of use, and method or route of delivery. There must be no significant medical differences between the two versions of the compound. However, exact reproducibility is impossible, and in fact discouraged. US law requires the manufacturer of the generic drug to recreate the brand-name version in a different shape, color, and size. The generic must be marketed under a different name. And although the generic drug must contain the same active ingredients as the brand-name, differences in non-active ingredients are allowed as long as these ingredients have no impact on the strength and route of administration. As a result of these small variations, different pharmacies produce and disperse different generics, so that a consumer will likely receive a different version of the generic ÂŠ 2017, The Triple Helix, Inc. All rights reserved.

THE TRIPLE HELIX Spring 2017

drug depending on where he or she purchases it.

Generic alternatives enter

The most significant difference the market at a lower price between these two versions most probably originates from point than the brandthe pharmaceutical manufacturing process. The low price of the name, but the opening of generic drugs is what sets them the market increases the apart from brand-name drugs. The high cost of brand-name competition between all drugs is a result of the company participating manufacturers that developed the drug bearing the cost of research and devel- and leads to an even further opment, and needing to recover price drop. their initial investment in the product. Drug development is remarkably expensive; before a new drug or therapy can be marketed to patients, it must go through multiple stages of clinical trials, often lasting years or decades. The price of brand-name drugs also tends to be higher because innovating companies want to recoup the money they have lost on failed products. The development of a generic drug generally requires far less research, since the brand-name manufacturer has already completed much of the high-risk development. Of course, a pharmaceutical patent gives the inventing company the chance to recoup their production costs without interference from competitors. However, once the patent expires and the generic alternatives hit the market, the original patent holder loses this monopoly. These generic alternatives enter the market at a lower price point than the brand-name, but the opening of the market increases the competition between all participating manufacturers and leads to an even further price drop. The conditions under which a drug can be manufactured and marketed as a generic one are the following: • The patent of the brandname drug must have expired or the patent protection has been revoked. • There currently exist no other patents on the drug.

Fig.1 Increase in generic drug use.6

• The patent and exclusivity protection has ended. • The FDA requirements for generics have been met.

Currently almost 80% of prescriptions in the U.S are for generic drugs. It is estimated that the sale of generic drugs at substantially lower prices than brandname ones helps consumers save significant sums every year. Between 2007 and 26

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2010 alone, approximately 110 medications that were previously approved by the F.D.A., including some commonly known drugs such as Norvasc, lost their patent protection resulting in an almost $150 billion in savings per year. Patents contribute to innovation and in design in a way that cannot be quantified in purely economic terms. Inventions have a strong impact on extending human life and alleviating suffering. In 2001 the pharmaceutical industry introduced around 400 new cancer treatments, 123 new heart disease treatments, 83 new AIDS medications and 176 new therapies for neurological diseases. There is a cost to innovation, and without a profit incentive to large companies it is unlikely that discovery would progress at its current rate.

References Frank, R. G. (2007). The ongoing regulation of generic drugs. New England Journal of Medicine, 357(20), 1993-1996.

Generic and brand name drugs: Understanding the basics (Issue brief). (2007). Retrieved November, 2016, from Depression and Bipolar Support Alliance website.

Generic drugs: The same medicine for less money (Issue brief). (2014, July). Retrieved November, 2016, from Consumer Reports Health website.

Lehman, B. (2003). The pharmaceutical industry and the patent system (Rep.). Retrieved December 29, 2016, from Wake Forest University website.

Mandal, A. (2014, September 8). Drug patents and generic pharmaceutical drugs. News Medical. Retrieved November, 2016.

Sherwood, T. (2008). Generic drugs. Address presented in FDA White Oaks Campus, Building 2, Silver Springs, MD. Retrieved November, 2016.

United States of America, Food and Drug Administration, Information for Consumers. (2016, June 28). Facts about Generic Drugs. Retrieved November, 2016.

