Personalized Healthcare: The New Era

Catalyst Volume 7

In medicine, the advent of personalized healthcare is showing that “one size” does not necessarily “fit all.” Specifically, personalized healthcare implies an ability to use an individual’s genetic characteristics to diagnose his or her condition with more precision and finesse. With this development, physicians can select treatments that have increased chances of success and minimal possibilities of adverse reactions. However, personalized medicine does not just imply better diagnostics and therapeutics: it also underlies an ability to better predict any given individual’s susceptibility to a particular disease. Thus, it can be used to devise a comprehensive plan to avoid the disease or reduce its extent.¹ The advent of personalization in healthcare has brought a preventative aspect to a field that has traditionally employed a reactive approach,² where patients are generally treated and diagnosed after symptoms appear.

Medicine has always been personalized: treatment is tailored to individuals following examination. However, the new movement to personalize medicine takes this individualization to the next level. The initial genome sequence was reported by the International Human Genome Sequencing Consortium in 2001; now, scientists can determine information about human physiology and evolution to a detail never before possible, creating a genetics-based foundation for biomedical research.³ Genes can help determine an individual’s health, and scientists can better identify and analyze the causes of disease based on genetic polymorphisms, or variations. This scientific advancement is an integral factor in the personalized healthcare revolution. Technological developments that allow the sequencing of the human genome on a real time scale at relatively low costs have also helped to move this new era of medicine forward.²

The science behind such personalized treatment plans and prediction capabilities follows simple logic: scientists can create a guide by identifying and characterizing genomic signatures associated with particular responses to chemotherapy drugs, such as sensitivity or resistance. They can then use the aforementioned patterns to understand the molecular mechanisms that create such responses and categorize genes based on these pathways and mutations.⁴ Therefore, physicians can compare the genetic makeup of patients’ tumors to these libraries of information. This genetic profiling matches patients with successfully-treated individuals who have similar polymorphisms to provide effective treatment that increases the accuracy of predictions, minimizes allergic reactions, and reduces unnecessary follow-up treatments. For example, efforts are underway to create individualized cancer therapy based on molecular analysis of patients. Traditionally, prediction of cancer recurrence is based on empirical lessons learned from past cases to treat current patients, looking specifically at metrics such as tumor size, lymph node status, response to systemic treatment, and remission intervals.⁴ While this type of prediction has merit, it only provides generalized estimates of recurrence and survival for patients; those with no risk of cancer relapse are often put through potentially toxic chemotherapy. With the new age of personalized medicine, powerful analytical methods, such as protein profiles and dysfunctional molecular pathways, will allow physicians to predict the behavior of a patient’s tumors on a whole new level. Personalized oncologic treatment can plot the clinical course for each patient with a particular disease based on his or her own conditions rather than generalizations from a heterogeneous sample of past cases. This type of healthcare thus improves upon current medicine by creating a subset of homogeneous groups within past cases, allowing physicians to make a more accurate prediction of an individual’s response to treatment.

Additionally, personalized medicine can prevent medical maladies such as adverse drug reactions, which lead to more than two million hospitalizations and 100,000 deaths per year in the U.S. alone.⁵ It can also lead to safer dosing and more focused drug testing. However, this approach is hindered by the nascent nature of genomics technology and the difficulty in identifying all possible genetic variations. Particularly challenging are cases where certain drug reactions result from multiple genes working in conjunction.⁶ Furthermore, opponents of gene sequencing argue that harnessing too much predictive information could be frightening for the patient. For example, patients shown to possess a genetic predisposition towards a degenerative disease such as Alzheimer’s could experience serious psychological effects and depression due to a sense of fatalism; this knowledge could adversely impact their motivation to reduce risks. This possibility has been demonstrated in clinical studies regarding genetic testing for familial hypercholesterolaemia, which measures predisposition to heart disease.⁷ This dilemma leads back to a fundamental question of gene sequencing—how much do we really want to know about our genetic nature?

As of today, personalized medicine is starting to make its mark through some commonly available tests such as the dihydropyrimidine dehydrogenase test, which can predict if a patient will have severe, sometimes fatal, reactions to 5-fluorouracil, a common chemotherapy medicine.⁸ Better known are the genetic tests for BRCA1 and BRCA2 mutations that reveal an increased risk of breast cancer,⁹ popularized by actress Angelina Jolie’s preventative double mastectomy. With these and other such genetics-based tests, the era of personalized medicine has begun, and only time can reveal what will come next.

References

1. Center for Personalized Genetic Medicine. http://pcpgm.partners.org/about-us/PM (accessed Oct 24, 2013).
2. Galas, D. J.; Hood L. IBC. 2009, 1, 1-4.
3. Venter, J. C. et al. Science 2001, 291, 1304-1351.
4. Mansour, J. C.; Schwarz, R. E. J. Am. Coll. Surgeons 2008, 207, 250-258.
5. Shastry, B. S. Nature 2006, 6, 16-21.
6. CNN Health. http://www-cgi.cnn.com/HEALTH/library/CA/00078.html (accessed Oct 24, 2013).
7. Senior, V. et al. Soc. Sci. Med. 1999, 48, 1857-1860.
8. Salonga, D. et al. Clin. Cancer Res. 2006, 6, 1322.
9. National Cancer Institute Fact Sheet. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA (accessed Oct 24, 2013).

How to Live Forever

Catalyst Volume 7

Despite common debate over its desirability, immortality has been an object of fascination for humans since the beginnings of recorded history. Why do we die in the first place? Religious and philosophical explanations abound. Evolution also provides important insights, and we are just beginning to understand the detailed molecular underpinnings of aging. With knowledge, of course, comes application. Whether or not you seek immortality, the technology for significant life extension may become available in our lifetimes.¹ Eventually, with these new advances, every year we live will add more than a year to our lifespans; this is the point when we become immortal.

Immortality is a more complex concept than many realize. In the dictionary, it is defined simply as “the ability to live forever.”² What if you lived forever as an extremely old man or woman, physically and mentally weak and handicapped? This is not often the image associated with eternal life. Immortality, then, would be desirable only if it came hand-in-hand with another important concept: eternal youth. Another notion of immortality is embodied by Superman or the mythic Greek hero Achilles: invulnerability. By definition, however, invulnerability is not an essential feature of immortality. The real obstacles to immortality are not freak accidents or acts of violence but aging. Aging causes the loss of both youth and immunity to disease. In fact, no one dies purely from the aging process; death is caused by one of many age-related complications.

