In order to give a sense of scale to the issue, one could compare availability of medical care in India to that in the United States. By the most recent data, the United States has 2.672 doctors per 1,000 people, and 3.1 hospital beds per 1,000 people. India, on the other hand, has a mere 0.599 doctors and 0.9 hospital beds per 1,000 people.1 Judging from those numbers, India would need almost 2.4 million new doctors and over 2 million more hospital beds to reach the same proportions as the United States.

This shortage stems from a lack medical infrastructure and difficulty in accessing available resources, and is especially felt in rural India. In a 2008 study focusing on the Ujjain district, researchers found that about 61% (almost 1.1 million people) of that district’s population lives in what is considered rural areas, served by only 39 professionally qualified doctors. As a result, those in rural areas turn to unqualified providers that the researchers refer to as “quacks”. Due to the shortage of professionally qualified doctors, the need for any form of medical care is extremely high. This results in the presence of 1,666 of these “quacks” in the Ujjain district. The unqualified providers often seek to meet the simplest needs of the patients who come to them, which is most often alleviating symptoms enough for patients to return to work. However, these types of treatments most often either leave the problem unsolved or require further treatment at a later date. Therefore, the care delivered in rural areas is frequently either insufficient or even deleterious for the patient. This, in turn, frequently produces a skewed view of standard of medical care.2

India has recognized that the shortage stems from an insufficient medical education system. India responded by creating a sprawling system of medical education that produces 31,000 doctors each year. Even at this prodigious rate, it would take several decades to close the gap between the need and the current supply of doctors.3 However, what normally happens is that the brightest new doctors get recruited to overseas positions, most frequently in the United Kingdom. This is known as brain drain, and besides losing promising doctors, many researchers go overseas, as India has an unproductive research network which has not yet yielded a single Nobel laureate in medicine.4

India has been seeking to deal with the shortage for years by increasing the number of medical schools. Since its independence, India’s medical schools have consistently increased in number, with 86 schools in 1965 swelling to 143 schools in 1990. Between 1990 and 2009, 128 more medical schools opened, bringing the total number of schools to 271 in 2009.5This drastic increase has overwhelmed both the available teachers and the educational and medical infrastructure, creating schools that are both underequipped and understaffed. Many lack dormitories and cafeterias for students, and some lack labs for complex procedures.

These schools are supposed to be overseen by the Medical Counsel of India (MCI), which is responsible for ensuring the quality of both the infrastructure and the professors at India’s medical institutes. However, many institutions do not meet the standards enumerated by the counsel, and therefore have developed a process of window dressing, where schools share equipment or professors during inspections in order to give the impression of compliance. There have been accounts of prestigious colleges adding names of non-existent professors to their lists. The scramble for all these medical schools to meet MCI requirements, and to even keep these schools running, creates a gargantuan demand for competent professors.5 Since demand is high, it is difficult for schools to retain faculty over the long term, which creates a lack of continuity in both the school’s practices and its policy.

The plethora of new and underequipped medical schools will create more doctors and healthcare professionals on paper, but will lower the quality of the doctors produced, further exacerbating the preexisting shortage. So, while attempting to alleviate a shortage of doctors, India has managed to create a completely new crisis on top of the preexisting one. In this case, the response could alleviate the symptoms but is creating a whole new set of additional problems.

References

1. “CIA World Factbook,” Central Intelligence Agency, Accessed 1/25/2012
2. Katrak, Homi. “Measuring the shortage of medical practitioners in rural and urban areas in developing countries: a simple framework and simulation exercises with data from India,” The International Journal of Health Planning and Management, No. 23 (2008): 93-105.
3. Yathish, TR. “How to Strengthen and Reform Indian Medical Education System: Is Nationalization the Only Answer?” Online J Health Allied Scs. 2009;8(4):1 http://www.ojhas.org/issue32/2009-4-1.htm
4. Tulenko, Kate. “Countries Without Doctors?” Foreign Policy, June 2010. http://www.foreignpolicy.com/articles/2010/06/11/countries_without_doctors
5. Deshpande Srinivas Ramachandra & Deshpande-Naik Gayathree Srinivas. Crass commercialization and corruption of the Indian medical education system and the resultant decay of the Indian Health Education in the last two decades. A case for urgent international review and monitoring.” Electronic Pysicician 2009, 1:9-16, http://www.ephysician.ir/2009/9-16.pdf
6. Image: Witlin, Ray. “World Bank: Medical Checkup.” Flickr, last modified January 7, 2008, http://www.flickr.com/photos/worldbank/2182854821/

Ted Gannett is a first-year student at the University of Chicago majoring in Chemistry and minoring in East Asian Languages and Civilizations. He also volunteers with Health Leads Chicago, a volunteer organization that works in several Chicago hospitals. Follow The Triple Helix Online on Twitter and join us on Facebook.