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THE MORE YOU KNOW

On Sleep Deprivation

Georgia Katsioudi (Aristotle)

Edited by Luke Braidwood (Cambridge)

in his book Aphorisms in 400 BC that “Sleep as well as arousal, when unbalanced, can be harmful.” The role of sleep has been researched since antiquity. However, sleep’s regulation and function are yet to be elucidated. ippocrates stated

Sleep is more than a state of quiescence. It is an alternating pattern of neural activity that arises from multiple brain regions, several neurotransmitter systems and a wide variety of hormones. According to Hobson (2005), “Sleep is a function created of the brain, by the brain, for the brain.”21 Sleep is a universal and evolutionarily conserved behavior that stalls productive activity and most strikingly puts animals at increased risk of predation. This extreme fitness cost implies it is of great physiological significance to higher organisms. A number of studies suggest that a good night’s sleep improves physical activity and cognitive functions. Synaptic plasticity, memory consolidation and emotional regulation all appear to be promoted by sleep, as are metabolic functions, energy balance and waste removal. And yet, no study or group has put forth a comprehensive and widely accepted theory explaining just how sleep accomplishes these things. This is in part due to vast inconsistencies in sleep data. Perhaps the answer to this question lies in a more holistic view of sleep. Sleep is expressed in many forms, and should therefore be approached not as a distinct phenomenon but as an series of regulatory processes, which mirror the interactions between internal and external factors. Basic sleep mechanisms are genetically controlled. Scientists have identified loci that regulate sleep patterns or increase susceptibility to complex sleep disorders such as narcolepsy, restless leg syndrome, and familial fatal insomnia when mutated. Recent studies suggest that other biological processes have a role in sleep regulation as well. Loss of sleep, which refers to sleep of shorter duration than an individual needs to feel awake and alert (average of eight hours per night), is linked to many physical, psychological and neurocognitive health problems, as well as all-cause mortality. Disrupted sleep is associated with increased appetite, reduced energy expenditure and abnormal glucose metabolism, which subsequently increases the risk of obesity and diabetes. Sleep loss and circadian disruption is also linked to increased cancer risk, especially breast cancer in women with rotating or night shifts. Recent studies suggest that sleep deprivation might be a risk factor for neurological diseases, such as stroke, Alzheimer’s disease, and multiple sclerosis. In addition, compelling evidence links sleep deficiency to hypertension and abnormalities in the neuroendocrine, immune and inflammatory systems. Lack of sleep also reduces cognitive performance and motor function, has a negative impact on attention, memory and mood and is associated with a significant social and financial cost. Microsleeps and sleep attacks increase with deficient

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sleep, which is linked to an increased risk of injury and human errors. Based on a recent study, 1 in 25 American drivers admit to falling asleep while driving in the previous 30 days, while 2.5% of fatal motor vehicle crashes in 2009 involved drowsy drivers. In the elderly, sleep deficiency may contribute to an increased risk of falls and broken bones. Based on animal and clinical studies, sleep loss might be a causal factor in the development of emotional dysregulation, irritability, aggression, hostility and violence. Children and adolescents appear to be more vulnerable to the adverse effects of sleep deficits than adults, often developing severe academic and behavioral problems. Sleep deprived children become hyperactive rather than sleepy, and have difficulty focusing attention, so sleep deficiency may be wrongly diagnosed as attention-deficit hyperactivity disorder (ADHD). The duration of sleep is significantly associated with aggressive and delinquent behavior and attention and social problems in school-age children. Poor sleep quality in children, as in adults, is strongly correlated with aggression, hyperactivity, and depression. Persistent and temporary sleep problems increase the risk for psychiatric problems, whereas in children with mental disorders restless sleep is highly correlated with the severity of the psychiatric symptoms. Sleep deficiency and disturbances are widespread phenomena that continue increasing under the 24/7 pressures of modern society. Around 20% of the worldwide population gets insufficient sleep and children are sleeping about 1.2 hours less on school nights than a century ago. Almost half of employed US adults report a sleep duration of less than six hours per night, which is two hours less than the optimal eight, and 60% of all Americans experience a sleep problem every night or almost every night. Caffeine beverages, early starts at work or school, extensive use of new electronic devices, the internet and social media are only a few of the factors that reduce sleep quality. The prevalence of sleep-related health problems is expected to increase as sleep quality goes down. The cost of care and treatment for many of the aforementioned health problems is unbearable for both the patient and the state. A good night’s sleep may not be the cure for all of the health problems mentioned here. However, many of them might be prevented or improved with healthier sleep habits. Sleep hygiene was first introduced by Hauri (1977) and includes behavioral practices aiming to improve the quality of sleep. Sleep in a cool dark room, physical exercise, regular sleep timing, no consumption of caffeine in the evening, and no computer/TV use one hour prior to sleep are considered good practices. Several studies have shown that adopting good sleep habits can significantly impact the quality of sleep in children, adolescents and adults. Given the health risks of sleep deficiency and the direct impact of sleep quality on cognitive and physical performance, most people would benefit from a careful examination of their sleep habits. Parents often overlook the importance of their children’s bedtime habits and their effect on school performance. Only 50% of college students are aware about sleep hygiene and only 11% of them meet the criteria of good sleep quality. Early classes, environmental noise and stress are some of the factors that make students susceptible to poor sleep quality with adverse effects on mood and cognitive performance. Instead of spending vast sums of money on the treatment of sleep disorders, we © 2017, The Triple Helix, Inc. All rights reserved.