Eliminating aging is thus synonymous with achieving immortality. The first step in this direction, of course, is to understand the aging process and how it leads to disease. The best answer to this question has been offered by Cambridge biogerontologist Aubrey de Grey. De Grey argues that aging is the accumulation of damage as a result of the normal, essential biological processes of metabolism.² This damage accumulates over the course of our lifetimes and, once it passes a critical threshold, leads to pathological symptoms. The field of biogerontology mainly focuses on understanding the processes of metabolism in the hopes of preventing accumulation of damage. Geriatrics is a related specialty that focuses on mitigating the symptoms of age-related disease. De Grey points to the enormous complexity of understanding either process and offers an alternative: identifying and directly dealing with the damage.³

What types of damage does this entail? To begin, it is essential to understand that the body is a collection of billions of cells. The health of these cells directly translates to the wellbeing of our bodies. Aging is caused by deterioration of our cells, which typically destroy and recycle substances to prevent accumulation of damage over time. De Grey believes there are seven categories of damage that lead to aging. Two are mutations of DNA, the molecule that stores our genetic information. Two are accumulations of molecules that our cells have lost the ability to destroy. One is an accumulation of crosslinks between our cells, causing our tissues to become constrained and brittle. Another is the loss of irreplaceable cells, such as those in our heart or brain. The final classification is an accumulation of death-resistant cells that cause damage to our bodies. De Grey has proposed Strategies for Engineered Negligible Senescence (SENS) for repairing each source of damage. Some of these strategies, such as stem cell therapy, are theoretical and unproven; others, like gene therapy, are modeled after pharmaceuticals that have already gone through clinical trials. De Grey’s SENS are innovative and radical by the standards of the medical and scientific community, causing many to question their viability.

The first SENS therapies will not be perfect. They will eliminate enough damage to keep us below the threshold of developing age-related diseases for a few extra decades, but they will leave even more stubborn forms of damage behind. A few decades, however, is a long time for modern science. By the time our bodies start to show signs of aging, more effective therapies will be available. This process would continue indefinitely.

The fundamental weakness of SENS is that it is based on keeping an imperfectly understood biological organism functioning long after it was ever designed to be. The alternative is to switch out of our flesh and blood homes and into new territory: electronics. For our bodies, this seems relatively straightforward; while fully functioning humanoid robots are far from perfect, it is not a great leap to assume that they will be as capable, if not far more powerful than human bodies in the future-certainly by the time SENS would begin to wear out. Transferring our minds to an electronic medium offers far more considerable challenges. Amazingly, progress in this direction is already under way. Many scientists believe that the first step is to create a map of the synaptic circuits that connect the neurons in our brain.⁴ Uploading this map into a computer, along with a model of how neurons function, would theoretically recreate our consciousness inside a computer. The process of mapping and simulating has already started with programs such as the Blue Brain Project and Obama’s BRAIN initiative. In particular, the former has already succeeded in modeling an important circuit that occurs repeatedly in the mouse brain.⁵

Transferring our minds to computers would mean that any damage that occurred could be reliably fixed, making us truly immortal. Interestingly, the switch would also fulfill many other ambitions. Our mental processes would be significantly faster. We would be able to upload our minds into an immense information cloud, powerful robots, or interstellar cruise vessels. We would be able to fundamentally alter the architecture of our minds, eliminating archaic evolutionary vestiges (such as our propensity toward violence) and endowing ourselves with perfect memories and vast intelligences. We would be able to store and reload previous versions of ourselves. We would be able to create unlimited copies of ourselves, bringing us as close as possible to invulnerability as we may ever get.⁶

While you may have never seriously considered the idea that you might be able to live forever, theoretically it possible; technologies for radical life extension are currently in development. Whether such advancements reach the market in our lifetimes is in large part dependent on the level of public support for key research. Although the hope of living forever comes with the risk of disappointment, keep in mind that efforts toward achieving immortality will increase, if not your lifespan, that of your children and future generations.

References

1. Kurzweil, R. The singularity is near: when humans transcend biology. Penguin Books: New York, 2006.
2. Oxford Dictionaries. http://www.oxforddictionaries.com/us/definition/american_english/immortality (accessed March 13, 2014).
3. De Grey, A. D. ; Rae, M. Ending aging: the rejuvenation breakthroughs that could reverse human aging in our lifetime. St. Martin’s Griffin: New York, 2008.
4. Morgan, J. L.; Lichtman, J. W.  Nature Methods 2013, 10, 494–500.
5. Requarth, T. http://www.nytimes.com/2013/03/19/science/bringing-a-virtual-brain-to-life.html (accessed March 13, 2014).
6. Hall, J. S. Nanofuture: What’s Next for Nanotechnology. Prometheus Books: New York, 2005.

Statins May Hold the Answer to Eternal Youth

Catalyst Volume 7

Abstract

The signs and symptoms of aging are mostly a consequence of impaired antioxidant function in the body. Statins are drugs that have recently been discovered to counter these age-related changes. These drugs are typically prescribed for long-term control of plasma cholesterol levels in patients with atherosclerotic coronary artery disease. Statins have been found to enhance the enzyme paraoxonase, a potent antioxidant molecule; as a result, statins are able to alleviate manifestations of aging and effectively retard the aging process. Supplementing statins with dimercaprol and restriction of calorie consumption may also prove helpful in decelerating aging. However, use of statins frequency causes myopathy. In order to establish statins as an effective anti-aging medication, the exact pathophysiology of this side-effect must be determined.

Keywords: statins, anti-aging, HMG Co-A reductase, paraoxonase, antioxidant, ROS, sulfhydryl, dimercaprol, caloric restriction

Introduction

Statins decrease low-density lipoprotein (LDL) cholesterol while simultaneously elevating high-density lipoprotein (HDL) cholesterol levels.³ Rise in serum LDL level is correlated to increased cellular uptake of cholesterol, especially in the endothelia.² During atherosclerosis, these LDL molecules undergo oxidation and amplify the inflammatory process through macrophage induced cytokine release. Cytokines then give rise to a prothrombotic state that leads to coronary artery thrombosis.³ HDL molecules, however, remove the excess cholesterol from body tissues and transport them to the liver for final degradation.² Since statins reduce the serum LDL levels and increase serum HDL concentration, the risk of morbidity and mortality associated with coronary artery disease (CAD) can be significantly reduced by taking this drug.

However, recent research has revealed that the typical mechanism of action used by statins to control atherosclerosis might be useful in synthesizing future anti-aging medication.⁵ Aging brings about inevitable physiological changes. Among these, cardiopulmonary and renal disorders are the leading causes of death in the geriatric population, while aging skin spoils the beauty of an eternal youth. Aging imposes a significant health burden on the economy of a country, especially in developing nations. Degradation of beauty, although less important, possesses significant social implications. Hence, discovery of a drug to minimize age-related health complications and maintain external beauty can be a boon to health welfare authorities of every country and contribute to the economic prosperity of their nations.