You’re old enough to feel like a child

When you cry.

You’re father died in 2005, you said

(by way of explanation)

To the undercover cop.

He said your small arms raged

Against his chest, he said

He wasn’t fast enough:

You drove a blade into your belly.

What is your name?

The gauze dressing oozes blood, and

We howl through red lights with sirens.

At least give me a name to put down –

Not for billing purposes, just

So I don’t have to write ‘Denied.’

I’ll be holding pressure by your side,

And the ETA is 5, 10 min.

We have a little while.”1

Sarah Buckley’s poem “Denied” skillfully highlights the intersecting roles of healthcare, politics, and socioeconomic iniquities in the context of medical practice. A personal and informative look at the causal roles of poverty and prostitution to produce self-harm, “Denied” is a gripping example of the creativity within the medical humanities. As part of a growing appreciation for human-centered medicine, the medical humanities aim to place what has become a biologically dominated practice into a broader context, while raising important questions about the role of the doctor, curing versus caring, the value of empathy, and an accompanying host of provocative issues that arise partially from increasing distrust in the U.S. medical system.2

While media reports of the healthcare debates tend to focus on insurance coverage, payment and distribution, the quality of healthcare offered is essential to healthcare reform. Contemporary issues such as public distrust in medicine and “overspecialization; technicism; over-professionalism; [as well as] insensitivity to personal and sociocultural values” should be equally alarming and call for critical attention.3 One way to analyze the current healthcare situation is to look at its historical context. It is widely held that many current realities in medicine can be traced to their origins in the Flexner report, which revolutionalized medical training more than a century ago.

In 1910, Abraham Flexner, a former schoolmaster, was commissioned by the American Medical Association’s Council on Medical Education (CME) to assess US medical education. After visiting all 155 existing North American medical schools at the time, he was struck by the enormous variations in scientific understanding and the slack standards of these predominantly for-profit trade schools. In an attempt to increase rigor and specialization, Flexner suggested four years of medical education, incorporation of medical schools into existing universities, and that admissions to medical school require on minimum, a high school diploma and two years of college education devoted to basic science. CME’s enforcement of the report’s recommendations resulted in the closure of over half of the existing medical schools that did not comply with its standards.

The Flexner Report greatly increased standardization of the scientific method, physician quality, income and prestige conferred upon doctors.4 However, Flexner also conflated humans with their biology, arguing that “clinicians must, in short, be impregnated with the fundamental truths of biology” because “the human body belongs to the animal world”.3 While a debatable assertion at the time, the biological foundation of illness has been made a touchstone of modern medicine, and Flexner’s criteria has largely determined today’s scientifically focused pre-medical track and medical school curriculum.

The problem with the Flexner Report for scholars in the medical humanities is its biological centrality. Recognizing that biology as a basis for the treatment of disease is important, Bradley Lewis, professor of cultural studies at NYU, argues that humans are more than biological animals, and therefore require care during illness above and beyond treating biological symptoms.3 Because humans center their lives around meaning, social, emotional, and biological realities work in synchrony to influence our health.

In the 1970s, the scientific notion of medicine was re-examined, which commenced the inauguration of various “human values teaching programs” in medical schools across the US.5 The curriculums of these interdisciplinary courses and their administration were locally decided and remain extremely inconsistent across schools. Although some faculties believe a core curriculum for the medical humanities would create clearer standards, others support localized control. No real consensus on the medical humanities curriculum exists. Still, healthcare began to resist Flexner’s exclusively biological approach. Some proposed that the goals of medicine should be redefined as tending to human suffering instead of treating disease, while others conceptualized the doctor-patient encounter as a “moral relationship”.3 These human-centered ideas would later become the unifying theme of the medical humanities.

Edmund Pellegrino, medical philosopher, summarized the plight of medicine seventy years after the Flexner report was published, criticizing its “too narrow a construal of the doctor’s role; too much “curing” rather than “caring”; not enough emphasis on prevention, patient participation, and patient education; too much economic incentive; a “trade school” mentality; over-medicalization of everyday life; inhumane treatment of medical students; over-work by house staff; and deficiencies in verbal and nonverbal communication”.3

The emphasis on objectivity following the Flexner Report ignored the subjective experience and created a way of life out of touch with human needs, human goals, human desires, and human suffering. In order to address these issues, Pellegrino suggested that “illness is an altered state of existence arising out of an ontological assault on the humanity of the person who is ill”.6 In short, the ill person loses freedom of physical movement, lack of knowledge to heal oneself and autonomy over the self, and consequently must redefine his or her self-image to match this newfound vulnerability. The question for medical practitioners then becomes how to heal both biologically and psychologically.

