Genae Girard, a 39-year-old woman living in the US, had to pay a staggering $3200 for a single genetic test for the BRCA gene associated with breast and ovarian cancer, only to find that she was unable to request a second opinion upon receiving the positive test result. After consulting with doctors, Ms Girard was advised to have her ovaries surgically removed in order to diminish the 60% risk of developing ovarian cancer indicated by the genetic test. Because Myriad Genetics, which holds a patent on the BRCA genes, is the only laboratory to provide the genetic test, Ms Girard had to undergo the life-changing surgery without knowing for certain whether it was absolutely necessary [1].

Ms Girard is only one of tens of thousands of women in this situation, left with no choice but to accept the outcome of a single indeterministic genetic test result, which in addition is subject to human errors in the test laboratory. Other companies are unable to provide an alternative method of diagnosis because the gene in question is protected under patent laws [2]. Currently 20% of human genes are “owned” by individual biotechnology companies and research labs, making it illegal for others to carry out diagnosis and therapy, and limiting research using those genes [1,3].

The underlying principles of patents are to promote openness of publically beneficial findings, and to reward investors for the capital endowed in innovating and developing a product. In return for disclosing the details of an invention and paying a maintenance fee, the patentee receives a 20-year monopoly over the patented product or process [4]. This argument has an appreciable value when considering inventions such as Tetra Pak® or SuperGlue. However, is the patenting of human genes a step too far? Do gene patents deprive the public of cost-effective health care, and what impact do they have on research in public institutions and competing companies?

The history of the British patent system as we know it today started in the 19th century, when the granting of patents became independent of the crown and turned into a regulatory matter for the state. With the passage of the Patent act in 1977, patent rights became an integrated part of British law.

It is worth noting that patents are country-specific, and the laws regulating them vary from country to country [4]. Generally, US patent laws are more liberal in the consideration of patentable matters than the European equivalent, allowing more gene patents to be approved [5]. The European Patents Office (EPO), an intergovernmental patent approval organisation, has 3 main criteria for the patentability of an invention: it has to be new, be susceptible to industrial application and involve an inventive step. In addition, the Biotech Patent Directive adopted in 1998 by the EPO contains further criteria and restrictions to clarify the patentability of biotechnological matters [6].

The association of BRCA1 with breast and ovarian cancer was discovered in 1994 by Mark Skolnick, founder of Myriad Genetics. He patented the gene and was granted a monopoly for the use of the gene in genetic testing, gene therapy, protein replacement therapy and the screening of drugs for cancer therapy [7]. In 1995, BRCA2, a related gene, was discovered and the patent rights were purchased by Myriad Genetics. The patents have allowed Myriad to, in effect, control the research and genetics testing of the BRCA genes in the US [8]. The BRCA1 and BRCA2 patents were approved by the EPO in 2001 and 2003 respectively, but cover a more restricted scope of rights than the US patents [1,9].

A law suit filed by the American Civil Liberties Union (ACLU) resulted in the invalidation of the BRCA gene patents in March 2010 at the US District Court for the Southern District of New York. The court decision taken by Judge Sweet was based on the argument that the isolated DNA is not markedly different from the natural state and that “DNA … should be treated as the physical embodiment of … nature”. In other words, although DNA is a chemical molecule, it should not simply be treated as other chemical compounds, since it also carries information and knowledge, which is not patentable. This is the first time an American court has found it unlawful to patent genes, a decision which could lead to the invalidation of 18.5% of the current patents of human genes [5,8].

Figure 1 (18)

Microorganisms, particularly bacteria, have the ability to learn from the environment at an amazing rate. They employ a method called horizontal gene transfer, HGT. Blessed with a vast gene pool to modify their genomic blueprints, bacteria can strengthen and reinforce existing resistance against threats like antibiotics [1, 7]. This article will delve into the realms that drive the mechanisms of antibiotics and how horizontal gene transfer translates into antibiotic resistance. After understanding the fundamental mechanisms, the next step is to understand how these mechanisms translate in clinical and community settings through a gram-positive bacterium, called Staphylococcus Aureus.

In the realms of horizontal gene transfer, bacteria engage in various mechanisms to achieve antibiotic resistance. One of the modes involves the uptake and expression of foreign RNA/DNA in the form of conjugated plasmids. Functioning independently of chromosomal DNA, plasmids are double-stranded and often appear circular [12]. Though not all plasmids are essential to the organism’s well being, it can carry essential instructions to initiate selective advantages for the microorganism [15]. Additionally, bacteria can replicate these plasmids for sharing with other microorganisms. Such genomic plasmids may allow the bacteria to synthesize an enzyme called beta-lactam that cleaves antibiotics, like penicillin, thus rendering them useless.

The second mode is transduction. Transduction involves the bacterial DNA transferred from one bacterium to another via a virus, i.e. bacteriophage. Even though bacteriophages hunt bacteria, certain bacteriophages may sometimes play a favorable role. They may allow bacteria to gain resistance against certain antibiotics through genetic recombination. Finally, the last method involves cell-to-cell contact where bacteria use their sex pilus to transfer genomic material to another bacteria [7]. It is particularly important to mention that not all bacteria practice all three modes of HGT since it highly depends on their physiologically characteristics and genetic construct.

From an evolutionary standpoint, it is advantageous for bacteria to carry out horizontal gene transfer. While HGT is beneficial to bacteria, the opposite is certainly true for healthcare. The rate at which antibiotic resistance can spread to other similar species is rising, and all of this is done through bacteria cooperative sharing, labeled horizontal gene transfer. Based on the alarming rate of bacteria conferring antibiotic resistance, the hope is to witness new stable but effective antibiotics to combat these newly mutated species. Hence, before we dive into the first pandemic case of S. Aureus and penicillin, the next part focuses on antibiotic mechanisms.

Designed to cripple the activities at the cellular levels, antibiotics work in four different ways. The first method is the inhibition of nucleic acids, the second is the inhibition of protein synthesis, while the third interferes with cell membrane/wall activities, and the final step involves enzyme system interference [11]. It is a beauty to picture all cells containing genomic material comprised of DNA/RNA. These blueprints are essential in the construction of organelles and enzymes and serve as genomic information for the next generation [13]. Biologists have developed a theory, termed the Central Dogma of “molecular biology”, to help explain the interactive roles DNA, RNA, and protein synthesis are all interrelated to each other and all play essential roles in cell vitality and survival. Hence, the nature of antibiotics to target the essential core element of the Central Dogma of “molecular biology” would impede survival. Placing this into perspectives, S. Aureus has to constantly maintain its thick peptidoglycan cell wall in order to prolong survival. Any disruption to the construction of its thick peptidoglycan cell wall would prove lethal to the microorganism. Thus, the final form of interaction involves enzyme regulation. Destroying enzymes crucial to catalyzing certain cellular functions at certain times would make the S. Aureus defenseless, making antibiotics such an effective weapon.

Figure 3 (13)

Fortunately for bacteria, they are equipped with the ability to share genomic information between different species that may allow the organisms to develop ways to circumvent death. Using the same example, the Staphylcoccus Aureus can engage in HGT to acquire immunity against drugs targeting peptidoglycan bonds linking to create the cell wall [14]. When the world first saw the development of penicillin, the drug was the perfect agent to target the formation of cell wall, a necessary agent for defense. The discovery that penicillin rendered the microorganisms defenseless against the immune system was astonishing. The ability for antibiotics to halt an essential process in the bacteria was never understood or thought possible. Despite the antibiotic’s abilities, bacteria were able to develop alternative methods to circumvent penicillin. Research found that bacteria, like the S. Aureus, were able to construct an antibiotic-cleaving enzyme called beta-lactum. Once S. Aureus gained the ability to overt cell death induced by antibiotics, it can construct conjugated plasmids and pass it along to other strains [3].

Immediately, the ability for bacteria to spread the news of an effective method to defeat antibiotics is a rising concern among researchers. All it takes is a single S. Aureus to propagate the resistance blueprint, especially if the likelihood of passing the resistance genome down to its progenies or to its neighbors is highly favored. This constant sharing of genetic information will only create more potent species. HGT is the most common mode of gene acquirement that will eventually lead to alternations in target antibiotic site and increase drug efflux to prevent further damage done to the microorganism [1, 7]. Additionally, HGT serves different functions, such as  “drug modifications, target protection, bypass resistance, replacement of susceptible drug target and acquisition of novel efflux pumps” [7]. Meanwhile, the multipurpose horizontal gene transfer provides a perfect cyclic ecosystem of community sharing among the microorganism world, while it brings both complexity and complications to the medical community and patients, in the form of treatment failure and antibiotic resistance.

After a thorough understanding of the mechanisms, it is important to examine how the lack of knowledge with penicillin and uncontrolled drug distribution in the United States all helped contribute to the rise of antibiotic resistance. Even before Alexander Fleming unveiled penicillin to the world, he had already stumbled upon the concept of antibiotic resistance. His idea arose from the mass commercialization of using antibiotics. He believes that this soon-to-be-dubbed “miracle drug” should sparingly be used in occasions that strictly demanded this drug instead of using it as an all-purpose drug [2]. The lack of proper understanding of how antibiotics work along with unregulated drug distributions all helped to contribute to the eventual downfall of penicillin. Since penicillin was effective against S. Aureus, it immediately became the drug of choice [16]. However, due to the highly unregulated usage of penicillin, by around 1944, S. Aureus was capable of using beta-lactam to destroy penicillin [1].

Figure 4 (10)

Upon closer examination of antibiotics distribution in local communities, it is not surprising to uncover that the combination of socioeconomically challenged individuals with inconsistent treatments may contribute to this developing crisis. Individuals contracted with S. Aureus often undergo uncomplicated skin lesions. However, more serious cases of septicaemia (Staph infection) are possible [8]. Penicillin was the choice of drug when patients were diagnosed with Staph infections. Unfortunately, the frequent uses of this drug ultimately rendered this drug useless.

When penicillin became obsolete, the world needed another effective antibiotic on the market. This alternative was methicillin. Upon releasing the drug, immediately, similar practices made with penicillin are witnessed. The lack of antibiotics controls and proper understandings of the antibiotic resistance once again stormed up a heap of problems. Eventually, the lack of drug control led to new strain of resistance that scientists had to coin a new name, methicillin-resistant S. Aureus (MRSA). During this time, what helped worsen the dilemma was that scientists did not completely understand how S. Aureus gained resistance against various antibiotics, although they suspected conjugated plasmids had a role in horizontal gene transfer. HGT allowed susceptible strains to attain the SCCmecA staphylococcal chromosomal cassette, a plasmid that can successfully integrate itself into the chromosome for replication and usage [3, 5, 7, 8]. By obtaining this staphylococcal chromosomal cassette mecA, S. Aureus is able to produce a penicillin binding protein called PBP2a that, when unregulated, will allow this organism to have low binding affinity against beta-lactam antibiotics like penicillin, methicillin, oxacillin [8].

The combination of decreased antibiotic control and a widespread lack of understanding the mechanism aided and strengthened the empowerment of the SCCmecA to develop into variant forms, each with its flavors of potency. Patients coming to the hospitals with different health backgrounds provided MRSA the ability to set up spawning pools. Primarily, two potent forms of MRSA particularly stand out, the hospital and community-associated MRSA.