The Mechanism of Statins in Opposing Atherosclerosis

The predominant mechanism of action of statins in preventing atherosclerotic CAD is by competitive inhibition of hexamethyl glutaryl Co-A (HMG Co-A) reductase enzyme, the key enzyme in the pathway of cholesterol biosynthesis. Statins also increase the expression of LDL receptors in the hepatocytes in order to clear plasma LDL molecules. In addition, the drugs increase the activity of paraoxonase-HDL enzyme complex.⁴ The functions of HDL and LDL molecules are exactly opposite to each other. LDL delivers cholesterol to the body tissues, while HDL removes the cellular cholesterol and presents them to the liver. Since low plasma cholesterol level is equivalent to low serum LDL concentration, LDL availability at the site of atherosclerosis is significantly decreased. As a result, LDL oxidation is reduced.

The alloenzyme PON 1 192 QQ of the paraoxonase-HDL complex is reported to possess the most prominent antioxidant action among all the enzymatic variants. It catalyzes the hydrolysis of phospholipid hydroperoxides in LDL.⁴ Paraoxonase plays an important role in preventing lipid peroxidation elsewhere in the body as well. Statins have been found to boost the activity of paraoxonase.⁵ Statins oppose atherosclerosis by using paraoxonase-HDL complex as the mediator.

Aging and Impaired Antioxidant Activity in the Body

Aging involves a significant deterioration in antioxidant activity of the body. There is a significant increase in mitochondrial activity as the body ages.⁶ As the site of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS) that are neutralized by superoxide dismutase (SOD), an important antioxidant molecule. With aging, the mitochondrial DNA may undergo mutations that amplify ROS generation.⁶ The free radicals alter the structure of mitochondrial membrane lipids and bring about undesirable changes in the organelle and other parts of the cell. This oxidative stress creates a functional deficiency of the SOD enzyme.⁶

ROS concentration has been found to rise in older age groups with unrestricted intake of calorie-rich foods (fats and carbohydrates). Metabolism of calorie-rich food increases the rate of transfer of electrons in oxidative phosphorylation, resulting in increased generation of ROS.⁷ Additionally, excessive calorie consumption leads to a dysregulation of cellular autophagy that, in turn, results in dolichol accumulation in the cells.⁸ Higher concentrations of dolichol lead to higher HMG Co-A reductase enzyme activity, thereby increasing serum cholesterol level in old age.⁸ Elevated serum cholesterol concentration increases rate of LDL oxidation and generates highly reactive LDL free radicals. Accumulation of free radicals and faulty SOD activity causes the loss of oxidant-antioxidant balance in the body tissues. The high level of oxidants then causes age-related changes in the different organ systems. Figure 1 below summarizes this relation between ROS production, excess calorie intake, and aging.

Statins as Possible Anti-aging Drugs

Their mechanism of action suggests that statins may be able to halt the natural process of aging by using HDL as a mediator. HDL downregulates LDL oxidation through paraoxonase;⁴ there is a time-regulated fall in the paraoxonase activity due to the accumulation of lipid peroxides, which are generated as byproducts of LDL oxidation.⁹ This decreased PON 1 192 QQ function is caused by interactions between its sulfhydryl groups and the metabolic by-products.⁹ Statins can reduce this interaction by decreasing the concentration of LDL molecules in the blood stream. If LDL levels are low, oxidation rate also drops, resulting in significantly reduced generation of oxidized byproducts that interact with paraoxonase.

Reduction of LDL oxidation, however, does not seem to be the definitive solution to this complex problem. Other non-high density lipoproteins such as intermediate-density lipoprotein (IDL) are independent risk factors for age-related CAD. Accumulation of IDL in high levels can bring about adverse effects despite low levels of LDL molecules. Nevertheless, new generations of statins have shown remarkable effects in reducing IDL levels in the blood stream.¹⁰

Statins can be combined with the drug dimercaprol to prevent decrease in paraoxonase activity. Dimercaprol is typically used as a chelating agent in heavy metal poisoning, such as arsenic poisoning. The drug possesses a large number of free sulfhydryl groups that attract metals; this unique property is used to free respiratory enzymes from inhibitory complexes with heavy metals (Figure 2). Because oxidized LDL products bind with the sulfhydryl radical of paraoxonase, dimercaprol can serve as a more attractive substrate for these oxidized products; this competition reduces paraoxonase inhibition (Figure 3). Unfortunately, dimercaprol is a nephrotoxic drug that can exacerbate the already-declining renal function of old age. Dimercaprol also leads to dose-related emesis, hypertension, and palpitation. To combat this, statins can be used in conjunction with dimercaprol to exert a synergistic effect in increasing paraoxonase activity. Therefore, the dose of dimercaprol can be decreased to a level where it will cause only minimal physiological distress.

In addition to these drug therapies, restricted calorie consumption can improve antioxidant effects in the body. Caloric restriction lowers both the HMG Co-A reductase activity and cholesterol biosynthesis. Low cholesterol production means a lower concentration of LDL and its subsequent oxidization, significantly enhancing paraoxonase activity and working with statin therapy to dampen generation of ROS.

Statins can be helpful in reducing incidence of atherosclerotic CAD, hypertension, hypertensive nephropathy, renal artery atherosclerosis, cerebral artery sclerosis, diabetic nephropathy, and dermatological changes. Slow progression of atherothrombotic changes in cerebral artery can lower incidences of cerebrovascular disease (stroke), improve cognition; the antioxidant activities of statins may also prevent cellular death, thus reducing development of skin wrinkles. Death of pancreatic beta cells due to ROS overproduction can be effectively limited and insulin sensitivity in the body tissues may be improved, which can decrease the risk of developing diabetic nephropathy and other micro and macrovascular changes.

A significant side effect, however, is the tendency of statins to cause myopathies.¹¹ This adverse effect must be reduced or eliminated before statins can be introduced as an anti-aging pill in the global market. Drug trials have failed to establish any specific dose-response relationship for this pathological condition.¹² However, lipophilic statins (simvastatin, lovastatin, atorvastatin) have been associated with a greater number of reported myopathy cases.¹³ As a result, statin-induced myopathy may be prevented by prescribing the lowest therapeutic dose of this group of drugs.

Conclusion

The antioxidant property of statins may be effective not only in treating dyslipidemia but also as a potential anti-aging medication. Although the combination of statins, dimercaprol, and caloric restriction seems promising towards reducing or even reversing the process of aging, the additive role of these therapies has not yet been studied fully. More intensive research is necessary to fill the gaps in our knowledge about aging mechanisms and to develop anti-aging drugs.