The 1970s, 80s, and 90s witnessed an upsurge of interest in the medical humanities and “narrative medicine”, the current umbrella term for “a range of contemporary efforts to humanize medicine and counterbalance the many problems of Flexner’s model”.3 Narratives in medicine encourage empathy, allow for the construction of meaning, encourage a holistic approach to management, and are grounded in experience and self-reflection, thereby validating the patient while challenging the physician to be more of an empathetic healer than a technocrat.7

The range of contemporary topics covered in the medical humanities is impressive. A skim through The Journal of Medical Humanities yields an analysis of doctor-patient encounters, a discourse on the constraints of medical ethics, and other captivating titles such as “Psychopathology and Literature”, “Dissecting Dad”, “The Medical-Industrial Complex”, and “Chess & Schizophrenia”. The past forty years have also witnessed the rise of a slew of journals dedicated to the medical humanities, as well as centers in universities dedicated to the teaching of the medical humanities. Notable initiatives include a master’s degree program in Narrative Medicine at Columbia University targeted towards established doctors, nurses, social workers, and therapists, as well as a comprehensive database and directory for the medical humanities established by New York University.

While many medical schools have already integrated the medical humanities into their medical school curriculum, the future of the field looks more promising than ever as increasing numbers of healthcare professionals recognize the need for less impersonal interactions in the hospital setting. Thanks to the medical humanities, future medical students have the chance of becoming well-rounded and well-read, just as enthusiastic about Nabokov as about nucleophilic substitution reactions.

References

1. Buckley S. For There is Work to be Done: Poetry and Commentary. J Med Humanit. 2011; 32(3): 245-250.
2. Armstrong K. Distrust of the Health Care System and Self-Reported Health in the United States. J Gen Intern Med. 2006 April; 21(4): 292–297.
3. Lewis B. Narrative Medicine and Healthcare Reform. J Med Humanit. 2011; 32 (1): 9-20.
4. Beck, AH. “The Flexner Report and the Standardization of American Medical Education”, JAMA. 2004; 291 (17): 2139–2140,
5. Wear D. The Medical Humanities: Toward a Renewed Praxis, J Med Humanit. 2009; 30(4):209-20.
6. Pellegrino E. Being Ill and Being Healed: Some Reflections on the Grounding of Medical Morality. Bull N Y Acad Med. 1981; 57(1): 70–79.
7. Greenhalgh T, Hurwitz B. Narrative based medicine: Why study narrative? BMJ. 1999; 318:48-50.
8. Image: Westfall, Greg. Happy. Flickr. JPG, http://www.flickr.com/photos/imagesbywestfall/4311832482/in/photostream/ (accessed 3/1/2012)
9. Image: vaXzine. Pain-map. Flickr. JPG, http://www.flickr.com/photos/vaxzine/2642346629/in/photostream/ (accessed 3/1/2012)

Wujun Ke is a third-year student at the University of Chicago majoring in Comparative Literature. Follow The Triple Helix Online on Twitter and join us on Facebook.

There are two types of cancer vaccines: autologous and allogeneic. Autologous vaccines are made from cancer cells that are taken from the human body, and then reinserted back into the body to mark matching cells as antigens. While autologous vaccines are promising because of their adaptability to the cancer patient, they are limited by their steep price and chance that scientists may not be able to extract cells from a cancerous growth. Allogeneic vaccines are currently more prevalent than autologous vaccines since they are made from an already cultivated batch of cancerous cells from previous clinical trials; however, the vaccine’s effects may only be temporary because of the adaptable nature of cancer cells.1 Having such vaccines allows for proactive care, which can attack the disease at its source. Now patients can effectively have their immune system ready for cancers, especially if they are thought to have a genetic predisposition for the disease.

These treatments have already started to become mainstream with autologous vaccines such as Panvac and Gardisil hitting the market. Panvac is a type of vaccine that targets the body’s own immune system as a way to fight cancer. The vaccine consists of the patient’s own cells that have been modified by adding viruses that code for proteins associated with cancer cells.2 The body’s own T-Cells are able to recognize these proteins as antigen markers and hone in on cancerous cells. Another vaccine called Gardisil has preventive effects on certain kinds of cancer. It targets HPV antigens that are proteins commonly associated with cancerous growths. These proteins are used in the laboratory to make four different types of “virus-like particles,” or VLPs, that correspond to HPV types 6, 11, 16, and 18.3 Meanwhile, at the University of Pennsylvania, the research pipeline is fully in effect with a breakthrough in a vaccine against Chronic lymphocytic leukemia (CLL), which is a cancer of the white blood cells. This CLL vaccine has been able to send a large proportion of its patients’ cancers into remission for more than a year and could prospectively be changed in order to target other cancers.4 Therefore, cancer vaccines begin treatment at the inception of the disease, but are evolving to the next step of eliminating the cancerous cells that already exist as well. The potential growth in the field is almost limitless and should appear to continue as long as interest remains in the long-term results of vaccines.