The more potent form, hospital-associated MRSA, possessed the SCCmecA type I-III, which allows these microorganisms to be “multidrug-resistant and manifest by infecting wounds, ventilator-associated pneumonia, line infections, and other infections” [8]. Counter to its partner, community-associated MRSA has similar plasmid cassette construction but a less potent type (the SCCmecA type IV cassette). However, both forms target different groups of individuals from various backgrounds [2, 19]. Most importantly, however, we would like to understand how these two forms fit into the overall community and healthcare policies.

Originally, hospitals only witnessed HA-MRSA cases in elderly and younger age groups [4,5]. Nonetheless, with MRSA becoming more rampant and immune to various antibiotics, methicillin-resistant S. Aureus are suddenly appearing in communities. Studies indicate that there is a sudden surge in CA-MRSA cases in places like collegiate football [19]. The synergy between increased risk and prolonged exposure in collegiate football players under skin trauma and crowded environments will lead to more sightings of skin and soft tissue infections (SSTIs).  This continuation of CA-MRSA sightings continues to complicate medical treatments since local communities may not have effective treatment methods to deal with increasingly resistive S. Aureus [20].

Comparing the two different forms of MRSA, CA-MRSA is neither as virulent nor as resistive to antibiotics as its cousin strain. In spite of lacking similar resistance, the type IV cassette allows CA-MRSA to secrete a virulent factor Panton-Valentine leukocidin (PVL) that is “capable of causing severe tissue necrosis and leukocyte destruction” [8, 20]. Even though all strains of MRSA are resistant to penicillin and methicillin, almost all MRSA strains elicit similar symptoms. However, due to socioeconomic disparities at the individual and community levels, physicians may often prescribe ineffective treatments, like penicillin to treat bacteria that may carry resistive plasmids. Hence, patients may not be receiving the best form of treatment and, as a result, may cause the bacteria strain to spread and further inflict more damage [4].

Another problematic issue epidemiologists have identified is specific MRSA strains native only to certain regions of the globe. However, with increasing diversity trends and international traveling, MRSA strains can be carried from, for example, Europe to the United States [20]. Even though most MRSA share similar resistive mechanisms to circumvent antibiotics, they may not share the same plasmid cassette constructs [20]. Intermixing different plasmid constructs will not only increase antibiotic resistance possibilities, but will also complicate medical efforts to contain the problems. Thus, antibiotic treatment alternatives must be readily available and cost-effective compared to today’s antibiotics treatment costs.

While researchers have understood the mechanisms behind how HGT functions in S. Aureus the current problem still lies in educating the public and seeking effective alternatives. In term of alternatives, effective treatment options are available. One research conducted in Poland demonstrated it is possible. The research has indicated that using bacteriophages to target bacteria strains, like CA-MRSA, can be an effective alternative. Not only is targeting specific bacteria strains with bacteriophages a cost-effective method, it is also a highly effective technique to ward off antibiotic resistance [9].

Today, the governmental agencies are investing strongly in media and organizations to educate the consumers of excessive use of antibiotics and new strains. Unlike the efforts by the current Center of Disease Control (CDC) to curb influenza infections by yearly vaccination, educating the average consumer on antibiotic resistance on alternatives is challenging. Fundamentally, the processes of horizontal gene transfer would always remain the same, but keeping up with the constant mutations in field of prokaryotes may add another layer of complication. A probable solution involves the governmental agencies collaborating with the current scientific findings to create usable and understandable information that the consumers will comprehend and practice. Successfully incorporating all these elements can educate the public on how excessive antibiotic usages may have severe consequences. The World Health Organization and the CDC along with other major organizations are teaming together to develop effective policies to deal with drug usages, public awareness, and drug distributions. The collaborative efforts are certainly a positive trend to bringing the warfare on antibiotic resistance to a close.

References:

1. Neu, H. C. “The Crisis in Antibiotic Resistance.” Science 257.5073 (1992): 1064-073. Print.
2. French, G. I. “The Continuing Crisis in Antibiotic Resistance.” International Journal of Antimicrobial Agents 36 (2010): S3-S7. Print.
3. Garriss, Genevieve, Matthew Waldor, and Vincent Burrus. “PLoS Genetics: Mobile Antibiotic Resistance Encoding Elements Promote Their Own Diversity.” PLoS Genetics: A Peer-Reviewed Open-Access Journal. Dec. 2009. Web. 15 May 2011. <http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000775>.
4. Davis, Julian, and Dorothy Davies. “Origins and Evolution of Antibiotic Resistance — Davies and Davies 74 (3): 417.” Microbiology and Molecular Biology Reviews. American Society for Microbiology, Sept. 2010. Web. 15 May 2011. <http://mmbr.asm.org/cgi/content/short/74/3/417?rss=1>.
5. Walsh, Christopher. “Molecular Mechanisms That Confer Antibacterial Drug Resistance.” Nature 406 (2000): 775-81. Print.
6. Goossens, H., M. Ferech, R. Vanderstichele, and M. Elseviers. “Outpatient Antibiotic Use in Europe and Association with Resistance: a Cross-national Database Study.” The Lancet365.9459 (2005): 579-87. Print.
7. Andersson, Dan I., and Diarmaid Hudges. “Antibiotic Resistance and Its Cost: Is It Possible to Reverse Resistance.” Nature April 8 (2010): 260-71. Print.
8. Wilson, Jeff, John Conly, Tom Wong, Gayatri Jayaraman, et al. “Strategies to Control Community-Associated Antimicrobial Resistance Among Enteric Bacteria and MRSA in Canada: A Comprehensive Review.” National Collaborating Centre of Infectious Diseases. Jan. 2010. Web. 17 May 2011. <http://www.nccid.ca/en/files/Novometrix_summary_en_final.pdf>.
9. Międzybrodzki, Ryszard, et al. “Phage Therapy of Staphylococcal Infections (including MRSA) May Be Less Expensive than Antibiotic Treatment.” Postępy Higieny. Postępy Higieny, 03 Aug. 2007. Web. 17 May 2011. <www.phmd.pl/fulltxt.php?ICID=495359>.
10. Staphylococcus aureus VISA 2 (Wikipedia) [image on the internet]. 2001 [cited 9 Oct. 2011] Available from: http://en.wikipedia.org/wiki/File:Staphylococcus_aureus_VISA_2.jpg
11. Yim, Grace. “The Science Creative Quarterly » ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE.” The Science Creative Quarterly. University of British Columbia, 2011. Web. 01 June 2011. <http://www.scq.ubc.ca/attack-of-the-superbugs-antibiotic-resistance/>.
12. Lipps G (editor). Plasmids: Current Research and Future Trends Caister Academic Press. ISBN 978-1-904455-35-6 (2008).
13. Central Dogma of Molecular Biochemistry with Enzymes (Wikipedia) [image on the internet]. 2008 Nov. 28 [cited 9 Oct. 2011] Available from: http://en.wikipedia.org/wiki/File:Central_Dogma_of_Molecular_Biochemistry_with_Enzymes.jpg
14. STROMINGER, J. T., J. L. Park, and Richard E. Thompson. “Composition of the Cell Wall of Staphylococcus Aureus: Its Relation to the Mechanism of Action of Penicillin.” Journal of Biological Chemistry 234.12 (1959): 3263-268. Print.
15. Heinemann, Jack A., and George F. Sprague. “Bacterial Conjugative Plasmids Mobilize DNA Transfer Between Bacteria and Yeasts.” University of Minnesota. Nature, 20 July 1989. Web. 24 Aug. 2011. <http://www.micab.umn.edu/courses/8002/heinemann.pdf>.
16. Baquero, F. “Gram-positive Resistance: Challenge for the Development of New Antibiotics.” Oxford Journals | Medicine | Journal of Antimicrobial Chemotherapy. Journal of Antimicrobial Chemotherapy, 1997. Web. 27 Aug. 2011. <http://jac.oxfordjournals.org/content/39/suppl_1/1.short>.
17. “Antibiotics, Antibiotic Use in Animal – The Issues – Sustainable Table.” Sustainable Table. Sustainable Table, Oct. 2009. Web. 27 Aug. 2011. <http://www.sustainabletable.org/issues/antibiotics/>.
18. Mechanisms of Antibiotic Resistance (Flickr) [image on the internet]. 2010 Mar. 24 [cited 2011 Oct. 9] Available from: http://www.flickr.com/photos/ajc1/4459956372/sizes/m/in/photostream/
19. Romano, Russ, Doanh Lu, and Paul Holtom. “Outbreak of Community-Acquired Methicillin-Resistant Staphylococcus Aureus Skin Infections Among a Collegiate Football Team.” Journal of Athletic Training 41.2 (2006): 141-45. Journal of Athletic Training. National Center for Biotechnology Information, 2006. Web. 17 Sept. 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472644/pdf/i1062-6050-41-2-141.pdf>.
20. Chambers, Henry F., and Frank R. Deleo. “Waves of Resistance: Staphylococcus Aureus in the Antibiotic Era.” Nature Review Microbiology 7.9 (2009): 629-541. National Center for Biotechnological Information. Macmillan Publishers Limited, Sept. 2009. Web. 17 Sept. 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871281/pdf/nihms186211.pdf>.
21. MRSA exploded (Flickr) [image on the internet]. 2009 Jul. 14 [cited 2011 Oct. 9]. Available from: http://www.flickr.com/photos/jbtiv/3721064969/

Tsung Ming Hung is a third-year student at the University of Chicago majoring in Visual Arts with a Pre-Medical curriculum. Join The Triple Helix Online on Facebook and follow us on Twitter.

Doctor and Patients Interacting on the Internet

Introduction

The advent of the “information technology age” has led to a rapid change in the doctor‐patient dynamic. Before the Internet became host to a plethora of medical information and advice, the doctor‐patient relationship was confined primarily to office consultations. In that setting, doctors advised patients on the best course of medical action, and the patients weighed their options before proceeding. Now, the modern patient has the ability to access extensive information on nearly every medical condition. Today, the patient arrives armed with information about potential diagnoses and courses of treatment. This inversion of roles presents a number of ramifications for the routine practice of medicine. Patients are in a position to lobby their doctors about treatment, and treat medical advice with skepticism and concern.[1] However, despite the fact that access to a wealth of online resources has the potential to alter the doctor‐patient dynamic, it has not necessarily replaced healthcare providers as the essential medium of care.[2] The full scope of this new doctor‐patient relationship involves access to information, the quality of the information accessed, and how that information is interpreted by patients.

Use of the Internet for Medical Research

In a study published by the Journal of Medical Internet Research in 2003, 85% of American physicians surveyed indicated that a patient had researched medical information online and brought that information to a visit.[3] This high percentage is mitigated by the fact that the same physicians reported that less than one‐fifth of their patients had come to an appointment with Internet research.[4] This suggests that only a small number of patients were presenting research found online to their physicians. In that same year, however, a poll published in the Journal of Patient Education and Counseling reported that 80% of American adults who used the Internet had researched health information, and the share of adult Internet users searching for medical information had been rapidly increasing since the proliferation of the Internet.[5] At the beginning of the decade, a study published in the Journal of General Internal Medicine in 2002 indicated that patients who had accessed medical information on the Internet were better educated and had a higher socioeconomic status.[6] Yet by the end of the decade, a study published in the Journal of Health Communication in 2008 noted that while sociodemographic factors contributed to some of the variance in whether or not a physician was contacted after turning to the Internet for research, Internet research was positively linked to physician visits, even when sociodemographic factors were controlled.[7] Regardless, it is clear that Americans are increasingly turning to the internet to fill gaps in their own knowledge about medical conditions.