References

1. Malloy, M. J.; Kane, J. P. Agents Used in Dyslipidemia. In Basic & Clinical Pharmacology, 11th ed.; Katzung, B. G. et al. Eds.; Tata McGraw-Hill: New Delhi, 2009; p 605-620.
2. Botham, K. M.; Mayes, P. A. Lipid Transport and Storage. In Harper’s Illustrated Biochemistry, 27th ed.; Murray, R. K. et al. Eds.; McGraw-Hill: Singapore, 2006; p217-229.
3. Mitchell, R. N.; Schoen, F. J. Blood Vessels. In Robbins and Cotran’s Pathological Basis of Disease, 8th ed.; Kumar, V. et al., Eds.; Elsevier: Haryana, 2010; p 487-528.
4. Mahley, R. W.; Bersot, T.P. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.; Hardman, J. G. et al., Eds.; McGraw-Hill: New York, 2010; p 971-1002.
5. Durrington, P. N. et al. Arterioscler. Thromb., Vasc. Biol. 2001, 21, 473-480.
6. Pollack, M.; Leeuwenburgh, C. Molecular Mechanisms of Oxidative Stress in Aging: Free Radicals, Aging, Antioxidants and Disease. In Handbook of Oxidants and Antioxidants in Exercise; Sen, C. K. et al., Eds.; Elsevier Science: Amsterdam; p 881-923.
7. de Grey, A. D. N. J. History of the Mitochondrial Free Radical Theory of Aging, 1954-1995. In The Mitochondrial Free Radical Theory of Aging; de Grey, A. D. N. J., Ed.; R. G. Landes: Austin, Texas; p 65-84.
8. Cavallini, G. et al. Curr. Aging Sci. 1999, 1, 4-9.
9. Aviram, M. et al. Free Radic. Biol. Med. 1999, 26, 892-904.
10. Stein, D. T. et al. Arterioscler. Thromb. Vasc. Biol. 2001, 21, 2026-2031.
11. Amato, A. A.; Brown Jr, R. H. Muscular Dystrophies and Other Muscle Diseases. In Harrison’s Principles of Internal Medicine, 18th ed.; Longo, D.L. et al., Eds.; McGraw-Hill: New York, 2012; p 3487-3508.
12. Stewart, A. PLoS Curr. [Online] 2013, 1. http://currents.plos.org/genomictests/article/slco1b1-polymorphisms-and-statin-induced-myopathy/ (accessed March 14, 2013).
13. Sathasivam, S; Lecky, B. Statin Induced Myopathy. BMJ [Online] 2008, 337:a2286. 

Aquaporin-4 and Brain Therapy

Catalyst Volume 7

Introduction

One of the tasks of modern medicine is to address the many diseases affecting the brain. These maladies come in various forms – including neurodegenerative complications, tumors, vascular constriction, and buildup of intracranial pressure.^1,2,3 Several of these disease classes are caused, in part or in full, by a faulty waste clearance or water flux. Although a pervasive system of slow cerebrospinal fluid (CSF) movement in the brain’s ventricles is present, a rapid method for clearing solutes from the cortex’s interstitial space, which contains neural tissue and the surrounding extracellular matrix, was unknown.^4,5 Recently, Iliff et al discovered a new mechanism for the flow of CSF in the mouse brain – the “glymphatic” system.^5,6 This pathway provides an accelerated mechanism to clear dissolved materials from the interstitial space, preventing a buildup of solutes and toxins.^5,6 At the center of this system is the water transport protein aquaporin-4 (AQP4), and the extent of this water channel’s various roles are only now being identified. New perspectives on the mechanism by which the brain is “cleansed” may lead to breakthroughs in therapeutics for brain disorders such as Alzheimer’s Disease (AD), which is the sixth leading cause of death in the US each year.⁷

The Infrastructure

To understand AQP4 and its role in the brain, the environment in which it operates must be examined. As seen in Figure 1, surrounding the brain are three meninges, protective layers between the skull and the cortex.⁸ Between these layers – the dura, arachnoid, and pia maters – are cavities, including the subarachnoid space that lies just below the arachnoid layer.⁹ As the figure shows, directly underneath the pia mater are the cortex and interstitial space. Within the cortex, CSF flows through a system of chambers called the ventricles, illustrated in Figure 2.10 CSF suffuses the brain and has several vital functions, namely shock absorption, nutrient provision, and waste clearance.¹¹ CSF is produced in a mass of capillaries called the choroid plexus and flows through the ventricles into the subarachnoid space, bathing the brain and never crossing the blood-brain barrier.¹⁰ After circulating through the brain’s interstitial space and ventricles, the CSF then leaves the brain through aquaporin channels surrounding the cephalic veins.⁶

A New Plumbing System

A team of researchers has discovered an alternate pathway for CSF that clears water-soluble materials from the interstitial space.⁶ CSF in this so-called “glymphatic pathway” starts in the subarachnoid cavity and then seeps into the cortex, as seen in Figure 3.⁶ This fluid eventually leaves the brain, carrying with it the waste generated by cells. CSF enters the parenchyma from the subarachnoid cavity and travels immediately alongside the blood vessels.⁶ This route, which forms a sheath around the blood vessels, is dubbed the “paravascular” pathway, and CSF enters and exits the interstitial space through these avenues.⁶ The pia membrane guides this pathway until the artery penetrates the cortex, as seen in Figure 3. From there, the endfeet of astrocytes bind the outer wall.⁶ Astrocytes are glial cells that play structural roles in the nervous system, and endfeet are the enlarged endings of the astrocytes that contact other cell bodies and contain AQP4 proteins.^6,12

Iliff et al found that AQP4 are highly polarized at the endfeet of astrocytes, which suggested that these proteins provide a pathway for CSF into the parenchyma.⁶ To test this hypothesis, they compared wild type and Aqp4-null mice on the basis of CSF influx into the parenchyma.⁶ They injected tracers such as radiolabeled TR-d3 intracisternally, finding that that tracer influx into the parenchyma was significantly reduced in Aqp4-null mice.⁴ According to their model, AQP4 facilitates CSF flow into the parenchyma. There, CSF mixes with the interstitial fluid in the parenchyma; AQP4 then drives these fluids out and into the paravenous pathway by bulk flow.⁶ The rapid clearance of tracer in wild type mice and the significantly reduced clearance in Aqp4-null mice demonstrated the pathway’s ability to clear solutes from the brain. This finding is important because the build-up of Aβ is often associated with the onset and progression of AD.