Although researchers have identified many cancer-associated antigens, these molecules vary widely in their capacity to stimulate a strong anticancer immune response. Therefore, there remain many avenues to look into for future research. Two major areas of research aimed at developing better cancer treatment vaccines involve strengthening current vaccine-based treatments and probing for more effective protein markers. Researchers are also looking for ways to combine multiple antigens into a single cancer vaccine for more comprehensive results.5 However, one of the most promising fields of cancer vaccine research aims at better understanding the basic biology underlying the interaction between the immune system and cancer cells. New technologies are being created as part of this effort. One new type of imaging technology allows researchers to observe killer T cells and cancer cells interacting inside the body.6 Researchers are also trying to identify the mechanisms by which cancer cells evade or suppress anticancer immune responses.7 Ultimately, this will help fight the disease after the initial usage of vaccines and further prolong a patient’s life. For example, some cancerous cells produce chemical signals that attract white blood cells known as regulatory T cells, or Tregs, to a tumor site. These Tregs are used to suppress the destructive activity of killer T Cells, which would normally be able to identify certain cancerous cells. It has been suggested that combining cytokine suppressor drugs, which allow for a greater concentration of active killer T Cells, with a cancer vaccine would create the most effective solution.8 Therefore, despite the many varieties of cancer, there appears to be just as much diversity in the vaccines that intend to end them.

Slice of the brain taken with positron emission tomography. Red areas indicate accumulated tracer substance, while blue areas represent areas of low tracer substance. Source: Wikimedia Commons.

In the long term, cancer research will revolutionize both the cost structure and the way in which patients are treated. However, the effects of these changes on doctors are something that cannot be overlooked. In order to better frame cancer from a doctor’s perspective, I had the chance to sit down with one of the finest minds in the field of cancer research and medical care, Dr. Richard Schilsky. Dr. Schilsky has worked at the University of Chicago Medical Center since 1984 and served as chairman of the Cancer and Leukemia Group B (CALGB), the largest and oldest cancer clinical trials group in the United States until 2010. When posed the question of how cancer treatments have changed, he spoke of his own specialization in cancer drugs. For several decades, the drugs used for cancer treatment were non-specific (they were not individualized). The goal of this “cytotoxic chemotherapy” was to destroy cancer cells, yet in the process, it also ended up destroying the surrounding tissue as well. However, Dr. Schilsky reiterated that, “We are still using these drugs but in a more limited way.” For example, he spoke of the increased prevalence of oral drugs that “target the molecular drivers of cancer cells” much like cancer vaccines have been shown to do. The changes in the cancer field as a whole reflect a paradigm shift in order to “understand at the molecular level what makes the cancer tick.” Furthermore, Dr. Schilsky spoke of the “complementary” processes that aid in cancer detection. Most scanning techniques of the human body for the disease are anatomical, such as MRI (Magnetic Resonance Imaging) and reflect the actual contours of the scanned area. However, with scanning methods such as the PET (Positron Emission Tomography), there is hope to more readily see the effects of treatments on areas with cancer. The PET scan for example is able to pick up on FDG molecules, which are effectively glucose-type molecules with a radioactive-Fluorine atom. Cancer cells are more active than the average cell so they take up more glucose and, in the process, FDG that can be monitored by the scan. These tests can provide information on whether the mass is still present and its relative size.

Doctors themselves have also had to adapt to the new findings in cancer. The effects of cancer are multifarious in the medical field. The expected growth and higher demand for cancer vaccines and other similarly targeted treatments over previous cancer treatments may adversely affect cancer chemotherapy and radiation fields. Dr. Schilsky emphasized a change in the reimbursement for oncologists. Previously oncologists were paid mainly for buying, prescribing, and administering cancer treatments. However, this system is being rethought as such treatments are not useful and their counterparts can be fulfilled without the need for a doctor present. “I no longer have to be the one dispersing the drug as it has been for intravenous chemotherapy,” said Schilsky. In addition to the shift in reimbursement, medical schools and residency programs will also change to teaching the usage of newer methods of treatment. However, “medical schools are in a way the last responders,” to changing standards in cancer care due to the lengthy approval process, Schilsky explained.

The prognosis of cancer is slowly changing and with it comes hope for the future. “We are making more progress now than in any other time in our history,” as Dr. Schilsky aptly puts it. We have come a long way in treating cancer and have a ways to go yet the discoveries that keep pouring in allow for an optimism unheard of decades ago. Dr. Schilsky emphasized this when he said “A person diagnosed with cancer in the 1970’s had a 50/50 chance of surviving. Today they have a two thirds chance.” We have been able to contain the spread of cancer and save lives, yet our ultimate goal is to eradicate this disease, which begins with a new age in its treatment.