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could redirect funding to increase awareness of good sleep hygiene. The Sleep Treatment and Education Program for Students (STEPS) is a fine example of a psychoeducational sleep intervention program for the alleviation of the most common sleep complaints of college students. Given the increased accident risk and performance reduction associated with sleep deficiency, employers should be incentivized to invest in sleep hygiene courses and design improved shift patterns to help their employees get sufficient rest. Sleep plays a pivotal role in human health and behavior with direct impacts at all levels of society. Sleep influences physical and mental health, productivity and safety. Thus it is of paramount importance to increase our understanding of the function and effects of sleep, and to increase awareness of good sleeping habits and improve sleep hygiene. It is now time to reassess the early assurances of Benjamin Franklin that “there will be sleeping enough in the grave,” as researchers assure us that not enough sleep may actually bring us there sooner. References Aronen, E. T., Paavonen, E. J., Fjällberg, M., Soininen, M., & Törrönen, J. (2000). Sleep and psychiatric symptoms in school-age children. Journal of the American Academy of Child & Adolescent Psychiatry, 39(4), 502-508.

Baran, B., Pace-Schott, E. F., Ericson, C., & Spencer, R. M. (2012). Processing of emotional reactivity and emotional memory over sleep. The Journal of Neuroscience, 32(3), 1035-1042.

Barber, L., Grawitch, M. J., & Munz, D. C. (2013). Are better sleepers more engaged workers? A self-regulatory approach to sleep hygiene and work engagement. Stress and Health, 29(4), 307-316.

Benington, J. H., & Heller, H. C. (1995). Restoration of brain energy metabolism as the function of sleep. Progress in neurobiology, 45(4), 347-360.

Bootzin, R. R., & Perlis, M. (1992). Nonpharmacologic treatments of insomnia. The Journal of clinical psychiatry, 53, 37-41.

Brown, F. C., Buboltz Jr, W. C., & Soper, B. (2002). Relationship of sleep hygiene awareness, sleep hygiene practices, and sleep quality in university students. Behavioral medicine, 28(1), 33-38.

Brown, F. C., Buboltz Jr, W. C., & Soper, B. (2006). Development and evaluation of the Sleep Treatment and Education Program for Students (STEPS). Journal of American college health, 54(4), 231-237.

Buboltz Jr, W. C., Brown, F., & Soper, B. (2001). Sleep habits and patterns of college students: a preliminary study. Journal of American college health, 50(3), 131-135.

Calamaro, C. J., Mason, T. B., & Ratcliffe, S. J. (2009). Adolescents living the 24/7 lifestyle: effects of caffeine and technology on sleep duration and daytime functioning. Pediatrics, 123(6), e1005-e1010.

Czeisler, C. A. (2013). Perspective: casting light on sleep deficiency. Nature, 497(7450), S13-S13.