Effects of Online Research

The early evidence of this shift in patient‐centered information resulted in a number of theories on how the change would affect the doctor‐patient relationship. The multitude of medical information online allowed for potential positive effects for the patient; the access to knowledge had the potential to democratize the healthcare process. Patients would theoretically have the ability to play a larger role in medical decision‐making, while the clinician would serve as an informed guide.[8] This drive to the Internet for information may have been fueled by an already strained doctor‐patient relationship. As the time doctors spent with their patients declined, the power of the Internet grew, and patients began to use the Internet out of frustration.[9] The benefits of the Internet do not end with access to information, as support groups for individual disease have grown in popularity, and a number of studies suggest that patients who participate in these groups “gained satisfaction” with their medical experience.[10]

Furthermore, a Harris Interactive poll conducted in 2001 indicated that patients who have done research are more likely to have more educated interactions with their physicians, where they ask more detailed questions regarding their conditions and proper treatment.[11] A British study published in BMC Family Practice in 2007 confirmed this poll, as patients reported feeling that they had used the limited time they had with their physician more effectively when equipped with the proper information before making a visit.[12] As medical information has become widely accessible online, its use has grown to be second‐nature for patients, who can research their symptoms and ailments to complement the information they receive from medical professionals. Ultimately, this research positively reinforces interactions with physicians, as patients are not relying on online information, but rather using it to augment the traditional clinical experience.

Potential Negative Aspects of Medical Information Online

The resistance to the use of online medical information is often rooted in questions about the quality of the available information. Physicians have indicated that only a small percentage of the information that patients bring is either “very relevant” or “very accurate” to their condition, yet the same physicians report that in the majority of cases, this information has little effect on the outcome or quality of care.[13] Although there are authoritative websites, the medical information available online is often unscientific and self‐published, by other patients reporting their personal experiences, rather than by clinicians submitting a peer‐reviewed report of an ailment. A substantial concern about online medical information is that it will dissuade patients from pursuing medical care because they feel as if they have sufficient information for self‐treatment or do not need to seek treatment; however, patients appear to turn to their physicians to evaluate the information they find online.[14]

Another significant and potentially negative effect of online medical information relates to the historical nature of the doctor‐patient relationship. The use of online medical information by a patient in a clinical setting can be interpreted as a challenge to the authority of the doctor. This challenge is exacerbated when patients decide to follow a course of treatment based on their own research that is contrary to the advice of their

physician. Historically, patients have abided by the advice of physicians without the resources to question this information. Unfortunately, physicians are often unfamiliar with the medical resources their patients use, and physicians retain a higher degree of skepticism about online data than their patients.[15] The potential for this antagonistic relationship becoming the standard dynamic, however, is slim. With the excess of information online, doctors can become “partners” to their patients rather than authoritarian guides, but still retain their clinical authority during this transition.[16]

Conclusion

Doctors, especially primary care physicians, have the opportunity to take an active role in how their patients use the Internet. If clinicians accept that their patients are likely to use online resources, they can assist their patients by providing a list of websites that have been noted for scientific accuracy and peer review. Patients may read extensively about treatments on the Internet, but they are still required to visit a physician to receive any of those treatments. Recently, a number of medical websites have contracted physicians to write articles and give advice on content. Although physicians must take great care when providing advice online, an appropriate intersection between in‐office care and virtual advice contributes to better patient well‐being. If doctors do not focus on authority structures but instead anticipate the incorporation of online information into their practice, the dynamic between doctor and patient may successfully be transformed into a partnership.

1. Akerkar, SM, and LS Bichille. “Doctor Patient Relationship.” Journal of Postgraduate Medicine 50.2 (2004): 120‐122. Print.

2. Lee, Chul‐Joo. “Does the Internet Displace Health Professionals?” Journal of Health Communication 13.5 (2008): 450‐464

3. Murray, Elizabeth. “The Impact of Health Information on the Internet on Healthcare and the Physician‐Patient Relationship.” Journal of Medical Internet Research.

4. Ibid.

5. McMullan, Miriam. “Patients Using the Internet to Obtain Health Information.” Patient Education and Counseling 63 (2006): 24‐28. Print.

6. Diaz, Joseph. “Patients’ Use of the Internet for Medical Information.” Journal of

General Internal Medicine 17.3 (2002): 180‐185. Print.

7. Lee, Chul‐Joo. “Does the Internet Displace Health Professionals?”

8. Chin, JJ. “Doctor‐Patient Relationship: From Medical Paternalism to Enhanced Autonomy.” Singapore Med 43.3 (2002): 152‐155. Print.

9. Anderson, James, Michelle Rainey, and Gunther Eysenbach. “The Impact of CyberHealthcare on the Doctor‐Patient Relationship.” Journal of Medical Systems 27.1 (2003) Print.

10. Akerkar, SM and LS Bichille. “Doctor Patient Relationship.”

11. Ibid.

12. Stevenson, Fiona. “Information from the Internet and the Doctor‐Patient Relationship.” BMC Family Practice 8.47 (2007). Print.

13. Murray, Elizabeth. “The Impact of Health Information on the Internet on Healthcare and the Physician‐Patient Relationship.”

14. Lee, Chul‐Joo. “Does the Internet Displace Health Professionals?”

15. Diaz, Joseph. “Patients’ Use of the Internet for Medical Information.”

16 . Anderson, James et. al. “The Impact of CyberHealthcare on the Doctor‐Patient Relationship.” 17Ibid.

This article was originally published in The Science in Society Review at Harvard University by The Triple Helix Inc. Follow The Triple Helix Online on Twitter. Join us on Facebook

Medical Tourism

In a country where 62% of all bankruptcies are the result of skyrocketing healthcare bills, it’s clear that the U.S. has a healthcare expenses problem [1]. Combine that with some of the worst mortality rates in the developed world, and you start to understand how Americans are in a lose-lose situation when it comes to healthcare options. In contrast, countries like India, China and Thailand offer healthcare procedures of the same caliber of the United States at up to one tenth of the cost. With that in mind, it shouldn’t come as a surprise that medical tourism is on the rise.

Medical tourism is the process of traveling to another country for medical procedures that may not be offered in one’s home country or are too expensive in the country an individual resides in. The concept of traveling for healthcare initially began as a way for people from less developed countries to receive medical treatment that was not yet available in their own countries by traveling to more developed countries. Now, however, people from more developed countries like the United States are actually traveling to less developed countries for medical procedures [2]. In these less developed countries, people are able to have medical procedures done at a fraction of the cost it would have taken back home, and often they receive better patient care than they would at home. In addition, patients find it attractive that many of these countries offer procedures that have not yet been approved by the FDA.

Medical tourism offers many people an alternative to their healthcare plan’s coverage, especially for those individuals who find that their conventional healthcare options aren’t the most effective or rational. For those who do not have health insurance, it allows for a much less expensive option than traditional healthcare. In fact, medical procedures in countries such as India, Thailand, and South America, are a fraction of the cost of medical procedures in the United States. For instance, while open heart surgery would cost up to $150,000 in the United States, it ranges from only $10,000 in Iran. Cosmetic surgeries in Costa Rica are normally a third of the cost that they are in the United States [3], and procedures in India can be as low as 10% of the cost of procedures in the United States [2].

Price, however, is not the only factor increasing the demand for medical tourism. A demand for anonymity also drives people to look for healthcare abroad. For example, people can go to a foreign country under the guise of a vacation, undergo cosmetic or sexual reassignment surgery, and then return to their home country with no one the wiser. Medical tourism also allows people the option of having surgeries and medical practices that aren’t approved in their home country.

In India, people are offered the option of having a hip resurfacing surgery instead of a hip replacement surgery. Hip resurfacing surgery, which has not yet been approved by the FDA, allows for a shorter recovery period than hip replacement surgery as well as increased mobility compared to traditional hip replacement [4].

Medical tourism also provides a faster option for undergoing medical procedures than in the United States. In cases where waiting lists for certain procedures are rather long, it is often much quicker (and in many cases, cheaper) to go to a foreign country and get the procedure done there. Often wait times for certain surgeries can be up to eighteen months in a home country, while the same surgery in India or Thailand could be completed within a week and the patient would be home within two weeks [2].

As medical tourism is still a new trend, it does have its drawbacks. If any complications from the procedure arise after the patient has returned to their home country there is little they can do. There are no laws or regulations concerning international medical procedures, and in effect, those who do partake in medical tourism do so at their own risk. If medical malpractice occurs in the foreign country that an individual has decided to have the procedure in, they would have to try the case in that foreign country, a process that is often long and laborious [5]. To make matters worse, many patients are asked to sign liability forms that prevent them from being able to take foreign clinics to court. The procedures in foreign countries aren’t as strictly mandated, and while this allows them to offer procedures that are not offered in other countries, it also means that there is less of a concern for patient safety.

Though going abroad for medical procedures has its drawbacks, it is mostly beneficial for those coming in from other countries to have procedures done. Yet, the development of medical tourism has had an adverse impact on lower income families that are native to the countries providing services for medical tourism. While medical facilities are targeting their business to foreigners, medical care for those who actually reside in the country are being put on back burners. In the case of India, medical facilities are being expanded and the government is putting even more money into the medical tourism sector, and at the same time they are ignoring the lack of medical facilities in remote regions of the country [3,6]. So while medical tourism might be helping the economy of less developed countries grow it has a negative impact on the native population of the region.

In China, India, and Moldova, to get organs for organ transplantation, people are reimbursed for giving up their organs. While people are not actually paid for their organs, they are reimbursed for expenses that they incur as well as for loss of earnings as a result of the surgery. This then results in poor people giving up their organs so that they can receive money. Yet while aspects of medical tourism are unethical with respect to the individuals native to these foreign countries, this doesn’t seem to be slowing the growth of medical tourism.

President Obama’s healthcare plans, however, may dramatically change the market for medical tourism. Since the healthcare bill requires that a majority of Americans have insurance by 2014, this seems to predict a fall in medical tourism as a whole. If more Americans have insurance, then it seems logical to conclude that less Americans will have to turn to foreign countries for medical procedures that they cannot afford otherwise. However, the situation isn’t as simple as that. A shift to government sponsored healthcare could also lead to a further increase in wait times for medical procedures. As a result, the demand for medical tourism could remain high, as foreign healthcare services would be much more prompt than procedures in the U.S. [7]. This seems like a reasonable conclusion to make, as it is the current situation in countries like Canada and the UK, who do have government sponsored healthcare [2].