References:

1. American Cancer Society, “Cancer Vaccines.” Accessed January 17, 2012. http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/immunotherapy-cancer-vaccines.
2. Carollo, Kim. “Cancer Vaccine Shows Early Promise.” Accessed January 17, 2012. http://abcnews.go.com/blogs/health/2011/11/08/cancer-vaccine-shows-early-promise/
3. Lowy Dr., Schiller JT. “Prophylactic human papillomavirus vaccines.” Journal of Clinical Investigation 116, no. 5 (2006):1167–1173
4. Begley, Sharon. “Could This be the end of Cancer?” Accessed January 17, 2012. http://www.thedailybeast.com/newsweek/2011/12/11/could-this-be-the-end-of-cancer.html
5. Schlom J, Arlen PM, Gulley JL. “Cancer vaccines: moving beyond current paradigm.” Clinical Cancer Research 13, no. 13 (2007): 3776–3782
6. Ng LG, Mrass P, Kinjyo I, Reiner SL, Weninger W. “Two-photon imaging of effector T-cell behavior: lessons from a tumor model.” Immunological Reviews. 221 (2008):147–162.
7. Garnett CT, Greiner JW, Tsang KY, et al. “TRICOM vector based cancer vaccines.” Current Pharmaceutical Design 12, no. 3 (2006): 351–361
8. Zou W. “Regulatory T cells, tumour immunity and immunotherapy.” Nature Reviews Immunology 6, no. 4 (2006): 295–307.
9. US Government. “Vaccine in leg.” Wikimedia Commons. 15 Apr. 2005. http://commons.wikimedia.org/wiki/File:Vaccine-in-leg.jpg (accessed February 5, 2012).
10. Langner, Jens. “PET image.” Wikimedia Commons. 2010. http://commons.wikimedia.org/wiki/File:PET-image.jpg (accessed February 5, 2012).

Jawad is a first-year student at the University of Chicago majoring in economics and biological sciences. He has interests in both medicine and financial consulting and hopes to apply his passion for both of these topics in his articles. Follow The Triple Helix Online on Twitter and join us on Facebook.

A bio-engineered heart-valve, a small example of the top-down approach. Courtesy of Wikimedia Commons.

Since the development of in-depth stem cell research and particularly the ability to induce pluripotency – the ability to differentiate cells into many or all cell-types – the promise of generating replacement tissues and organs for patients has been a virtual “holy grail” for the field of regenerative medicine. Many advances have been made in transforming somatic body cells into pluripotent stem cells, and pathways have been uncovered to differentiate those cells into almost any known cell type in a controlled manner. However, these cells need to be organized into a defined structure for the engineered tissue to be of any use for transplantation. Two conflicting camps have advocated for distinctly different methods, one using a framework of biodegradable polymer treated with drugs to encourage cell growth within the matrix, and the other using direct cell “printing,” which deposits individual cells to create complex structures. Both of these methods have their merits, and the argument essentially boils down to building top-down versus bottom-up – there is, however, a lot of common ground between the two.

As early as the late 1990’s, the most popular idea for organizing cells into an organ was the top-down scaffolding concept. This approach involves developing some biocompatible structure on which seeded cells could grow and differentiate in a controlled way. This idea was in development in multiple forms before the big stem cell boom — when it became possible to reprogram somatic cells to stem cells instead of finding a donor — when it became possible to reprogram somatic cells to stem cells instead of finding a donor – and subsequently became massively popular as the potential to combine the potency of stem cells with the organization of a scaffold electrified the regenerative medicine field. Numerous methods of producing a scaffold have since been developed. The most organic, though perhaps least clinically relevant, is a method that involves de-cellularizing a cadaveric organ using detergents delivered via the organ’s vasculature.4 After this, the remaining connective tissue structure is re-populated with cells. This method has demonstrated a degree of potential: one group reported success using neonatal rat cardiac cells to repopulate an adult heart to create a functional organ, and another group used a similar procedure on an adult mouse kidney and repopulated it with murine embryonic stem cells, with similar success.4 While these experiments present the promise of scaffolds in tissue engineering, they also come with severe drawbacks, namely the need for an existing cadaveric organ (which in the clinical case would have to come from a different individual than the patient, introducing complications to the transplantation procedure).