Dauvilliers, Y., & Winkelmann, J. (2013). Restless legs syndrome: update on pathogenesis. Current opinion in pulmonary medicine, 19(6), 594-600.

Duncan, D. F., Bomar, G. J., Nicholson, T., Wilson, R., & Higgins, W. (1995). Health practices and mental health revisited. Psychological reports, 77(1), 205-206.

Durmer, J. S., & Dinges, D. F. (2005). Neurocognitive consequences of sleep deprivation. Paper presented at the Seminars in neurology.

Faraut, B., Boudjeltia, K. Z., Vanhamme, L., & Kerkhofs, M. (2012). Immune, inflammatory and cardiovascular consequences of sleep restriction and recovery. Sleep medicine reviews, 16(2), 137-149.

Frank, M. G. (2006). The mystery of sleep function: current perspectives and future directions. Reviews in the Neurosciences, 17(4), 375-392.

Gradisar, M., & Short, M. A. Sleep Hygiene and Environment. The Oxford Handbook of Infant, Child, and Adolescent Sleep and Behavior.

Harvey, C.-J., Gehrman, P., & Espie, C. A. (2014). Who is predisposed to insomnia: a review of familial aggregation, stress-reactivity, personality and coping style. Sleep medicine reviews, 18(3), 237-247.

Hauri, P. (1977). The sleep disorders: Upjohn.

Haus, E. L., & Smolensky, M. H. (2013). Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep medicine reviews, 17(4), 273-284.

Hicks, R. A., Lucero-Gorman, K., Bautista, J., & Hicks, G. J. (1999). Ethnicity, sleep hygiene knowledge, and sleep hygiene practices. Perceptual and motor skills, 88(3 suppl), 1095-1096.

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Hobson, J. A. (2005). Sleep is of the brain, by the brain and for the brain. Nature, 437(7063), 1254-1256.

Ivanenko, A., Crabtree, V., Obrien, L., & Gozal, D. (2006). Sleep complaints and psychiatric symptoms in children evaluated at a pediatric mental health clinic. J. Clin. Sleep Med., 2(1), 42-48.

Jones, C. H., & Ball, H. (2014). Exploring socioeconomic differences in bedtime behaviours and sleep duration in english preschool children. Infant and child development, 23(5), 518-531.

Kamphuis, J., Meerlo, P., Koolhaas, J. M., & Lancel, M. (2012). Poor sleep as a potential causal factor in aggression and violence. Sleep medicine, 13(4), 327-334.

Knutson, K. L., Spiegel, K., Penev, P., & Van Cauter, E. (2007). The metabolic consequences of sleep deprivation. Sleep medicine reviews, 11(3), 163-178.

Kornum, B. R., Kawashima, M., Faraco, J., Lin, L., Rico, T. J., Hesselson, S., . . . Hamacher, A. (2011). Common variants in P2RY11 are associated with narcolepsy. Nature genetics, 43(1), 66-71.

Lane, J. M., Vlasac, I., Anderson, S. G., Kyle, S. D., Dixon, W. G., Bechtold, D. A., . . . Loudon, A. (2016). Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. Nature communications, 7.

LeBourgeois, M. K., Giannotti, F., Cortesi, F., Wolfson, A. R., & Harsh, J. (2005). The relationship between reported sleep quality and sleep hygiene in Italian and American adolescents. Pediatrics, 115(Supplement 1), 257-265.

Lieberman, H. R., Bathalon, G. P., Falco, C. M., Kramer, F. M., Morgan, C. A., & Niro, P. (2005). Severe decrements in cognition function and mood induced by sleep loss, heat, dehydration, and undernutrition during simulated combat. Biological psychiatry, 57(4), 422-429.

Mariotto, A. B., Yabroff, K. R., Shao, Y., Feuer, E. J., & Brown, M. L. (2011). Projections of the cost of cancer care in the United States: 2010â&#x20AC;&#x201C;2020. Journal of the National Cancer Institute.