Over the last few years, medical tourism has been steadily rising. In 2008, 540,000 Americans traveled abroad for medical procedures. In 2009, that number rose to 648,000, and in 2010 it was 878,000. It is expected to rise to 1,300,000 individuals by this year [7]. This shows a steady rise for the demand for global healthcare, and it is unlikely that a health care reform will drastically change those numbers. When both insured and uninsured Americans were surveyed on whether they would consider going abroad for medical treatment if it was recommended to them by a doctor, 28% of the uninsured individuals said they wouldn’t consider it, compared to 22% of the insured individuals [7]. This shows that though cheaper healthcare might be one of the key reasons that individuals go to foreign countries for medical procedures, it is not the only reason, and the advent of more insured individuals may not result in a fall in the numbers of medical tourism.

The growth of medical tourism parallels globalization across the world. As globalization becomes a more common phenomenon, it becomes increasingly clear that no profession is nationally exclusive. Not only do American companies not have to hire American workers, but Americans can also choose not to use American healthcare. The balance of the world is shifting in a way that is equalizing all nations, and this change is going to occur in all fields of work.

References

1. Cussen MP. Top Five Reasons Why People Go Bankrupt. Forbes. 2010 Mar. 25.

2. Horowitz MD, Rosensweig JA, Jones CA. Medical Tourism: Globalization of the Healthcare Marketplace. Medscape J. Med. 2007 Nov. 13; 9(4):33.

3. Connel J. Medical Tourism: Sea, Sand, Sun, Surgery. Tourism Manag. 2005 Nov. 29; 27:1093-1100.

4. Leung R. Vacation, Adventure And Surgery?. CBS News. 2005 Sept. 4.

5. Mirrer-Singer P. Medical Malpractice Overseas: The Legal Uncertainty Surrounding Medical Tourism. Law Contemp Probl. 2007 Aug. 8; 70: 211-32.

6. Gray HH, Poland CS. Medical Tourism:Crossing Borders to Access Healthcare. Kennedy Inst Ethics J. 2008;18(2):193-201.

7. Baran M. Medical tourism pros consider impact of healthcare reform. Travel Weekly. 2011 Jan. 25.

This article was originally published in The Science in Society Review at the University of California at San Diego by The Triple Helix Inc. Follow The Triple Helix Online on Twitter. Join us on Facebook

Neuroscience is an area of science that has faced its fair share of failures, yet that doesn’t mean scientists should give up on the field itself. Recently, researchers at the Alpert Medical School made an important discovery that may change the face of brain tumor treatments and diagnosis forever.

This new discovery is developed from the hypothesis that a relationship exists between mutations in tumors and methylation patterns found in their genomes (2). Chemically speaking, methylation is the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. When DNA is methylated, gene silencing often occurs which could be the cause of the tumor. Gene silencing is a process of gene regulation which “switches off” a gene through a mechanism. Researchers and neuroscientists speculate that the methylated regions mark the genes involved in metabolic processes which explain the abnormal behavior of tumor cells [2]

Brooke Christiansen, a Brown post-doctoral research associate conducted a study using the Illumina GoldenGate methylation array. The research associate speculated that brain tumors specifically dealt with the IDH gene, an enzyme that is involved in glucose sensing which is an important aspect for metabolic processing. The study found that brain tumor patients with the IDH gene survive longer than those without the mutation. The reason behind this is unknown, however pharmaceutical companies are trying to develop  a drug that inhibits the process of methylation. If such a drug is developed, then perhaps the cell will return to its normal state instead of undergoing methylation. Christiansen’s research may be a medical breakthrough however his hypothesis’ have a long way to go until they can be considered true. An immediate result of his research is that IDH mutation can be measured clinically [2].

The National Cancer Society has recently conducted similar research on a type of brain tumor common in children called medulloblastoma. Similar to Christiansen’s research, researchers such as Dr. Victor Velculescu of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discovered that some tumors harbored previously unknown mutations in the genes MLL2 and MLL3. These genes are involved in histone methylation, an epigenetic process that affects the structure of chromatin and the regulation of other genes. While the drug that inhibits methylation hasn’t been discovered yet, an experimental drug called GDC-0449, which inhibits the hedgehog signaling pathway, is being evaluated in children with recurrent medulloblastoma [3].

“Right now, there is hope and excitement that we may have new therapies to introduce for these patients,” said Dr. Amar Gajjar of St. Jude, who is leading ongoing NCI-sponsored trials with the drug on behalf of the Pediatric Brain Tumor Consortium [3].

Brain tumor may not be the first thing on the minds of people when they hear the word cancer, however it is one of the most vigorous and brutal forms of cancer. Almost every single patient with an inoperable tumor dies within a 5 year set time interval after diagnosis. However, with the new studies being conducted on histone methylation and developing a drug that inhibits this epigenetic process, the cure for brain tumor isn’t far away.  Furthermore, the studies that have already been conducted in the pediatric field dealing with medulloblastoma can prove to be helpful in developing a way to inhibit methylation. The cure to brain tumor is in sight, however there is still a long way to go in curing one of the most deadliest disease in the world.

When one thinks of the word “cancer” breast cancer, lung cancer, and skin cancer are among the various types that first come to mind. One type of cancer that is often neglected is Brain Tumor. According to the National Tumor Society, more than 500 people per day are diagnosed with primary or metastatic brain tumor and what’s worse is that the mortality rates for those diagnosed with brain and nervous system tumors haven’t improved over the past decade. The desperate need for new treatments and therapies for brain tumor is evident and it is the hope of many people whose loved one have suffered the wrath of this incurable disease that 2011 will bring new treatments and bring the path to the cure closer than ever before [1].

Neuroscience is an area of science that has faced its fair share of failures, yet that doesn’t mean scientists should give up on the field itself. Recently, researchers at the Alpert Medical School made an important discovery that may change the face of brain tumor treatments and diagnosis forever.

This new discovery is developed from the hypothesis that a relationship exists between mutations in tumors and methylation patterns found in their genomes (2). Chemically speaking, methylation is the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. When DNA is methylated, gene silencing often occurs which could be the cause of the tumor. Gene silencing is a process of gene regulation which “switches off” a gene through a mechanism. Researchers and neuroscientists speculate that the methylated regions mark the genes involved in metabolic processes which explain the abnormal behavior of tumor cells [2]

Brooke Christiansen, a Brown post-doctoral research associate conducted a study using the Illumina GoldenGate methylation array. The research associate speculated that brain tumors specifically dealt with the IDH gene, an enzyme that is involved in glucose sensing which is an important aspect for metabolic processing. The study found that brain tumor patients with the IDH gene survive longer than those without the mutation. The reason behind this is unknown, however pharmaceutical companies are trying to develop  a drug that inhibits the process of methylation. If such a drug is developed, then perhaps the cell will return to its normal state instead of undergoing methylation. Christiansen’s research may be a medical breakthrough however his hypothesis’ have a long way to go until they can be considered true. An immediate result of his research is that IDH mutation can be measured clinically [2].

The National Cancer Society has recently conducted similar research on a type of brain tumor common in children called medulloblastoma. Similar to Christiansen’s research, researchers such as Dr. Victor Velculescu of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discovered that some tumors harbored previously unknown mutations in the genes MLL2 and MLL3. These genes are involved in histone methylation, an epigenetic process that affects the structure of chromatin and the regulation of other genes. While the drug that inhibits methylation hasn’t been discovered yet, an experimental drug called GDC-0449, which inhibits the hedgehog signaling pathway, is being evaluated in children with recurrent medulloblastoma [3].

“Right now, there is hope and excitement that we may have new therapies to introduce for these patients,” said Dr. Amar Gajjar of St. Jude, who is leading ongoing NCI-sponsored trials with the drug on behalf of the Pediatric Brain Tumor Consortium [3].

Brain tumor may not be the first thing on the minds of people when they hear the word cancer, however it is one of the most vigorous and brutal forms of cancer. Almost every single patient with an inoperable tumor dies within a 5 year set time interval after diagnosis. However, with the new studies being conducted on histone methylation and developing a drug that inhibits this epigenetic process, the cure for brain tumor isn’t far away.  Furthermore, the studies that have already been conducted in the pediatric field dealing with medulloblastoma can prove to be helpful in developing a way to inhibit methylation. The cure to brain tumor is in sight, however there is still a long way to go in curing one of the most deadliest disease in the world.

References

1. http://presszoom.com/story_164408.html
2. Villacorta, Natalie. Tumor Research Could Lead to Treatment Breakthrough. http://www.browndailyherald.com/mobile/tumor-research-could-lead-to-treatment-breakthrough-1.2450647
3. Seeking Better Treaments for Brain Tumors in Children <http://www.cancer.gov/ncicancerbulletin/012511/page6>.

Written by The Triple Helix at Ohio State University

Ideally, humans sleep for at least eight hours every day, meaning that we spend about a third of our lives “unconscious.” Scientists have yet to agree on why this unconsciousness is vital, but we know that without sleep, all mammals and birds would die [1]. Because sleep has only become the subject of research in the recent past, rare neurological disorders like fatal familial insomnia (FFI), which causes patients to die within a year or two of its onset, (usually in the patient’s early fifties) ranks very low on the list of things to cure. Though in this case the cause of death is mostly attributable to neural degeneration, death is clearly hastened by a marked “disruption of critical functions” due to lack of sleep [2]. And before death, all FFI patients display symptoms that are clear manifestations of damage to a mass of grey brain matter called the thalamus.  In fact, according to National Geographic, “before FFI was investigated, most researchers didn’t even know the thalamus had anything to do with sleep” [1]. By studying the effects of FFI, it is likely that scientists will accrue key insight into the exact role of the thalamus in sleep—and maybe even insights into the function of sleep as well.

The thalamus belongs to the limbic system, which lies deep in the cortex and extends to the top of the brain stem [4]. The cortex is the outer layer of the cerebrum, the front part of the mammalian brain. Generally, scientists agree that the limbic system is involved in olfaction, the interpretation of emotions, storage of certain types of memories, and regulation of certain hormones. [4] The thalamus itself acts as a sort of control tower, receiving sensory messages from the spinal cord and then relaying those signals along to their corresponding locations in the cerebrum [5].  Ann M. Akroush of the University of Michigan’s Department of Natural Sciences calls the thalamus “the area [of the brain] responsible for sleep,” noting that during sleep, it is generally thought that “the thalamus becomes less efficient…allowing for the vegetative state of sleep to come over an individual” [3].

Sleep includes long periods of non-rapid eye movement, punctuated by rapid eye movement (REM), the latter that amounts to about a quarter of the total sleeping time. During non-REM sleep, most neurons in the brain stem, cerebral cortex, and adjacent forebrain regions—all connected to the thalamus—stop firing [6].  Non-REM sleep, it seems, gives cells a chance to repair themselves from daily wear and tear. Jerome M. Siegel of the Brain Research Institute at University of California, Los Angeles, accounts for this conjecture by pointing to the fact that “bigger animals,” such as humans, “need less sleep” on the whole than smaller animals, such as cats, because smaller animals “have higher metabolic rates” [6]. The set of chemical reactions that constitute a metabolism generate free radicals, chemicals that are known to cause a lot of damage to or even kill cells; thus, these smaller animals are likely to experience greater rates of tissue injury, and a higher need for self-repair [6].