To address these issues, scientists have been pursuing multiple avenues for the generation of artificial, biodegradable polymer scaffolds, using techniques ranging from photolithography to syringe-based gel deposition to freeform solid fabrication. However, most of these methods lack important features, such as internal architecture resolution, which allows for more complex internal structures to develop (such as, very importantly, vasculature), flexibility or simply the capacity for “high-throughput” production, the ability to produce tissue quickly and efficiently.1 It has proven difficult to find a balance between the ability to carefully define intricate internal structures, defined by multiple cell types, and the fabrication time necessary to produce a prototype which can then be seeded with organs. Furthermore, many cell-types (typically mesoderm-derived types, like muscle cells) often require a biomechanical force to be applied to promote cell growth and organization, which is something that current polymer scaffolds cannot address.8 As a result of these drawbacks, scaffolding methods have had the most success in tissue generation that involves relatively simple layouts, such as the engineered cartilaginous tissue developed by Feng-Huei Lin’s group for the potential treatment of osteoporosis.5

An alternative camp developed sometime around 2003, when Roger Markwald and Thomas Boland modified a commercial inkjet printer to print protein solutions and individual cells on glass and gel surfaces.2,6 The software they developed to accompany their custom cell-printer allowed them to deposit cells on a gel in pre-defined, high resolution patterns with very high cell viability. Further modifications to the system by subsequent researchers allowed for printing inside of a three-dimensional block of gel to create intricate cell structures, internal and external, of varying cell-types, with very high viability and cell-cell fusion to create solid surfaces of tissues. Using this method, very intricate organ structures can be designed using the computer software and then printed using “bioinks” made from partially or fully differentiated cells and proteins that promote cell adhesion.2 The drawback, however, is the time necessary to produce the organ itself, since the process involves building the organ cell by cell, layer by layer, which is a lengthy process for something as complex and large as an adult heart, for instance. Other groups have been experimenting with alternate printing methods to improve printing speed and resolution further, such as Fabien Guillemot’s group, which used laser assisted printing to print slightly faster with increased cell density and resolution depending on the laser’s scanning frequency (how rapidly it passes over the surface to be printed).3 The scaling and throughput issue intrinsic to this approach to organ building is a continuous source of new work in the field, with new innovations coming in by the droves.

Finally, Ulrich Schubert’s group has arrived at an unconventional middle-ground between these two methods: organ weaving. Their method involves using suturing threads that are coated in an alginate gel with suspended cells, and then taking multiple threads, coated with either the same or different cell types, and literally weaving them around a base structure.7 They experiment using gradients of cell types based on the pattern used in the weave, and in all cases achieve very high cell viability. Their method combines the high-throughput ease and speed of artificial scaffolding with the ability to better control the resolution and cell types used like with cell-printing. This is a unique and very promising approach to tissue engineering.

As stem cell technology advances further, making patient-specific stem cells easier to make, maintain, and differentiate into target cell types, tissue engineering is evolving to keep in step with the demands of the clinical promise of custom organs. Though some critics are concerned that in vitro organogenesis is the first step on the “slippery slope” of human cloning, the promise for highly beneficial clinical application under careful and insightful oversight is enough to calm most opponents’ fears. As the technology develops, we see less conflict between the top-down and bottom-up approaches, and instead see a harmonious combination of the two approaches, melding the benefits of both to create new avenues for successful organ growth in the future.

References:

1. Boland, Thomas, et al. “Advances in Tissue Engineering: Cell Printing.” Journal of Thoracic and Cardiovascular Surgery 129, no. 2, (2005): 470-472.
2. Boland, Thomas, et al. “Cell and Organ Printing 1: Protein and Cell Printers.” The Anatomical Record, Part A 272A, (2003): 491-496.
3. Guillemot, Fabien, et al. “Laser Assisted Bioprinting of Engineered Tissue with High Cell Density and Microscale Organization.” Biomaterials 31, (2010): 7250-7256.
4. Kobayashi, Eiji, et al. “Kidney Organogenesis and Regeneration: A New Era in the Treatment of Chronic Renal Failure?” Clinical Experimental Nephrology 12, (2008): 326-331.
5. Lin, Feng-Huei, et al. “A Highly Organized Three-Dimensional Alginate Scaffold for Cartilage Tissue Engineered Prepared by Microfluidic Technology.” Biomaterials 32, (2011): 7118-7126.
6. Markwald, Roger, et al. “Organ Printing: Computer-aided Jet-based 3D Tissue Engineering.” Trends in Biotechnology 21, no. 4, (2003): 157-161.
7. Schubert, Ulrich, et al. “Organ Weaving: Woven Threads and Sheets As a Step Towards a New Strategy for Artificial Organ Development.” Macromolecular Bioscience 11, (2011): 1491-1498.
8. Stoica, Adrian. “Robotic Scaffolds for Tissue Engineering and Organ Growth.” NASA Tech Briefs. Jan 23, 2012. http://www.techbriefs.com/component/content/article/10747.
9. HIA. “Herzklappe.” Wikimedia Commons. Dec. 2, 2010. http://en.wikipedia.org/wiki/File:Herzklappe.JPG

Aleks Penev is a third year student at the University of Chicago majoring in Biology with a minor in Computer Science. He is also currently doing research with induced pluripotent stem cells and hopes to extend his research focus into the translational aspects of patient-specific organogenesis and transplantation. Follow The Triple Helix Online on Twitter and join us on Facebook.