AQP4 and Aβ

To facilitate Aβ removal, astrocytes become activated at a threshold Aβ, but undergo apoptosis at high concentrations.^13,14,15 Thus, the concentration of astrocytes has to be in a narrow window. A study by Yang et al further explored the role of AQP4 in the removal of Aβ.¹⁶ They found that AQP4 deficiency reduced the astrocytic activation in response to Aβ in mice, and Aqp4-knockout reduced astrocyte death at high Aβ levels.¹⁶ Furthermore, AQP4 expression increased as Aβ concentration increased, likely due to a protein synthesis mechanism. Further investigation demonstrated that lipoprotein receptor-related protein-1 (LRP1) is directly involved in the uptake of Aβ, and knockout of Aqp4 reduced up-regulation of LRP1 in response to Aβ.^15,16 Finally, AQP4 deficiency was found to alter the levels and time-course of MAPKs, a family of protein kinases involved in the response to astrocyte stressors.¹⁶ The role of AQP4 in cleansing the parenchyma as well as modulating astrocytic responses to Aβ thus pinpoint it as a major target for the following potential therapies: repairing defects in toxin clearance from the interstitial space, increasing expression in AQP4-deficient patients to increase astrocyte response, and knocking out Aqp4 in patients with high levels of Aβ to prevent astrocyte damage.

Sleep and Aβ Clearance

Interestingly, there is a link between Aβ clearance and sleep. Xie et al. studied Aβ clearance from the parenchyma in sleeping, anesthetized, and wakeful rodents, obtaining evidence that sleep plays a role in solute clearance from the brain. The researchers found that glymphatic CSF influx was suppressed in wakeful rodents compared to sleeping rodents.¹⁷ Glymphatic CSF influx is vital because it clears solutes from the brain in a way somewhat analogous to the way kidneys filer the blood. Real-time measurements showed that the parenchymal space was reduced in wakeful rodents, which led to increased resistance to fluid influx.¹⁷ Moreover, Aβ clearance was faster in sleeping rodents. Adrenergic signaling was hypothesized as the cause of volume reduction, implicating hormones such as norepinephrine.¹⁷ AQP4 is implicated in this phenomenon, as constricted interstitial space resists the CSF influx that this protein enables.

Aquaporin Therapy

If future treatment will target AQP4 function, then researchers must learn to manipulate its expression. However such regulatory mechanisms are not well understood. It is well-known that cells can ingest proteins in the plasma membrane and thus modulate the membrane protein landscape. Huang et al studied this phenomenon with AQP4, utilizing the fact that occluding the middle cerebral artery mimics ischemia and alters AQP4 expression in astrocyte membranes.¹⁸ They found that artery occlusion down-regulates AQP4 expression and discovered various mechanisms behind this response.¹⁸ Specifically, they determined that AQP4 co-localized in the cytoplasm with several proteins involved in membrane protein endocytosis, after the onset of ischemia.¹⁸ They posited that this co-localization indicates the internalization of AQP4.¹⁸ These correlations indicate that AQP4 is intimately connected with fluctuations in brain oxygen and nutrient levels, which are limited when blood flow is restricted.

Future Research

Aquaporin-4 is vital to many processes in the brain, but the range and details of these roles are not yet fully understood. As demonstrated, this protein is the central actor in the newly defined glymphatic system responsible for clearing solutes from CSF in the interstitial space. This function implicates AQP4 in the progression of AD and suggests other brain states and neurological conditions may have links to the protein’s function. Studies have demonstrated that AQP4 expression is dynamic, indicating that it can be regulated. The hope is that modulation of aquaporin expression or function could be used in brain therapy. Future research will no doubt focus on these mechanisms, and discoveries will aid in developing a treatment for various brain disorders.

References

1. Goetz, C., Textbook of Clinical Neurology, 3rd Edition; Saunders: Philadelphia, 2007.
2. Goldman, L. Goldman’s Cecil Medicine; Saunders Elsevier: Philadelphia, 2008.
3. Karriem-Norwood, V. Brain Diseases, WebMD. http://www.webmd.com/brain/brain-diseases (Accessed December 1, 2013).
4. Crisan, E. Ventricles of the Brain, Medscape. http://emedicine.medscape.com/article/1923254-overview#aw2aab6b3 (Accessed December 1, 2013).
5. Scientists Discover Previously Unknown Cleansing System in Brain, University of Rochester Medical Center. http://www.urmc.rochester.edu/news/story/index.cfm?id=3584 (Accessed February 11, 2014).
6. Iliff J.J. Cerebrospinal Fluid Circulation: A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid ß. Sci Transl Med 2012, 4, 147ra111.
7. 2012 Alzheimer’s Disease Facts and Figures. Alzheimer’s Association. http://www.alz.org/downloads/facts_figures_2012.pdf (Accessed December 6, 2013).
8. Dugdale III, D. Meninges of the Brain. MedlinePlus, National Institutes of Health. http://www.nlm.nih.gov/medlineplus/ency/imagepages/19080.htm (Accessed December 1, 2013).
9. O’Rahilly, R.; Muller, F.; Carpenter, S.; Swenson, R. Chapter 43: The Brain, Cranial Nerves, and Meninges. Basic Human Anatomy. [Online] Dartmouth Medical School: Hanover, 2008. http://www.innerbody.com/anatomy/nervous/subarachnoid-space (Accessed December 1, 2013).
10. Agamanolis, Dimitri. Chapter 14 Cerebrospinal Fluid. Neuropathology. [Online] http://neuropathology-web.org/chapter14/chapter14CSF.html (Accessed Dec. 1, 2013).
11. Cerebrospinal Fluid (CSF), National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/diagnosing-ms/cerebrospinal-fluid/index.aspx (Accessed December 1, 2013).
12. Millodot, M. Astrocytes. Dictionary of Optometry and Visual Science, 7th edition; Butterworth-Heinemann: Oxford, U.K., 2009.
13. Nielsen, H.M. et al. Glia [Online] 2010, 58, 1235-1246.
14. Kobayashi, K. J Alzheimer’s Dis [Online] 2004, 6, 623-632.
15. Arelin, K. Brain Research Molecular/Brain Research [Online] 2002, 104, 38-46.
16. Yang, W. Mol Cell Neurosci [Online] 2012, 49, 406-414.
17. Xie, L Science [Online] 2013, 342, 373-377.
18. Huang, J. Brain Research [Online] 2013, 1539, 61-72.
19. Almodovar, B. et al. Rev Cubana Me Top [Online] 2005, 57, 3, 230-232.
20. Ibe, B.C., et al. J. Tropical Pediatr. [Online] 1994, 40, 315-316.
21. Slowik, G. What Is Meningitis? eHealthMD. http://ehealthmd.com/content/what-meningitis#axzz2l3OzwGfb (Accessed Dec. 1, 2013).
22. Iadecola C. and Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci [Online] 2007, 10, 1369-1376.

Cancer Ancestry: Identifying the Genomes of Individual Cancers

Catalyst Volume 7

Cancer-causing mutations in the human genome have been a subject of intense research over the past decade. With increasing numbers of mutations identified and linked to individual cancers, the possibility of treating individual patients with a customized treatment plan based on their individual cancer genome is quickly becoming a reality.