Location of the Thalamus

Victims of FFI are unable to “get past” the first stages of sleep and enter REM sleep, which is generated by the brain stem—right below the thalamus [1]. Although the exact purpose of REM sleep remains a mystery, we know it “profoundly affects brain systems that control the body’s internal organs” [6]. For example, during REM our heart rate and breathing become “irregular” as in our waking state [6]. Like a reptile’s, our body temperature drifts toward that of our environment [6]. The body temperature of sufferers of FFI instead “soars and crashes” marked by extensive sweating and chills [1].

Additionally, in 1973 a group of scientists discovered that during REM sleep, neurons completely cease their release of a group of neurotransmitters called monoamines—which include dopamine and serotonin [6].  Siegel believed that this halt could be “vital for the proper function of these neurons and of their receptors,” due to the fact that a “constant release” of monoamines tends to desensitize their receptors [6]. Thus, he says, the “interruption of monoamine release during REM sleep…may allow the receptor systems to “rest and regain full sensitivity” [6]. Without either type of sleep, and consequently neither a period of rest nor a chance for cell repair, the outlook for FFI patients seems dim. Furthermore, the question of whether FFI patients actually die from lack of sleep seems intimately tied to understanding the exact function of the thalamus, as evidenced by the locations of brain activity during sleep.  Could it be that the thalamus is most vital to us because of its connection to sleep?

FFI is part of a family of diseases called transmissible spongiform encephalopathy (TSE), or prion disease.  “Spongiform encephalopathies” are brain infections distinguished by the appearance of a bunch of little holes in the affected region, as in a sponge.  They are transmissible because they can spread.  TSEs are caused by fatal misfoldings of “prion” proteins, which in turn recruit the cells around them to misfold, and together these proteins become indigestible to enzymes [7]. In FFI patients, rogue malformed prion proteins attack the thalamus [1]. First, the victim will display signs of worsening insomnia. Then, he or she will start to panic, hallucinate and sweat. After the patient loses all ability to sleep, rapid weight loss will ensue. Next, the patient will experience dementia and irresponsiveness, and finally sudden death [3].  Like the rest of the TSEs, FFI is “autosomal dominant”: if one of your parents is a carrier of the gene for FFI, you are automatically doomed to be a victim of the disease.

A particular case report by psychologist Joyce Schenkein and neurologist Pasquale Montagna describes the efforts of one patient who was able to exceed the average survival time by nearly one year. He tried various strategies, including vitamin
therapy and meditation, using different stimulants and narcoleptics and even
complete sensory deprivation in an attempt to induce sleep at night and increase
alertness during the day [2]. Nonetheless, over the course of his trials, the patient succumbed to the classic four-stage progression of symptoms.  The fact remains that there is no cure for FFI.

We do not know if prions destroy every FFI victim’s thalamus in the same way—that is to say, if physiological function in the region directly corresponds to symptom manifestation.  Schenkein and Montagna concluded that death was hastened by “the disruption of critical functions,” including ones related to “hypometabolism,” in which biochemical processes of the body move at a slower pace, and others related to “dysautonomia”, in which, the sympathetic nervous system, the control center for the “fight-or-flight” response, goes into overdrive, resulting in metabolic exhaustion [2]. So, does the thalamus indeed become “less efficient” during sleep, as Akroush put it, or do its functions simply shift?  These directed questions could allow researchers to better understand the disease, its manifestations, and potential routes to cures.

Akroush cites gene therapy as a starting point for treatment possibilities. This would generally involve the re-introduction of a non-mutated version of the rogue gene into an affected individual’s genome with aims to correct his or her protein expressions.   But this treatment is only an option if it is performed far before any FFI symptoms visibly manifest [3]. Worse, scientists have yet to isolate the corrective gene or to identify a proper vector for transfer.  Indeed, if sleep weren’t such a private and mysterious bodily function, argues National Geographic, “governments would [themselves] declare war on” sleep disorders [1]. Still, our understanding does seem to be progressing, if slowly.  We know that patients diagnosed with fatal familial insomnia die after substantial damage to the thalamus that directly causes an inability to sleep.  From this, we can infer that the thalamus’s role is necessary to sustain human life and important for elucidating the mysteries behind mammalian sleep.

Yet the National Institutes of Health (NIH) contributes “only about $230 million a year to sleep research,” while spending well over $100 billion per year to treat obesity-related conditions, that might be solved simply with dietary modifications and moderate exercise.  While obesity has only become an issue in the last century, the first accepted case of FFI was recorded in the eighteenth century [1].  Similarly, about thirty percent of Americans are obese, while over fifty percent of Americans complain of symptoms of insomnia [8].  Incidentally, there is an increasing body of research linking certain obesity cases to lack of sleep— but we sleep about “an hour and a half less a night than we did just a century ago” and our struggles continue [1]. For now, the fight against insomnia has been “largely left to drug companies and commercial sleep centers,” who target general client bases, while FFI victims and future generations of their family will continue to die until a cure is found [1].

References:

1. Max DT. The Secrets of Sleep. National Geographic [serial on the Internet]. 2010 May; [cited 2011 January 24]; [about 5 screens]. Available from: http://ngm.nationalgeographic.com/2010/05/sleep/max-text
2. Schenkein J, Montagna, P. Self-management of Fatal Familial Insomnia Part 2: Case Report. MedGenMed [serial on the Internet]. 2006 September 12; [cited 2011 January 24]; 8(3): [about 12 screens].  Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781276/?tool=pmcentrez
3. Akroush, AM. Fatal Familial Insomnia [homepage on the Internet]. Case Studies in Virtual Genetics 1996-1997: John C. Thomas; [cited 2011 January 24]; Available from: http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html
4. Regina Bailey. Limbic System [homepage on the Internet]. Biology About.com Guide. [updated 2011; cited 2011 January 24]. Available from: http://biology.about.com/od/anatomy/a/aa042205a.htm
5. Thompson Learning, Inc. What are the main anatomical structures of the brain and what are their functions? [homepage on the Internet]. Thompson Learning, Inc; [updated 2002; cited 2011 January 24]. Available from: http://163.16.28.248/bio/activelearner/40/ch40c2.html
6. Siegel, JM. Why We Sleep. Scientific American. 2003 November: 92-97.
7. Zeman, A. A Portrait of the Brain. New Haven: Yale University Press; 2008.
8. WB&A Market Research. 2002 Sleep in America Poll [homepage on the Internet]. Washington DC: National Sleep Foundation [updated 2002 April 2; cited 2011 May 3] Available from: http://www.sleepfoundation.org/sites/default/files/2002SleepInAmericaPoll.pdf
9. Image: Steinert, L. Adapted from Spencer, C. Insomnia. Flickr; [taken 2010 Mar 7; cited 2011 May 5] Available at:http://www.flickr.com/photos/charlatrone/4411840607/ [Licensed under CC BY-NC-SA]
10. Image: Steinert, L. Adapted from NASA. MRI brain. Wikimedia Commons; [uploaded 2005 Feb 19; cited 2011 May 5] Available at:http://commons.wikimedia.org/wiki/File:MRI_brain.jpg [Public domain]

Luciana Steinert is a second-year student at the University of Chicago pursuing a major in the History, Philosophy, and Social Studies of Science and Medicine.

Although mortality rates from infectious diseases have decreased in recent years, a new type of affliction has arisen in its place. Autoimmune diseases are those in which our body’s own immune system attacks normal and healthy cells. This occurs because the immune system cannot tell the difference between foreign objects and normal body tissues. However, the reason why the immune system becomes unable to differentiate between normal tissues and foreign objects is unknown. Some theories include the involvement of microorganisms and drugs, but no studies have shown a conclusive link. The more common autoimmune diseases are rheumatoid arthritis, celiac disease, type I diabetes, multiple sclerosis (MS), and Lupus. Unlike infectious diseases, most autoimmune diseases are currently incurable because we don’t know why they occur; however, the symptoms can be managed to a certain degree using drugs. As such, the drive to find a cure for these diseases has become an objective for modern medicine. To start, scientists have turned to elucidating a trend in the incidence of autoimmune diseases.

As studies have found, the prevalence of these diseases over the past century has increased. For instance, the incidence of Celiac’s disease was found to have increased fourfold over the past fifty years [2]. Scientists have also found that the percentage of acute lymphoblastic leukemia patients has increased threefold in the past eighty years [3]. Though there is evidence that the incidence of diseases involving the immune system has increased over the past century, no definitive explanation has been found [4].

The most prominent explanation for this phenomenon looks at the basics of the immune system and its symbiotic relationships with other organisms. For the past 200,000 years, humans have lived in coexistence with microorganisms. This close proximity has inevitably fostered a long history of interactions between humans and these microbes. However, in recent history, we have mostly removed these microorganisms from our environment and daily lives by using cleaning agents such as soap in our everyday lives, and also by cleaning or removing previously common sources of microbes. Several examples include the sewage system, water treatment plants, and even public trash collection. Although microorganisms certainly have not completely disappeared from our day-to-day lives, they have been widely eradicated in a crucial moment in the development of the immune system, our infancy.

Our immune system grows and develops the most in childhood. Here, it is drastically different from the adult immune system. This difference is important to consider when developing vaccines, and when tackling issues of autoimmunity. Babies have a much stronger immune response to the proteins of biological organisms such as bacteria, viruses, and parasites [5], resulting in a large role for these microbes in the development of the early immune system. But in this new world, where hygiene has become of the utmost importance, the presence of bacteria, viruses, and other antigens is frowned upon, and all efforts are made to rigorously eradicate these microbes from the baby’s surrounding. Even though microbes will always persist, their diversity and potency are not as great as they would have been in times past. Thus, the baby’s immune system is denied the potential to fully develop at this crucial age.

Because our immune systems are not properly developed at a young age, they are at risk of malfunctioning later in our lives. One proposed mechanism is that this early lack of development causes regulatory T cell development to develop improperly, which causes the T helper cells that it normally regulates to become hyperactive [6]. This lack of “training” for our immune system in turn causes a higher incidence of autoimmune diseases. In fact, a hypothesis, aptly named the “hygiene hypothesis”, states that good hygiene inadvertently causes autoimmune diseases. Many studies have shown that this hypothesis is likely accurate. For example, one study on the relationship between MS and sanitation found that there is a statistically significant increase in risk for MS later in life if children had been in more sanitary environments [7]. Studies have also linked sanitation with increasing incidences of allergies and type I diabetes [8].

As such, if the hygiene hypothesis is correct, the cure for autoimmune diseases is simple: expose our bodies to organisms that can help properly develop and control our immune system. Currently, the most promising form of treatment for autoimmune diseases revolves around the use of parasitic worm infection. These worms have evolved parallel to humans for millennia, and so both worms and humans have learned, in some ways, to cooperate with each other. Parasitic worms thrive and reproduce using the nutrients from their host. In addition, they cleverly avoid the host’s immune system by suppressing it. In the past, it was likely that the vast majority of humanity were infected by these worms to some degree, meaning the suppressed immune system was actually a norm. Yet in the modern world, parasitic worm infections have been severely reduced. They are now only prevalent in Africa and third world countries, where shoes and clean drinking water are not always readily available to the populace [4].