Gene patenting is a broad term referring to the patenting of either a process that involves isolation of DNA or a chemical substance related to DNA.  This controversy first surfaced in the public arena in the spring of 2000, when the scientific world entered a ground breaking phase.  Two independent organizations announced that they had successfully mapped the human genome.  The Human Genome Project, as it is known, has redefined the capabilities of scientific research.  With such a vast array of information at scientists’ fingertips, the potential discoveries were endless.  However, shortly thereafter, private and public organizations submitted a deluge of patent requests for genes and small pieces of gene sequences [4].  Thus, a new issue of intellectual property over public health plagued the scientific and legal communities.

Early criticism of gene patenting revolved around the basic principles of obtaining patents.  A patent grants the right to exclude others from making, using, and selling the invention for a limited term of 20 years [5].  The USPTO judges a patent application on four criteria.  In order to be patentable, an invention must be useful, novel, non-obvious, and have an intended use.  In other words, the invention must be practical, original, not easily reproduced by someone trained in the relevant area [5], and the inventor must detail the creation and intended use of the invention.  Based on these conditions, physical products of nature are not patentable.  Logic implies that because scientists have only isolated something that already exists in nature, they have therefore not directly invented or produced anything.  However, patent applicants have asserted that since the DNA or genes that they wish to patent have been isolated from cDNA, complementary DNA, which does not naturally occur in nature, and rather it is a product of the laboratory, such genes are patentable.  In fact, intellectual property of genetic information dates back to the 1980 Supreme Court case Diamond v. Chakrabarty. The Supreme Court ruled that genetically engineered bacteria could be patented [4].  As a result, companies perceived lab-altered genetic material as intellectual property, in turn, the USPTO began granting patents for isolated segments of human genes and related genetic testing.

By gaining a gene patent, companies reserve the sole right to pursue research and development surrounding that specific genetic sequence.  Such monopolies of gene sequence research essentially translate into total control of gene function and disease related-research such as treatment development, and detection of malignant genes.  Thus, gene patenting extends far beyond a nucleotide code and stretches into the public health arena.

Supporters of gene patenting believe that it fuels scientific research and development.  They claim that because researchers are rewarded for their discoveries with patents, the royalty money can be used to further support their research. In addition, they assert that monopolies of certain genes prevent the waste of funds and effort [6].  Finally, because the USPTO requires a detailed explanation of the invention so that it could be made and used by others, the scientific community’s knowledge is increased.  Many say that without patents, scientists would resort to secrecy in order to ensure sole access to a new product or discovery.  With patents, however, all information is open and shared throughout the world.  The argument for gene patenting is also derived from facts about commercial patents.  Normally post-invention development costs are significantly greater than pre-invention research costs.  Based on this principle, organizations become reluctant and even unwilling to make substantial investment without protection from competition [4].  Companies therefore, tend to pursue research and development if they perceive a high probability of a profitable return.  Gene patenting provides the framework for such quasi-guaranteed successful turnout. Henceforth by eliminating the scientific competition, companies feel comfortable investing in research and development and thus gene patenting propagates scientific discovery. Patents thus protect the financial investments of companies.  In general, patents are generally considered to be very positive and many believe gene patenting to be no different.

There are however, many opponents to gene patenting. Critics say that patenting such discoveries is inappropriate because it places undue control over the commercial fruits of genome research [6].  In fact many patents actually grant companies the rights to future mutations discovered on a gene [8].  Similarly, companies often patent multiple parts of a genome sequence, such as a gene fragment, the gene, and the protein.  This patent ‘stacking’ puts financial strain upon researchers and allows patent holders to monopolize certain genes [9].  Other scientists examining the gene must then pay the patent holder for each patent, while just utilizing the one genomic sequence. This limits the research potential for scientists and thus the development of new innovations. They believe that science will advance more rapidly with an unlimited exchange of research ideas, in essence without patents.  Scientists are contrastingly swayed by the law of intellectual property which states that without exclusive rights no one will be willing to invest in research and development [4].  Gene patenting also directly affects individuals outside of the scientific field.  If scientists need to pay more to perform research, their eventual findings and inventions will cost more as well.  Thus the cost of pharmaceuticals, biotechnology, and other science discoveries will increase dramatically [9].