Cancer arises when individual cells acquire mutations in their DNA. These mutations allow cancerous cells to proliferate uncontrollably, aggressively invade surrounding tissues, and metastasize to distant locations. Based on this progression, a potentially tremendous implication emerges: if every type of cancer arises from an ancestor cell that acquires a single mutation, then scientists should be able to trace every type of cancer back to its original mutation through modern genomic sequencing technologies. High volumes of the human genome have been analyzed in search of these ancestor mutations using a variety of techniques, the most common of which is a large Polymerase Chain Reaction (PCR) screen. In this type of study, DNA of up to one hundred cancer patients is sequenced; the sequences are then analyzed for repeating codons, the DNA units that determine single amino acids in a protein. Analyzing the enormous volume of data from these screens requires the efforts of several institutions. The first 90 cancer-causing mutations were identified at the Johns Hopkins Medical Institute, where scientists screened 11 breast cancer and 11 colorectal cancer patients’ genomes.³ After this study was published in 2006, researchers found these 90 mutations across every known type of cancer. These findings stimulated even more ambitious projects: if the original cancer-causing mutations are identified, scientists may be able to reverse the cancer process by removing faulty DNA sequences using precisely targeted DNA truncation proteins.

However, such a feat is obviously more easily said than done. One of the many obstacles in identifying cancer genomes is the fact that approximately 10 to 15% of cancers derive large portions of their DNA from viruses such as HIV and Hepatitis B. The addition of foreign DNA complicates the search for the original mutation, since viral DNA and RNA are propagated in human cells. This phenomenon masks human mutations that may have existed before the virus entered the host cell. In addition, because tumors are inherently unstable, cancers may lose up to 25% of their genetic code due to errors in cell division, making the task of tracing them even more difficult. Finally, the mutations in every individual cancer have accumulated over the patient’s lifetime; differentiating between mutations of the original cancerous cell line and those caused by aging and environmental factors is an arduous task.

In order to overcome these challenges, scientists use several approaches. First, they increase the sample size—this strategy ensures that the mutations are not specific to an individual organism or geographic area but are common in all patients with that type of cancer. Second, accumulated data concerning viral genomes allow scientists to screen for and mark the areas of viral origin in patients’ DNA. Several advances have already been made despite the difficulties: for instance, in endometrial cancer—a cancer originating in the uterine lining—mutations in the Nucleotide Excision Repair (NER) and MisMatch Repair (MMR) genes have been found to occur in 13% of all affected patients.⁴ NER and MMR are involved in DNA repair mechanisms and act as the body’s “guardians” of the DNA replication process. In a healthy individual, both NER and MMR ensure that each new cell receives a complete set of functional chromosomes following cell division. In a cancerous cell, these two genes acquire a mutation that permits replication of damaged and mismatched DNA sequences. Similarly, mutations in the normally tumor-suppressing Breast Cancer Type 1 Susceptibility Gene 1 and Gene 2 (BRCA1 and BRCA2) have been identified as major culprits in breast cancer. In prostate cancer, E-26 Transformation Specific (ETS) and Transmembrane Protease, Serine 2 (TMPRSS2) are two DNA transcription regulatory proteins discovered to initiate the disease process.⁵

One of the latest frontiers in cancer treatment is the identification and study of individual, disease-causing mutations. Thousands of tumor genomes have been sequenced to discover recurring mutations in each cancer, and tremendous advances have been made in this emergent field of cancer genomics. Further study will ultimately aim to tailor cancer treatment to the patient’s specific set of mutations in the emerging field of personalized medicine. This strategy is already being used in the treatment of leukemia at the Cincinnati Children’s Hospital, where a clinical study has been underway since August 2013.² This trial uses a combined treatment program that includes standard drug therapy while targeting a specific mutation in the mTOR gene, which is responsible for DNA damage repair. Thus, less than a decade after researchers first began to identify unique cancer-causing mutations, treatment programs tailored to patient genomes are becoming a reality.

References

1. Lengauer, C. et al. Nature 1998, 396, 643-649.
2. Miller, N. http://www.cincinnatichildrens.org (accessed Nov 9, 2013).
3. Sjöblom, T. et al. Science 2006, 314, 268-274.
4. Stratton, M. et al. Nature 2009, 458, 719-724.
5. Tomlins, S. et al. Science 2005, 310, 644-648. 

Stem Cells and Hearts

Catalyst Volume 7

In the U.S., someone dies of heart disease every 33 seconds. Currently, heart disease is the number one cause of death in the U.S.; by 2020, this disease is predicted to be the leading cause of death worldwide.¹ Many of these deaths can be prevented with heart transplants. However, only about 2,000 of the 3,000 patients on the wait-list for heart donations actually receive heart transplants every year. Furthermore, patients who do receive donor hearts often have to wait for months.²

The shortage of organ donors and a rise in demand for organ transplants have instigated research on artificial organ engineering.⁵ In Tokyo, Japan, cell biologist Takanori Takebe has successfully synthesized and transplanted a “liver bud,” a tiny functioning portion of a liver, into a mouse; his experiment was able to partially restore liver function.³ Dr. Alex Seifalian from University College London, who has previously conducted artificial nose transplants, is now working on engineering artificial cardiovascular components.⁵

Breakthroughs in artificial organ engineering are also being made more locally. At St. Luke’s Episcopal Hospital in the Texas Medical Center, Dr. Doris Taylor is working on cultivating fully functional human hearts from proteins and stem cells. She is renowned for her discovery of “whole-organ decellularization,” a process where organs are stripped of all living cells to leave a protein framework. Taylor has successfully used this method as the first step in breathing life into artificially grown hearts of rats and pigs, and she is attempting to achieve the same results with a human heart.²

In this method, Taylor uses a pig heart as a scaffold, or protein template, for the growth of the human heart, as they are similar in size and physiological structure. In order to create such a scaffold, Taylor first strips pig hearts of all their cells, leaving behind the extracellular matrix and creating a framework free of foreign cells. The heart is then immersed for at least two days in a detergent found commonly in baby shampoo, which results in whole-organ decellularization. The decellularized pig heart emerges from the detergent bath completely white, since the red color of organs is usually derived from the now-absent hemoglobin and myoglobin (two oxygen-carrying proteins) in the cells. Therefore, only the structural proteins of the organ—devoid of both color and life—remain.²

To bring this ghost heart to life, Taylor enlists the aid of stem cells from human bone marrow, blood, and fat. The immature stem cells have the potential to differentiate into any cell in the body and stimulate the growth of the artificial organ. After the stem cells are added,² the artificial heart is placed in a bioreactor that mimics the exact conditions necessary for growth, including a separate blood and oxygen supply as well as a beating sensation.⁶ Amazingly, a heartbeat is observed after just a few days, and the artificial organ can successfully pump blood after just a few weeks.²