These worms helped regulate the immune system in our ancestors by keeping it in check against itself. But today, without the help of these worms, autoimmune diseases are manifest as an overreaction of our immune system; classifying certain elements as foreign even when they are a part of our body. Nevertheless, worm treatment has shown great promise in curing or at least mitigating the effects of autoimmune diseases. For instance, people with worm infections have lower chances of developing multiple sclerosis than people without infections. In fact, there have been documented cases where worm infection has actually cured multiple sclerosis, a feat that modern medicine has been unable to replicate [9]. The same effects have been seen in studies focusing on worm infection and Crohn’s disease [10]. Although autoimmune diseases may occur more frequently as we become more hygienic, the future also holds some promising potential in worm therapy.

References:

1. EA Mortimer, Jr. Immunization against infectious disease. Science. 1978;200 (4344): 902-907.
2. Alberto Rubio–Tapia, et al. Increased Prevalence and Mortality in Undiagnosed Celiac Disease. Gastroenterology. 2009; 137(1):88-93
3. Smith MA, et al. Evidence that childhood acute lymphoblastic leukemia is associated with an infectious agent linked to hygiene conditions. Cancer Causes Control. 1998 May;9(3):285-98.
4. Wilson MS, Maizels RM. Regulation of allergy and autoimmunity in helminth infection. Clin Rev Allergy Immunol. 2004 Feb;26(1):35-50.
5. Heather B. Jaspan, Stephen D. Lawn, Jeffrey T. Safrit, Linda-Gail Bekker. The Maturing Immune System: Implications for Development and Testing HIV-1 Vaccines for Children and Adolescents. AIDS. 2006 Feb 28;20(4):483-94.
6. Bufford JD, Gern JE. The hygiene hypothesis revisited. Immunol Allergy Clin North Am. 2005 May;25(2):247-62, v-vi.
7. Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern L, Alter M. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. J Neurol Neurosurg Psychiatry 1966;29:60-68
8. Onkamo P, Väänänen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of Type I diabetes–the analysis of the data on published incidence trends. Diabetologia. 1999 Dec;42(12):1395-403. Erratum in: Diabetologia 2000 May;43(5):685.
9. J. Correale and M. Farez. Association between parasite infection and immune responses in multiple sclerosis. Annals of Neurology, 2007;61:97.
10. R.W. Summers et al. Trichuris suis therapy in Crohn’s disease. Gut. 2005;54:87.
11. Lauke P. [photograph] 2009. Available at: http://www.flickr.com/photos/redux/3418936283/

Allan Zhang is a first-year student at the University of Chicago.

Prior to President Obama’s elimination of restrictions on federal funding for embryonic stem cell research in 2009 [4], private resources provided most of the funding and often reserved broad rights over the research. James Thomson, a scientist at the University of Wisconsin who was responsible for developing and maintaining the first human embryonic stem cell (hESC) line, received funding from the Geron Corporation in exchange for rights on consequent patents [3]. Patents on his work were also secured for the Wisconsin Alumni Research Foundation (WARF), a group in charge of patents from scientists at the university. Over the years, access to and licensing of these patents have become a source of controversy and has led to legal battles between public interest groups, the Geron Corporation, and WARF. Challenges from groups such as Consumer Watchdog and other advocates of stem cell research have criticized the extensive breadth and restrictions of the WARF patents. Even though WARF and the Geron Corporation later came to an agreement on patent sharing, they had disagreements on the licensing of the patent to other researchers. While none of the suits against WARF were successful in revoking the patents, they did lead to a substantial relaxation on the restrictions on licensing [3].

The controversy surrounding the patenting of stem cells is not limited to the United States, nor is it limited to the relatively restrictive terms of patents. In Europe, the European Patent Office (EPO) issued a directive in regards to the patenting of hESCs under the European Patent Convention (EPC) that includes a morality clause stating that no patent would be issued to an invention whose commercial use was contrary to the public order or morality [5]. It seems that in Europe the main opposition to patents on embryonic stem cells is tied to the ethical questions of morality and human dignity. A couple of patents have been contested as a result. The controversial “Edinburgh” patent that was issued for a method developed to isolate stem cells in Europe was successfully challenged and later restricted to exclude hESCs [6]. WARF, which had to deal with opposition to the restrictive nature of their patents in the United States, was denied a European patent, in 2004, because of the morality clause of the EPC [5]. A later appeal to the EPO’s Enlarged Board of Appeal (EBoA) in 2008 also turned out to be futile [5]. The acquisition of patents in Europe is further complicated by the fragmented legal landscape of the continent. A patent granted by the EPO to Oliver Bruestle, a German scientist on neuroprogenitor stem cells, was rendered partially invalid by the German Federal Patent Court [7]. An appeal by Bruestle was referred to the European Court of Justice (ECJ) leading to additional questions on the roles of supranational institutions such as the EPO and ECJ in the issuance of patents [7].

Stem cell technologies have advanced since the initial work of James Thomson. With the development of induced pluripotent stem cells (iPSCs) [8], one has to wonder how this new innovation and any other future advancement will affect patents on stem cells. Even though scientists working with iPSCs are less likely to be subjected to the same level of ethical controversy as their colleagues working with hESCs, they will probably be expected to follow policies and regulations formed as a result of the disagreements surrounding embryonic stem cells [8]. Following the reexamination of Thomson’s initial patents in 2007, the United States Patent and Trademark Office (USPTO) was able to provide a framework for determining the patentability of pluripotent stem cells by claiming that “the lack of stage-specific embryonic antigen-1 (SSEA-1) cell surface markers is a characteristic only of pluripotent hESCs, but not of other pluripotent kinds of human stem cells” [9]. While human iPSCs are not derived from embryos, they are very much like human embryonic stem cells in terms of “morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell–specific genes and telomerase activity”. However, almost all lack SSEA-1 cell surface markers [9]. This important distinction may mean that the patentability of iPSCs and other future innovations in the field may be judged not by their function but by their physical characteristics [9].

In light of all the controversy and issues related to stem cell research, it has become imperative that scientists and relevant interest groups work together to advance the field. Support for stem cell research is usually justified with promises of its economic potential [10], and considering the fact that the most important patents in the field are held equally between public and private sectors [11], it is necessary that these two branches cooperate to ensure future success. The conflict between WARF and the Geron Corporation regarding Thomson’s work was not only representative of the friction between the private and public sectors, but also indicative of how private financing can fund groundbreaking research that would have been impossible otherwise due to limitations on public funding [3]. Besides the fact that most patent offices around the world seem to lack the needed infrastructure to keep up with the fast paced advancement in the field, there is also the issue of inaccessibility of a patent database and newly published information [7].

In an attempt to foster international cooperation, the Hinxton Group [12], a consortium of professionals with a vested interest in stem cells, proposes establishing databases for patents and currently used stem cell lines [13]. Their proposals include the creation of an international human tissue and stem cell bank and the provision of conditional funding to improve data sharing. They also suggest implementing patenting policies that will encourage easy access and cooperation [13]. While some of the recommendations proposed by the Hinxton Group do not currently seem feasible, they do represent a positive motion of stem cell supporters. Furthermore, the formation of groups such as the NIH Stem Cell Task Force [14] and their European counterparts, the European Stem Cell Group [15] with similar goals as the Hinxton Group reinforces the determination of the stem cell community to work together and show their commitment to reduce conflicts and promote advancements in the field.

Stem cells represent the potential future of medicine and the continual advancement of the field translates into future treatments and therapies for diseases and medical disorders we currently have no effective medication for. The nature of stem cell research and its funding however has resulted in disputes over patents on cell lines and experimental procedures. These patent wars and their accompanied lack of cooperation have threatened to stifle progress in the field.  However, the stem cell community is fighting back with renewed proposals for policies and forming groups that will allow for better cooperation among its members. With adequate funding and effective collaboration between stem cell researchers, we can be hopeful that a cure for cancer and other diseases is on the horizon.

References

1. Ammann A. J, Meuwissen H. J, Good R. A and Hing R. Successful Bone Marrow Transplantation with Humoral and Cellular Immunity Deficiency. Clin. Exp. Immunol. 1970;7: 343-353.
2. Magnus D. Translating Stem Cell Research: Challenges at the Research Frontier. J Law Med Ethics. 2010;38(2):267-76
3. Golden, John M. WARF’s stem cell patents and tensions between public and private sector approaches to research. J Law Med Ethics. 2010; 38(2):314-31.
4. Robertson JA. Embryo stem cell research: ten years of controversy. J Law Med Ethics. 2010;38(2):191-203
5. Treichel P. Patenting of human embryonic stem cells in Europe. Biotechnol J. 2009; 4(4):462-4
6. Times Higher Education. “Edinburgh” patent limited after European Patent Office opposition hearing [document on the Internet].Munich: 2002 [updated 2002 July 25; cited 2011 March 4]. Available from: http://www.timeshighereducation.co.uk/story.asp?storyCode=170621&sectioncode=26 .
7. Aurora Plomer. Stem Cell Patents in a Global Economy: The Legal Challenges. Stanford Journal of Law, Science & Policy. 2010; 3: 5-15.
8. Caulfield T, Scott C, Hyun I, Lovell-Badge R, Kato K, Zarzeczny A. Stem cell research policy and iPS cells. Nat Methods. 2010; 7(1):28-33.
9. Vrtovec, Katja Triller & Scott, Christopher Thomas. Patenting pluripotence: the next battle for stem cell intellectual property. Nat Biotechnol. 2008; 26(4):393-5
10. Caulfield Timothy. Stem cell research and economic promises. J Law Med Ethics. 2010; 38(2):303-13.
11. Konski AF, Spielthenner DJ. Stem cell patents: a landscape analysis. Nat Biotechnol. 2009; 27(8):722-6.
12. Hinxton Group. [internet site]. 2006. [cited 2011 March 4]. Available from http://www.hinxtongroup.org/
13. Brice P. Will patents hinder equitable access to stem cell medicine? [document on the Internet]. The Phg Foundation; 2011. [updated 2011 January 30; cited 2011March 4]. Available from   http://www.phgfoundation.org/news/7458/.
14. NIH Stem Cell Task Force. [internet site]. 2008. [updated 2008 November 13; cited 2011 March 4]. Available from http://stemcells.nih.gov/policy/taskforce/
15. European Stem Cell Group. [internet site]. 2009. [cited 2011 March 4] Available from http://www.eurosystemproject.eu/news/european_group
16. Benvenisty, N. [photograph] 2005. Available at: http://commons.wikimedia.org/wiki/File:Human_embryonic_stem_cells.png

Emmanuel Aryee is a fourth-year biology major at the University of Chicago. Please join The Triple Helix Online on Facebook. Follow The Triple Helix Online on Twitter.

The central idea of epigentics is perhaps that the genomic information is not just a jumble of sequence to be read in a linear manner: the information is finely organized through a series of overlayed mechanisms that control how that information is utilized.

Fundamental shifts in the way we understand our world and ourselves are rare, and when they do happen it is often with uproar. When discovery of the DNA double helix by James Watson and Francis Crick in 1953 showed us that all of nature was bound together by a common molecular mechanism, it was assumed that the information held by the DNA sequence would be the primary determinant in the biology of any organism. After the last forty years of biological research and the completion of the human genome sequence a decade ago, the overwhelming realization is that the information contained in the DNA sequence alone is only a fraction of the total information needed to animate the cell, coordinate multicellular behavior, and orchestrate life’s unfathomably complex sequence of biological events. While the discovery that layers of information beyond DNA sequence are equally important to life is in many ways as fundamental a revelation as the discovery of DNA, it has not received such widespread recognition. This is surprising, considering that there are medical implications from choice of diet to cancer treatment. Epigenetics, as this fascinating range of mechanisms is called, deserves your attention and imagination because for the foreseeable future this new paradigm will be behind advances in our understanding of multicellularity, genome-environment interaction, and human disease.