Meropol, N. J., & Schulman, K. A. (2007). Cost of cancer care: issues and implications. Journal of Clinical Oncology, 25(2), 180-186.

Mignot, E. (2008). Why we sleep: the temporal organization of recovery. PLoS Biol, 6(4), e106.

Paavonen, E. J., Solantaus, T., Almqvist, F., & Aronen, E. T. (2003). Four-year follow-up study of sleep and psychiatric symptoms in preadolescents: relationship of persistent and temporary sleep problems to psychiatric symptoms. Journal of Developmental & Behavioral Pediatrics, 24(5), 307-314.

Palagini, L., Maria Bruno, R., Gemignani, A., Baglioni, C., Ghiadoni, L., & Riemann, D. (2013). Sleep loss and hypertension: a systematic review. Current pharmaceutical design, 19(13), 2409-2419.

Palma, J.-A., Urrestarazu, E., & Iriarte, J. (2013). Sleep loss as risk factor for neurologic disorders: a review. Sleep medicine, 14(3), 229-236.

Peng, B., Zhang, S., Dong, H., & Lu, Z. (2015). Clinical, histopathological and genetic studies in a case of fatal familial insomnia with review of the literature. International Journal of Clinical and Experimental Pathology, 8(9), 10171.

Reppert, S. M., & Weaver, D. R. (2002). Coordination of circadian timing in mammals. Nature, 418(6901), 935-941.

Schmid, S. M., Hallschmid, M., Jauch-Chara, K., Wilms, B., Benedict, C., Lehnert, H., . . . Schultes, B. (2009). Short-term sleep loss decreases physical activity under free-living conditions but does not increase food intake under time-deprived laboratory conditions in healthy men. The American journal of clinical nutrition, 90(6), 1476-1482.

Sehgal, A., & Mignot, E. (2011). Genetics of sleep and sleep disorders. Cell, 146(2), 194-207.

Stone, K. L., Ensrud, K. E., & Ancoli-Israel, S. (2008). Sleep, insomnia and falls in elderly patients. Sleep medicine, 9, S18-S22.

Tononi, G., & Cirelli, C. (2014). Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron, 81(1), 12-34.

Vyazovskiy, V. V. (2015). Sleep, recovery, and metaregulation: explaining the benefits of sleep. Nature and science of sleep, 7, 171.

Warren, J. L., Yabroff, K. R., Meekins, A., Topor, M., Lamont, E. B., & Brown, M. L. (2008). Evaluation of trends in the cost of initial cancer treatment. Journal of the National Cancer Institute, 100(12), 888-897.

Weber, L. (2013). Go ahead, hit the snooze button. The Wall Street Journal.

Wheaton, A. G., Chapman, D. P., Presley-Cantrell, L. R., Croft, J. B., & Roehler, D. R. (2013). Drowsy Driving-19 States and the District of Columbia, 2009-2010 (Reprinted from MMWR, vol 51, pg 1033-1037, 2013) (Vol. 309, pp. 760-762): AMER MEDICAL ASSOC 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA.

Wulff, K., Porcheret, K., Cussans, E., & Foster, R. G. (2009). Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Current opinion in genetics & development, 19(3), 237-246.

Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., . . . Iliff, J. J. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342(6156), 373-377.

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GOING FORWARD

Wearable Kidneys

Filippos Karageorgos (Aristotle)

Edited by Kathy Le (Johns Hopkins)

for transplantation has been an ongoing and devastating issue for decades. The gap between the number of patients on organ waiting lists and the number of healthy individuals donating increases each year, and the shortage of kidney donors in particular keeps some patients on the waiting list for years and years. In 2016, the waiting list for organ transplantation consisted of 121,678 people of which 100,791 were people waiting for kidney transplantation. For this reason, the international transplant community has looked to alternative sources to replace malfunctioning or diseased kidneys. For many years, research into one potential source for renal replacement has looked particularly bright: the artificial, or mechanical, kidney. he shortage of donated organs