Of course, this method is not limited to the development of a single type of organ. Not only will Taylor’s research benefit patients suffering from heart failure, it will also increase availability of other artificial organs like livers, pancreases, kidneys, and lungs. Taylor has already proven that decellularization and stem cell scaffolding is a practical possibility with other organs; additionally, she has completed successful lab trials with organ implants in rats.⁴ While the full growth of a human heart is still being refined and other organ experiments have recently been completed, Taylor predicts that her team will be able to approach the Food and Drug Administration (FDA) with proposals for clinical trials within the next two years. The trial of integrating entire organ into human patients may be further into the future, but Taylor proposes that they will begin with cardiac patches and valves, smaller functioning artificial portions of a heart, to show the safety and superiority of the decellularization and stem cell scaffolding process. Hopefully, after refining the procedure and proving its success, whole-organ decellularization will be used to grow organs unique to every individual who needs it.²

While this process is useful for all transplant patients, it is especially important for people with heart disease. The muscle cells of the heart, cardiomyocytes, have no regenerative capabilities.⁴ Not only is heart tissue incapable of regeneration, but the transplant window for hearts is also extremely short: donor hearts will typically only last four hours before they are rendered useless to the patient, which means that a heart of matching blood type and proteins must be transported to the hospital within that time period. Due to high demand and time limitations, finding compatible hearts within a reasonable distance is difficult. Though mechanical hearts are emerging as possible replacements for donor hearts, they are not perfect; use of a natural heart would be vastly superior.² Mechanical hearts face the issue of unnatural malfunction; natural hearts, which are designed for a human body, will better “fit” the individual and can be tailored to avoid patient rejection. With the advent of biologically grown hearts, more hospitals will have access to replacement organs, increasing the patients’ options for transplant. Another critical advantage of artificially grown hearts lies in the fact that the patient may not need anti-rejection medication. The patient’s own stem cells could be used to grow the heart. The artificial tissue would then grow to have the same protein markers as the rest of the cells in the body, minimizing the chances that the organ would be rejected.² Still, the use of stem cells could be potentially problematic, as human stem cells decrease in number and deteriorate in function over time. In this respect, stem cells from younger patients are usually desirable, so the eradication of all anti-rejection medication is not feasible in the near future.

The development of artificial organs provides a solution to issues of organ rejection, availability, compatibility, and mechanical failure. Dr. Taylor’s stem cell research also presents the possibility of improving current technologies that help patients with partially functioning hearts. Her work has the potential to grow skin grafts for burn centers and aid in dialysis treatment for liver failure in the near future.²

While other organs are not as fragile as the heart, decellularization and protein scaffolding can potentially benefit the body holistically. Similar to the heart, other organs such as the kidney are capable of healing themselves of small injuries as opposed to major ones requiring transplant and emergency care. Taylor’s research, though still very much in development, could change the future of transplant medicine across all organs.

References

1. The Heart Foundation. http://www.theheartfoundation.org/heart-disease-facts/heart-disease-statistics/ (accessed Oct 14, 2013).
2. Galehouse, M. Saving Lives With Help From Pigs and Cells. Houston Chronicle, Houston, Jan 23, 2013.
3. Jacobson, R. Liver Buds Show Promise, but Growing New Organs is Still a Long Way Off. http://www.pbs.org/newshour/rundown/2013/07/liver-buds-show-promise-but-growing-new-organs-is-still-a-long-way-off.html (accessed Oct 14, 2013).
4. Moore, Charles. Texas Heart Institute’s Dr. Doris Taylor in the Forefront of Heart Tissue Regeneration Research. http://bionews-tx.com/news/2013/07/04/texas-heart-institutes-dr-doris-taylor-in-the-forefront-of-heart-tissue-regeneration-research/ (accessed Oct 14, 2013).
5. Naik, G. Science Fiction Comes Alive as Researchers Grow Organs in Lab. http://online.wsj.com/news/articles/SB10001424127887323699704578328251335196648 (accessed Oct 14, 2013).
6. Suchetka, D. 'Ghost Heart,' a Framework for Growing New Human Hearts, Could Be Answer for Thousands Waiting for New Heart. http://www.cleveland.com/healthfit/index.ssf/2012/08/ghost_heart_a_framework_for_gr.html (accessed Oct 14, 2013). 

Farming the Unknown: The Role of the Livestock Industry in Preserving Human Health

Catalyst Volume 7

The livestock industry is a vast network of expectations. A farmer expects meat, dairy, and eggs from his animals, and a consumer expects to obtain these products from grocery stores. Industry expects profitable revenue from the sales of these products. Given the intensiveness of modern agriculture, this chain of action has been massively amplified. Meat production has doubled since the 1950s, and currently almost 10 billion animals—not including additional goods such as dairy and eggs—are consumed every year in the United States alone.¹ Due to the magnitude of this industry, even small changes can bring about large scale effects. Infections exemplify this chain of events.

Though animal infections might initially seem to be a lesser concern, their effects on human health are rapidly becoming more pronounced and pervasive. During the past few years, an increased number of food-borne disease outbreaks have been traced to products such as beef, pork, poultry, and milk.² These outbreaks are especially concerning because the pathogens involved are new strains previously harmless to humans. Rather, these pathogens have become infectious to humans due to mutations that occur in animal hosts; such diseases that jump from animals to humans are termed zoonotic. Within the food industry, zoonotic illnesses can be transmitted by consumption or through contact with animals. Crucially, zoonotic cases are much harder to treat because there is no precedent for their treatment.

How often does this transmission occur? Since 1980, 87 new human pathogens have been identified, out of which a staggering 80% are zoonotic.³ Furthermore, many of these have been found in domestic animals, which serve as reservoirs for a variety of infectious agents. The large number of zoonoses raises several key questions. Are these outbreaks the product of our management of livestock or simply a natural phenomenon? How far could zoonotic illnesses escalate in terms of human cases and mortality? What practices or perspectives should we modify to prevent further damage?

Prominent virologist and Nobel laureate in medicine Sir Frank MacFarlane Burnet provided a timeless perspective to this issue in the mid-20th century. He conceptualized infectious disease as equally fundamental to other interactions between organisms such as predation, decomposition, and competition.⁴ Taking into account how we have harnessed nature, particularly with the aim of producing more food, we can see how farming animals has also inadvertently farmed pathogens.