Gene patenting actually extends far beyond the DNA itself.  As disease genes are identified, gene tests are then developed to screen for the gene in humans who may be at risk for that disease.  Such tests are eligible and usually become patented by the gene patent holder.  Royalties must therefore be paid to patent holder each time the tests are administered.  Gene patents can make genetic testing prohibitively expensive and thus unavailable to deserving patients [4].  This argument has come to fruition with the Association for Molecular Pathology, et al. v. United State Patent and Trademark Office, et al. case.  Women, with a family history of breast and ovarian cancer, often undergo genetic testing for cancer-related mutations in the BRCA gene to determine their risk of developing those diseases.  This invaluable information helps women decide on a plan of action be it increased observation or preventive mastectomies or ovaries removal [7].  However, Myriad’s gene patents give the company the exclusive right to perform BRCA genetic testing.  Several negative consequences for patients ensue: many women cannot afford the $3,000 or more Myriad charges for the test; patients are prevented from getting second opinions on their test results, such as with Genae Girard; and patients whose tests come back with inconclusive results, do not have the option to seek additional testing elsewhere [8].  As Sandra Park, staff attorney with the ACLU, said “The patents on the BRCA genes block women’s access to medical information necessary for making vital health care decisions, impeding their control over their own bodies.” [8] This lawsuit combines patent law, medical science, breast cancer activism and an unusual civil liberties argument in ways that have made it a landmark case. [3].

On March 29, 2010, Judge Robert Sweet ruled against Myriad Genetics.  Stating that Myriad’s patents did not display “markedly different characteristics from what is found in nature” [11], his verdict invalidated many of those patents.  Yet despite this ruling, the United States continues to grant gene patents.  Most recently, Myriad Genetics has obtained a new gene patent for the pancreatic cancer gene, PALB2. [12]

The limiting nature of gene patenting threatens to place the United States behind other countries.  Rulings in 2004 by the European Patent Office eliminated U.S. patent jurisdiction in Europe.  Now while U.S. scientists are forced to pay fines or stop research altogether, other researchers around the world have free access to the patent information, via internet databases, and can examine them without any penalties [10].  While the future of gene patenting in the United States remains uncertain, the European Union has recently taken decisive steps limiting the propagation of gene patents.  In the European Union, the question of gene patents’ originality and inventiveness has prompted many to support a decrease in the number of gene patents [10].

In conclusion, the dilemma over issuing patents for genetic reasoning is an uncharted territory.  The unrequited question remains is genetic discovery novel or is it simply the uncovering of that which already exists in nature.  The direction that the US has taken in comparison to the European Union serves as a call to arms for scientists opposing gene patents. They cite the EU as a pioneer in unrestricted scientific communication and the recent ruling against Myriad Genetics as ignition for their cause.  Additionally, gene patenting raises a moral issue; many believe that gene patent holders, despite the USPTO’s ruling, are actually being allowed to patent a part of nature.  In contrast, many argue that without gene patents scientific progress would stagnate because companies would no longer feel confident investing in an unguaranteed endeavor [8].  Such a dichotomy within the hearts and minds of scientists creates the friction evident in the gene patenting controversy.  This division has left the world wondering which direction the United States will take in the gene patenting quandary.  The question to ask is what takes precedence intellectual property or public health?

References:

[1] Department of Health & Human Services. U.S. System of Oversight of Genetic Testing: A Response to the Chanrge of the Secretary of Health and Human Services Report of the Secretary’s Advisory Committee on Genetics, Health, and Society. National Institute of Health. April 2008

[2] J. Mullin. Lawsuit Looks to ‘Take Down’ Patents on Human Genes. IP Law & Business. May 15, 2009.

[3] J. Schwartz. Cancer Patients Challenge the Patenting of a Gene. The New York Times. May 12, 2009.

[4] C. Dummer. Genetics and Patenting. Human Genome Project Information. 29 Aug. 2006. <http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml>.

[5] American Medical Association. Guidelines: Gene Patents. AMA: Helping Doctors Help Patients. 19 Feb. 2008. <http://www.ama-assn.org/ama/pub/category/3607.html>.

[6] “‘Owning’ Genes: The Debate Over Patents (sidebar).” Issues & Controversies On File 28 Apr. 2000. Issues & Controversies. Facts On File News Services. <http://www.2facts.com>.

[7] National Cancer Institute. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. <www.cancer.gov>.

[8] American Civil Liberties Union. Gene Patents Stifle Patient Access to Medical Care and Critical Research. May 12, 2009. <www.aclu.org>.

[9]  American Medical Association. Gene patenting. AMA: Helping Doctors Help Patients. 17 Mar. 2008. <http://www.ama-assn.org/ama/pub/category/2314.html>.

[10] A. Coghlan. Europe revokes controversial gene patent, New Scientist (19 May 2004).

[11] A. Kesselheim. M. Mello. Gene Patenting — Is the Pendulum Swinging Back? The New England Journal of Medicine. April 7, 2010.

[12] S. Barton. Myriad Genetics Acquires Exclusive Rights to Pancreatic Cancer Gene Patents From Johns Hopkins. Myriad Genetics Announcements. October 15, 2009.

By Timothy Buckey and Marie Smithgall of Georgetown University. Follow The Triple Helix Online on Twitter & join us on Facebook

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.