All of the cells in your body have the same genetic code, and hence the same set of instructions, but carry out drastically different functions. This begs several questions. How does a cell know which instructions to carry out? How can the genetic instructions of a cell or an organism respond to their environment? How can some cells become cancerous while others remain healthy? The answers to these questions lie in the differences in epigenetic information between cells. The Greek prefix epi- means “above” or “in addition to”, and epigenetics refers to the layers of information superimposed on top of the genetic information contained in DNA sequence. If your genetic code gives you your individual identity, epigenetics gives each of your cells their own identity. Thus, any organism is a manifestation not only of its genetic content, but also of the sum total of its epigenetic states.

The term epigenetics dates back to 1942, before the discovery of DNA [1], but it has taken sixty years of biology to describe how it works on the molecular level. To understand why epigenetics is distinct from “regular” genetics, posing a new set of challenges and fundamentally altering the way we perceive biological information, we must get into the gritty details of DNA and its multitude of partners.

DNA, by itself, does not do anything. It is chemically inert, and the information it contains is only relevant when accessed by proteins and RNA machinery. The central idea of epigentics is perhaps that the genomic information is not just a jumble of sequence to be read in a linear manner: the information is finely organized through a series of overlayed mechanisms that control how that information is utilized.

The first level of epigenetic regulation and higher order genome structure is the way in which strands of DNA are packaged by proteins called histones. Imagine a string (the DNA) being wound around a hockey puck (the histone). These string-wrapped hockey pucks (protein-DNA complexes) are bundled into a solenoid-like pattern, which are then wrapped into even larger strands called chromatin, which make up whole chromosomes. Chromatin is the basic structure of the genome in a cellular context, but it is not all in a uniform state. Some regions are tightly packed together, which means genes in those regions are turned off, while others are less tightly packed and the genes inside can be turned on.  Strands of DNA can be chemically modified by addition of a single carbon atom (methylation), which causes chromatin to pack together more tightly, leading to repression of that area of the genome [2]. Think of it as making the string stickier. The clumps of hockey pucks would be hard to unwrap.

The second level is the behavior of the histones themselves. For the string of DNA to be read by the transcriptional machinery, the hockey pucks must slide away or be removed to allow proteins to bind to the DNA. The behavior of histones, and therefore the transcriptional status of a gene, is modulated by chemical modifications that cause the hockey pucks of the histones to move further away from one another and expose the DNA string, or clump together and conceal it. Patterns of these modifications are closely related to levels of gene expression, and it appears that cells have an epigenetic “histone code” of sorts, adding another layer of information with strong consequences for cellular activity and development [3].

The third level of epigenetic regulation occurs on a larger scale. The vast majority of your genome is full of long repeats, remnants of erstwhile genes, and a hefty portion of viruses that encountered us at some ancient point in evolutionary history and decided to stay. Most of this is hardly transcribed, if at all, but it must be managed in a way that does not interfere with the active regions of the genome. This leads to a non-random ordering of the genome within the nucleus, and of regions within the same chromosome [4]. Active regions clump together, and inactive regions are repressed in a common space [5]. The spatial organization of the genome is a problem of third-order complexity, and today it is unclear what functional consequences these arrangements have. However, recent work shows that genome organization is to some degree cell-type specific, and changes during development [6].

These regulatory mechanisms, along with others such as the surprisingly varied role of RNA, comprise a rich network of information that influences cellular and organismal behavior in profound ways. Epigenetic mechanisms explain why two individuals with extremely similar genome sequence can have different physical characteristics. Identical twins have identical genomes, and are epigenetically identical at birth, but as they age, different environmental factors cause their methylation and histone modification profiles diverge, and they end up with differing patterns of gene expression and disease [7]. These changes arise within a single lifetime, but some epigenetic traits can be inherited across generations. For example, the diet of pregnant mothers can change DNA methylation patterns in the fetus, which may lead to various diseases later in life for their children [8].

Epigenetic approaches to therapy are showing promise as well, particularly in cancer, where both genetic and epigenetic profiles are drastically altered. The FDA has approved the drug decitabine, which inhibits enzymes that methylate DNA. Aberrant methylation patterns are a hallmark of several blood cancers, including acute myeloid leukemia, where decitabine has shown the most success [9]. Inhibitors of histone-modifying enzymes have also been approved for treating cancer of immune cells. Unfortunately, the complexity and redundancy of methylation and histone modifications makes it difficult to use single inhibitors of epigenetic machinery. For unknown reasons they are most effective in blood cancers, but have little effect on solid tumors. It seems that epigenetic therapies will have the most benefit when they are used in combination with one another and as supplemental therapy for more decisive interventions like bone marrow transplants or radiation therapy [10].

But there’s still the question: why should you care about epigenetics? Most importantly, epigenetics has opened new approaches to treating disease, and is promising to unleash the power of personalized medicine that sequence information alone was unable to provide. It also unravels the connections between our environment and our genomes, and provides a mechanism for how our experiences can feed back into our genetic identity. Lastly, it has redefined our understanding of how biological information is stored, processed, and transmitted. Together, these advances constitute a profound shift in how we conceptualize life, and are the foundation for the next century of biology and medicine. That is certainly worthy of an uproar.

References:

1. Waddington, CH. The epigenotype. Endeavour. 1942;1:18–20.
2. Bird, A. DNA mehtylation patterns and epigenetic memory. Genes & Dev. 2002;16:6-21.
3. Jenuwein T, Allis CD. Translating the histone code. Science. 2001 Aug;293(5532):1074-80.
4. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289-93.
5. Misteli T. Beyond the sequence: cellular organization of genome function. Cell. 2007;128:787-800.
6. Rajapaske I, Groudine M. On emerging nuclear order. JCB. 2011;192(5):711-721.
7. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102(30):10604-10609.
8. Heijmans B, Tobi EW, Stein AD, Putter H, Blauw GJ, SUsser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. . Proc Natl Acad Sci USA. 2008:105(44);17046-17049.
9. Claes B, Buysschaert I, Lambrechts D. Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy. Heredity. 2010;105(1):152-60.
10. Thurn KT, Thomas S, Moore A, Munster PN. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer.  Future Oncol. 2011;7(2):263-83.
11. Image: Cann AJ. Epigenetics. Flickr; [uploaded 2010 Aug 23; cited 2011 May 3] Available at:http://www.flickr.com/photos/ajc1/4920090582/ [Licensed under CC BY-SA]

Justin Demmerle is a fourth-year biology major at the University of Chicago. Please join The Triple Helix Online on Facebook. Follow The Triple Helix Online on Twitter.

In large part, translational research is mediated by the pharmaceutical industry. One of the largest disincentives to cancer drug development— and a driving force behind negotiations on the Biologics Price Competition and Innovation Act of 2009— has been the development of cheaper derivative biosimilars. This act vaguely defines biosimilars as “‘highly similar’ to the reference product ‘notwithstanding minor differences in clinically active components’” [1]. The research costs associated with developing reference biologics, or original molecules upon which these patented biosimilars are based, are significant and include large expenditures on production technology and clinical trials [2]. While there has been some debate about the amount of time necessary for a drug company to receive a return on its original investments, PhRMA (Pharmaceutical Manufacturers Association) has controversially pushed 12 years as the “bare minimum” for market exclusivity, a standard currently supported by the International Intellectual Property Institute [2, 3].

When considering the competing motivations of the pharmaceutical industry and its clients, it is important to reconcile the interests of each stakeholder. This was the primary aim behind the Biologics Price Competition and Innovation Act. Because they monopolize the market, biologics remain some of the most expensive drugs available, rendering 12 years of patent exclusivity highly restrictive. On the other hand, current legislation permits competitors to run tests on the original product and to develop generic alternatives while its patent is still in effect. This allows “a generic product to be marketed virtually the moment the [original] patent expires” [2]. The market, originally under-stocked and overpriced, quickly becomes saturated with derivative generics because of the lack of financial incentive to research novel drugs.

One temporary solution proposed for the initial cost problem has been governmental subsidy, granted directly to the pharmaceutical company or indirectly to patients. The former idea, while intended to lower prices and foster development of new bio-technologies, has been criticized for placing too much power in the hands of large bio-tech companies. There looms the possibility that companies might use the spare money to “tinker with” existing products, rather than investing it in the more costly task of developing new formulas [4]. The latter idea, through the distribution of pharma coupons, tends to favor “commercially insured eligible patients”, yet excludes the uninsured or those with publicly funded health insurance plans [5]. For different reasons, neither of these solutions arrives at the root of the problem.

Might there be a better way to defray development costs—and concurrently, lower pricing? The answer could lie in formal collaboration. While highly prolific, academic institutions do not always experience the practical application of their research. Drug companies, on the other hand, have the resources to disseminate facets of this research at large. Governmental support for pharmaceutical initiatives is tentative at best. Universities, however, tend to be attractive candidates for federal funding. Jose Carlos Gutierrez-Ramos—Head of the Immuno-Inflamation Center of Excellence for Drug Discovery—comments on his partnership with the Immune Disease Institute at Harvard University: “[we wish to] capitalize on their science and on our ability to develop drugs…in a way that is mutually beneficial—certainly for society but also for the principal investigator and the organization” [6]. Admittedly, the motivations of each party may not always align. For instance, the desire of academics to publish their research may conflict with the industry’s wish to protect proprietary information for marketing purposes. Nonetheless, the benefits of an academic-industrial alliance generally outweigh its potential disadvantages, and these collaborations are making an impact on the global scale. In March 2011 Europe witnessed the launch of OncoTrack, a five year, $35.6 million project to evaluate and implement new techniques in the treatment of colon cancer [7].

The second, critical barrier between bench and bedside is the inefficiency of clinical trials, and their associated misconceptions. While trials are capable of granting patients the most scientifically advanced treatments available, they fail to attract more than 5% of adults diagnosed with cancer each year [8]. One recent study at the Department of Radiation Oncology explored reasons for low clinical trial participation rates, revealing noteworthy trends amongst certain cohorts of the population [9]. In this particular study, minority groups were 12% more likely to decline participation than non-minority groups. This finding is attributed to possible mistrust in the healthcare system, exacerbated by the lack of minority physicians who might help overcome said mistrust.  Another surprising finding revealed that married patients were more likely to decline participation than single patients. Because consent forms for cancer clinical trials are notoriously lengthy (on the order of 50 pages) and explicit (listing in detail every potential side effect, in many cases including death), they are thought to elicit spouse dissuasion. This attitude might be symptomatic of a larger misunderstanding of the comparative benefits and disadvantages of clinical trial participation, making effective, intuitive liaisons between researchers and the general public all the more pressing.