Designing an artificial organ is no easy task. The replacement must replicate the function of the original organ in almost every capacity, and most organs play multiple homeostatic roles. Such a replacement must modulate incredibly specific parameters including pH and blood pressure, and operate under very specific parameters including temperature and blood flow. The device must be both biocompatible and hemocompatible, so that it does not cause life-threatening rejection. Current technology cannot yet replace most organs in an efficient and economical way. However, since the 1940s doctors and researchers have had remarkable success replacing the functionality of the kidney through dialysis. The first dialysis device was created by Dr. Willem Kolff in 1943, and despite its simplicity, the device was used to treat patients with failing kidneys for years. What does the kidney do and why is it a target for artificial replacement? The kidney works mainly as a filtration system. Its primary job is to remove excess and harmful substances from the blood. The kidney regulates blood pH, blood pressure, and various ion concentrations in the blood. Besides that, it is also important in hormone regulation and in homeostatic maintenance; due to its ability to secrete hormone, kidneys are also characterized as endocrine organs. Hemodialysis represents the first attempt to artificially replace some of the functions of a human kidney, and it is still the most frequently utilized method of renal replacement. Hemodialysis consists of an extracorporeal machine working as a filter through which blood flows and substances from the blood are removed. Dialysis machines function using diffusion across a semi-permeable membrane. On either side of this membrane blood flows in one direction, and dialysate fluid flows in the other. Waste materials from the blood cross the membrane and into the dialysate fluid. The therapy is repeated three to four times per week and takes about 4 hours per session. Unfortunately, the care cannot be delivered at home and patients often have to visit the hospital for each session, which presents a multitude of medical and social problems. First, the lack of continuity of blood filtration is not ideal. Second, the dependence on a non-transportable machine limits where patients requiring hemodialysis can live (not every hospital has dialysis machines) 32

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and how much they can work (due to the length of the sessions). Finally, although hemodialysis replaces the kidney’s filtration ability, it does not replace other kidney functions including hormone production. Some of these necessary hormones must be replaced by medication. After hemodialysis the second most commonly used replacement for renal function is peritoneal dialysis. Peritoneal dialysis is similar to hemodialysis, but utilizes the abdominal cavity as a site of filtration. This kind of treatment relies on the use of a permanent tube placed in the belly of the patient. Both of these techniques fail to totally replace renal function in a time and cost efficient manner, making artificial kidneys a viable treatment option. Wearable Artificial Kidneys (WAK) are devices that can be worn on a belt or vest that enable patients to clean their blood frequently and without trips to the hospital. The first wearable artificial kidneys weighed about 3.5 and needed to be connected to 20 L of dialysis fluid. However, by 1986 WAKs began using more advanced sorbents and enzymes became more effective and efficient. In 2012 a WAK device was one of three projects to win the FDA’s Innovation Pathway 2.0 competition. Recently, a WAK device was tested through an FDA-approved human trial, in which 10 patients underwent dialysis for 24 hours with promising results. Figure 1 shows a representation of the newer, 2012 device.

Fig. 1 WAK’s schematic representation.2

Researchers have also created a wearable kidney treatment device that uses the peritoneal dialysis method. One such device is the ViWAK PD. This device has not been tested clinically and uses continuous ambulatory peritoneal dialysis (CAPD). The device uses a minimum amount of dialysis fluid which regenerates through sorbents. The patient can monitor the dialysis process through a remote controller that regulates the system wirelessly. This controller can also give information about cartridge saturation, flow, and pressure conditions. Figure 2 shows a representation of the device. © 2017, The Triple Helix, Inc. All rights reserved.

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Fig. 2 VIWAKâ&#x20AC;&#x2122;s representation.16

Another promising device is the wearable bioartificial kidney (WEBAK). This is similar to the VIWAK in that it uses peritoneal dialysis and contains sorbents for regenerating the peritoneal fluid. However, the WEBAK uses bioartificial renal epithelial cell systems (BRECS) to replicate the metabolic functions of kidney epithelial cells. Figure 3 shows a representation of such a device.

Fig. 3 representation of WEBAK function.7

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These devices offer a potential alternative to conventional dialysis treatment. They offer many benefits over the current method, including increased patient mobility and flexibility. One drawback of these devices is that although they are smaller than the machines used in hospitals, WAK-type devices (in their current stage of development) are still easily visible and distracting. Operating a WAK-type device may make some patients uncomfortable. WAK devices must be highly personalized and are extremely expensive. Finally, current technology still requires WAKs to be periodically maintained by physicians and health care providers, so the patient must still frequently visit the hospital. While these drawbacks represent very real issues in the development of the perfect renal replacement therapy, artificial kidneys will no doubt be an avenue for research for years to come.

References AWAK Technologies - Scientific Publication. (2016). Awak.com. Retrieved 20 November 2016, from http://awak.com/technology/publication.htm.

Davenport, A., Gura, V., Ronco, C., Beizai, M., Ezon, C., & Rambod, E. (2007). A wearable haemodialysis device for patients with end-stage renal failure: a pilot study. The Lancet, 370(9604), 2005-2010. http://dx.doi.org/10.1016/s0140-6736(07)61864-9

The Editors of Encyclopedia Britannica. erythropoietin. (2015). Encyclopedia Britannica. Retrieved 13 January 2017.

Grassmann, A., Gioberge, S., Moeller, S., & Brown, G. (2005). ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends. Nephrology Dialysis Transplantation, 20(12), 2587-2593.

Gura, V., Rivara, M., Bieber, S., Munshi, R., Smith, N., & Linke, L. et al. (2016). A wearable artificial kidney for patients with end-stage renal disease. JCI Insight, 1(8).

Gura, V., Ronco, C., & Davenport, A. (2009). The Wearable Artificial Kidney, Why and How: From Holy Grail to Reality. Seminars In Dialysis, 22(1), 13-17.

Humes, H., Buffington, D., Westover, A., Roy, S., & Fissell, W. (2013). The bioartificial kidney: current status and future promise. Pediatric Nephrology, 29(3), 343-351.

Innovation Challenge: End-Stage Renal Disease. (2016). Fda.gov. Retrieved 20 November 2016.

Kooman, J., Joles, J., & Gerritsen, K. (2015). Creating a wearable artificial kidney: where are we now? Expert Review Of Medical Devices, 12(4), 373-376.

Lee, D. & Roberts, M. (2008). A peritoneal-based automated wearable artificial kidney. Clinical And Experimental Nephrology, 12(3), 171-180.

Organ Donation and Transplantation Statistics. (2016). The National Kidney Foundation. Retrieved 20 November 2016. Peritoneal Dialysis. (2015). WebMD. Retrieved 13 January 2017.

The Editors of Encyclopedia Britannica. prostaglandin. (2009). Encyclopedia Britannica. Retrieved 13 January 2017.

The Editors of Encyclopedia Britannica. renin. (2015). Encyclopedia Britannica. Retrieved 13 January 2017.

The Editors of Encyclopedia Britannica. rickets. (2011). Encyclopedia Britannica. Retrieved 13 January 2017.

Ronco, C. & Fecondini, L. (2007). The Vicenza Wearable Artificial Kidney for Peritoneal Dialysis (ViWAK PD). Blood Purification, 25(4), 383-388.

Stevenson, F. (2005). Renal systems (2nd ed., pp. 41-42). Philadelphia, PA: Elsevier Mosby.

The history of dialysis - DaVita. (2016). Davita.com. Retrieved 20 November 2016.

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The Triple Helix International Leadership

The Triple Helix, Inc. is an undergraduate, student-run organization dedicated to the promotion of interdisciplinary discussion. We encourage critical analysis of legally and socially important issues in science and promote the exchange of ideas. Our flagship publication, the Science in Society Review, and our online blog, The Triple Helix Online, provide research-based perspectives on pertinent scientific issues facing society today. Our students at twenty chapters at some of the most renowned universities in the world form a diverse, intellectual, and global society. We aim to inspire scientific curiosity and discovery, encouraging undergraduates to explore interdisciplinary careers that push traditional professional boundaries. In doing so, we hope to create global citizen scientists. www.thetriplehelix.org

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