The National Cancer Institute (NCI) has proven instrumental in facilitating clinical trial participation (one of its many services) but is not perfect by any means. A 2010 report by the Institute of Medicine outlines several suggestions for improvement [10]. For one, the report recommends a tighter methodological uniformity amongst clinical trials, which would facilitate subsequent “comparative effectiveness studies” [11]. These studies are designed to draft an informative hierarchy of the most efficient clinical treatments. Moreover, in order to ensure the broadest applicability of trial results (considering the inconsistent features of different cancers and the highly variable genetic makeup of distinct individuals), the NCI might expand patient advocacy programs to recruit subjects of diverse backgrounds, and principal investigators may reconsider eligibility restrictions when formulating clinical trial protocols.

Furthermore, the NCI is in the position to advocate better recognition (i.e. pay raises, more generous tenure considerations) of physicians working in clinical trials, and to support emerging physicians (i.e. grants, fellowships), thus encouraging sustained interest in medical research [12].

Finally, the NCI could more aggressively lobby for insurance coverage of non-experimental patient healthcare costs while they are enrolled in clinical trials [10]. Currently, insurance companies widely believe that the expense of putting their clients through clinical trials outstrips that of pursuing traditional medical treatment. However, one 2001 study showed this to be a misconception. In this study, Dr. Thomas N. Chirikos and colleagues examined the hospital billing records for nearly 2,000 cancer patients participating in clinical trials and compared them to those of patients who received regular treatment. “When the researchers adjusted the data to isolate the effect of trial participation alone, the investigators found that in all but one case, there was no statistically significant difference in the costs of care for patients who were enrolled in trials compared to those who were not” [11].

Although particularly worrisome when dealing with serious diseases like cancer, the policy pitfalls that prevent effective research and application can be applied to any medical context. The first step in streamlining the research-healthcare pipeline is to raise awareness, and thereafter, to enact legislation that expedites the development pathway from research labs to hospitals— resulting in one that is efficient, yet still adheres to acceptable standards of ethics and scientific rigor.

References:

1. Loren R. New Law! The Biologics Price Competition and Innovation Act of 2009. Martindale [Internet]. 2010 Apr. Available from: http://www.martindale.com/health-care-law/article_Edwards-Angell-Palmer-Dodge-LLP_976250.htm
2. Lehman B. The Pharmaceutical Industry and the Patent System. [Internet]. 2003 Dec. Available from: http://www.earth.columbia.edu/cgsd/documents/lehman.pdf
3. Tumulty K, Scherer M. How Drug-Industry Lobbyists Won on Health-Care. Time [Internet]. 2009 Oct 22. Available from: http://www.time.com/time/politics/article/0,8599,1931595-2,00.html
4. Holden C. Research on Contraception Still in the Doldrums. Science [Internet]. 2002 Jun 21; 296:5576. p. 2172-2173. Available at: http://www.sciencemag.org/content/296/5576/2172.full
5. Wellsphere. Pharma Coupons: Enriching the Drug Companies. Wellsphere [Internet]. 2001 Jan 11. Available from: http://www.wellsphere.com/healthcare-industry-policy-article/pharma-coupons-enriching-the-drug-companies/1327876
6. Hughes B. Pharma pursues novel models for academic collaboration. Nature [Internet]. 2008 Aug; 7. p. 631-632. Doi: 10.1038/nrd2648. Available from: http://www.nature.com/nrd/journal/v7/n8/full/nrd2648.html
7. GenomeWeb. OncoTrack Consortium Launches $35.6M Colon Cancer Initiative. GenomeWeb [Internet]. 2011 Mar 11. Available at: http://www.genomeweb.com/oncotrack-consortium-launches-356m-colon-cancer-initiative
8. American Association for Cancer Research. Cancer Policy Issue Briefs. ARC [Internet]. Available at: http://www.aacr.org/home/public–media/science-policy–government-affairs/cancer-policy-issue-briefs/cancer-research.aspx#D
9. Marinucci M. Barriers to Participation in Cancer Clinical Trials: Improvement Recommendations for Missed Opportunities to Address Disparities. Jefferson Health Policy Capstone 5 [Internet]. 2009 Aug 4. Available at: http://aisr3.jefferson.edu:880/ess/echo/presentation/d5349536-a4d5-4c7e-bb05-7b3279450b99
10. Institute of Medicine. A National Cancer Clinical Trials System for the 21^st Century: Reinvigorating the NCI Cooperative Group Program. IOM [Internet]. 2010 Apr 15. Available at:  http://www.iom.edu/Reports/2010/A-National-Cancer-Clinical-Trials-System-for-the-21st-Century-Reinvigorating-the-NCI-Cooperative.aspx
11. National Cancer Institute. Cancer Trials Appear Not to Drive Up Cost of Cancer Treatment. NCI [Internet]. 2003 Jan 27. Available at:  http://www.cancer.gov/clinicaltrials/conducting/developments/notcostly0103
12. Nelson R. NCI Cooperative Group Program in Need of an Overhaul. Medscape [Internet]. 2010 Apr 16. Available at: http://www.medscape.com/viewarticle/720386
13. Varian, H. [photograph] 2008. Available at:  http://www.flickr.com/photos/horiavarlan/4273968004/

Isabelle Boni is a third-year biology and psychology major at the University of Chicago. Please join The Triple Helix Online on Facebook. Follow The Triple Helix Online on Twitter.

It is thus no surprise that the advantages athletes cultivate to win have come under a high level of scrutiny. Whether these advantages are lauded or vilified turns on whether they are perceived as natural or unnatural – that is, fair or unfair. But while the public lauds swimming competitively by the age of six, why does it scorn the use of PEDs? Many would-be figure skating champions begin training on the ice before they have even learned to read. In the world of beauty competitions, coloring one’s hair, reshaping one’s nose or implanting silicone is considered normal and even rewarding. Are PEDs any more unnatural? What, indeed, is natural?

In short, PEDs are not the only performance enhancers in sports. It is not immediately obvious that PED-use is fundamentally different or any more unfair than other enhancers. A wealthy or pushy parent, for instance, could be the difference between success or failure. Golf and tennis players are often endowed with wealthy parents capable of affording the high costs associated with the sport, while baseball players such as Ichiro Suzuki of the Seattle Mariners were hitting baseballs by the age of three in large part due to highly determined fathers. But should overbearing parents be banned as well? Millions of teenagers would probably agree that they should.

PEDs became widely used throughout the sporting world since the 1950s when weight lifters in Russia injected themselves with anabolic steroids. By the end of the decade, elite athletes all over the world had discovered the drugs, and despite stringent testing procedures, PEDs continue to follow the Olympic Games, the Tour de France, Major League Baseball, and other professional and amateur sports. PEDs can range from anabolic steroids, human growth hormone, sedatives, to even certain types of painkillers. Anabolic steroids are by far the most common drugs in the sporting world as their short-term benefits are relatively easy to replicate: strength and stamina are significantly enhanced. Anabolic steroids increase the production of proteins and substantially reduce recovery time by blocking the effects of the stress hormone cortisol on muscle tissue [1]. They also affect the number of cells that develop into fat-storage cells by favoring cellular differentiation into muscle cells instead, and they reduce fat by increasing the body’s base metabolic rate [2]. Steroids are membrane permeable and thus operate by affecting the nucleus of cells directly, penetrating the membrane of the target cell and binding to the androgen receptor located within the cytoplasm [3]. The compound hormone-receptor then diffuses into the nucleus, where it alters the expression of genes or activates processes that send signals to other parts of the cell [4].

While the benefits are enticing, many argue that the risks of biological alterations caused by PEDs heavily outweigh their benefits. For athletes, the risks range from mood swings to infertility [5]. For the pastimes they participate in, the risks involve an erosion of credibility and confidence in the idea of fairness, the foundation of all competitive sports.

But are competitive sports truly fair? The fact is that there has always been a certain degree of unfairness inherent in athletic contests. The general consensus in the scientific community is that elite athletic performance is a complex fitness phenotype substantially determined by genetic potential [6]. Research over the past decades has revealed a strong correlation between the natural genetic makeup of athletes and elite sporting status. Although training and nutrition significantly contribute to sporting performance, such factors alone are not sufficient; most students at the University of Chicago, for instance, will never achieve elite athlete status however hard they train. Athletes endowed with such genetic traits as cardio-respiratory and skeletal muscle efficiency will inevitably perform at higher levels of endurance [7].

For example, several studies have shown that sprint and endurance performance is affected by different genotypes of the gene encoding angiotensin-converting enzyme (ACE). The ACE gene has two alleles, termed “I” and “D;” the I allele is associated with lower ACE activity resulting in endurance [8] and efficiency of muscle contraction [9]. An increased frequency of the ACE I allele has been observed in elite endurance athletes [10]. In contrast, an increased frequency of the ACE D allele is associated with elite sprint performance [11]. It is likely that there is a trade-off between sprint and endurance traits as performance in the 100 meter sprint (which relies on explosive power and fast fatigue-susceptible muscle fibers), is negatively correlated with performance in the 1,500 meter race (which requires endurance and fatigue resistant slow fiber activity) [12].

Genetically, it is inevitable that some athletes simply perform better in certain areas of athleticism or are capable of enduring pain and physical stress more efficiently than their opponents. The use of PEDs, then, may be an attempt to provide a level playing field amongst disparate opponents. It may, on the other hand, deepen the already existing performance gap among athletes by favoring those with access to wealthy parents, coaches and sponsors. In any case, the question of whether PEDs are any more unnatural than the existing genetic gap still remains. In a world where athletes are pressured to do anything and everything to win, the unfair and unnatural boundaries of competitive advantages continue to be pushed.

References:

1. Singh R, et al. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003. p. 144.
2. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men – a clinical research center study. The Journal of Clinical Endocrinology & Metabolism. 1996. http://jcem.endojournals.org/cgi/content/abstract/81/10/3469.
3. Lavery DN, McEwan IJ. Structure and function of steroid recepto AF1 transactivation domains: induction of active conformations. The Biochemical Society. 2005. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1276946/?tool=pubmed.
4. Cheskis BJ. Regulation of cell signalling cascades by steroid hormones. J Cell Biochem. 2004. http://www.ncbi.nlm.nih.gov/pubmed/15352158.
5. Pagonis TA, et al. Psychiatric side effects induced by supraphysiological doses of combinations of anabolic steroids correlate to the severity of abuse. Eur. Psychiatry. 2006. p. 551–62.
6. MacArthur DG, North KN. Genes and human elite athletic performance, http://www.springerlink.com/content/kdrvbp3xlv1tct22/. February 22, 2005.
7. Montgomery HE, et al. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation. 1997. p.741–747.
8. Williams AG, Rayson MP, Jubb M, et al. The ACE gene and muscle performance. Nature. 2000. p. 614.
9. Gayagay G, Yu B, Hambly B, et al. Elite endurance athletes and the ACE I allele—the role of genes in athletic performance. Hum Genet. 1998. p. 48–50.
10. Niemi AK, Majamaa K. Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. European Journal of Human Genetics. 2005. http://www.nature.com/ejhg/journal/v13/n8/full/5201438a.html.
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Evan WooSuk Choi is a third-year student at the University of Chicago pursuing a double major in political science and economics. Please join The Triple Helix Online on Facebook. Follow The Triple Helix Online on Twitter.