Treating animals as living environments that can promote pathogenic evolution and diffusion is crucial to creating proper regulations in the livestock industry that protect the safety of consumers in the long run. Current practices risk the emergence of zoonotic diseases by facilitating transmission under heavily industrialized environments and by fostering antibiotic resistance in bacteria. Cooperative action between government, producers, and educated consumers is necessary to improve current practices and preserve good health for everyone.

Influenza: Old Threats, New Fears

The flu is not exactly a stranger to human health, but we must realize that the influenza virus not only affects humans but also other species such as pigs and birds. In fact, what is known as “the flu” is not a single virus but rather a whole family of viruses. The largest family of influenza viruses, influenza A, has different strains of viruses classified with a shorthand notation for their main surface glycoproteins –H for hemagglutinin and N for neuraminidase (Figure 1). These surface glycoproteins are important because their structure and shape determines if the virus will attach to the cellular receptors of its host and infect it. For example, the influenza H7N7 virus has a structure that allows it to specifically infect horses but not humans. Trouble arises when these surface glycoproteins undergo structural changes and the virus gains the capacity to infect humans, as was the case during the 2003 avian flu and the 2009 swine flu pandemics, when the influenza virus jumped from poultry and swine to humans.

Since 2003 when it was first documented in humans, avian influenza H5N1 has been responsible for over 600 human infections and associated with a 60% mortality rate due to severe respiratory failure.⁵ The majority of these cases occurred in Asia and Africa, particularly in countries such as Indonesia, Vietnam, and Egypt, which accounted for over 75% of all cases.^5-6 Though no H5N1 cases have been reported in the U.S., there have been 17 low-pathogenicity outbreaks of avian flu in American poultry since 1997, and one highly pathogenic outbreak of H5N2 in 2004 with 7,000 chickens infected in Texas.⁵

Poultry is not the only area of livestock industry where flu viruses are a human health concern. The 2009 outbreak of influenza H1N1—popularly termed “swine flu” from its origin in pigs—was officially declared a pandemic by the WHO and the CDC. With an estimated 61 million cases and over 12,000 deaths attributed to the swine flu since 2009, H1N1 is an example of a zoonotic disease that became pandemic due to an interspecies jump that turned it from a regular pig virus to a multi-species contagion.⁷

The theory of how influenza viruses mutate to infect humans includes the role of birds and pigs as “mixing vessels” for mutant viruses to arise.⁸ In pigs, the genetic material from pig, bird, and human viruses (in any combination) reassorts within the cells to produce a virus that can be transmitted among several species. This process also occurs in birds with the mixing of human viruses and domestic and wild avian viral strains. If this theory is accurate, one can infer that a high density of pigs in an enclosed area could easily be a springboard for the emergence of new, infectious influenza strains. Thus, the “new” farms of America where pigs and poultry are stocked to minimize space and maximize production provide just the right environment for one infected pig to transfer the disease to the rest. Human handlers then face the risk of exposure to a new disease that can be as fatal as it is infectious, as the 2009 swine flu pandemic and the 2003 avian flu cases demonstrated. As consumers, adequate care of our food sources should not only be priority in avoiding disease but also in national and global health.

Feeding our Food: Antibiotic Resistance in the Food Industry

Interspecies transmission is not the only way through which new diseases can become pathogenic to humans. In the case of bacteria, new pathogenic strains can arise in animals from the action of another mechanism: antibiotic resistance. Antibiotic resistance is the result of the fundamental concept of evolutionary biology—individuals with advantageous traits that allow survival and reproduction will perpetuate these traits to their offspring. Even within the same population, antibiotic resistance varies among individual bacteria—some have a natural resistance to certain antibiotics while others simply die off when exposed. Thus, antibiotic use effectively selects bacteria with such resistance or, in some cases, total immunity. In this way, the livestock industry provides a selective environment.

The rise of these resistant strains—commonly termed “superbugs” for their extensive resistance to a variety of common antibiotics—has been a serious threat in hospitals; there, antibiotic use is widespread, and drug resistance causes almost 100,000 deaths each year from pathogens such as Methicillin-resistant Streptococcus aureus, Candida albicans, Acenitobacter baumanni, and dozens of other species.⁹ Our attention should not be exclusively focused to hospitals as sources of superbug infections, however. The widespread use of antibiotics in the livestock industry to avoid common bacterial diseases in food animals also poses the risk of emerging superbug strains, and it has not been without its share of outbreaks and casualties.

The Center for Science in the Public Interest –a non-profit organization that focuses on advocating for increased food safety in the US—has reported that antibiotic-resistant pathogens have been the cause of 55 major outbreaks since 1973, and that the majority of cases have come from dairy products, beef, and poultry. Furthermore, the same study reported that most of these pathogens exhibit resistance to over 7 different antibiotics.¹⁰ One of the main culprits identified in these outbreaks is the bacterium Salmonella typhimurium along with other Salmonella species, which account for over half of these cases. Salmonella is especially dangerous because it is so pervasive; it is able to lay dormant in a variety of livestock products such as uncooked eggs, milk, cheese, poultry, and beef until incubating in a live host for infection. Escherichia coli 0157:H7 (commonly known as E. coli), a bacterium that usually resides in the intestines of mammals, has also been implicated in a number of outbreaks related primarily to beef products. Overall, antibiotic-resistant pathogens have been the cause of over 20,500 illnesses, with over 31,000 hospitalizations and 27 deaths.¹⁰

These cases demonstrate how the widespread use of antibiotics in the food industry is perpetuating the risk of infections and damage to human health with antibiotic-resistant bacteria. Currently, the Food and Drug Administration (FDA) in the U.S. still approves of the use of antibiotics as a treatment for sick animals; furthermore, the organization allows antibiotic use in healthy animals as prevention and even as growth enhancers.¹¹ In fact, over 74% of all antibiotics produced in the United States are used in livestock animals for these reasons.^9,11 Using antibiotics in non-infected animals in this way generates a greater environmental pressure for superbugs to emerge; this type of use in particular should be restricted. Managing a proper use of antibiotics to reduce the risk of emerging strains of superbugs should be prioritized in the food industry just as it is in health care.

Hungry for a Solution

Still open to debate is the question of how many resources should be allocated to the problem of widespread antibiotic use. Currently, diseases are transmitted from animals to humans faster than they are evolving within humans. Not only that, many of these zoonotic diseases have high potential to become a pandemic due to their high infectivity, as in the case of H5N1 avian influenza. Measures to prevent the transmission of viruses among livestock animals and to reduce the rate of emergent antibiotic-resistant strains need to take into account the environmental and evolutionary nature of a zoonosis.

A more thorough surveillance of livestock animals and monitoring signs of new emerging strains are important in preventing the spread of such deadly pathogens. This strategy requires intensive molecular analysis, a larger number of professionals working in the field, and a nationwide initiative. Keeping an accurate record of where new strains arise and the number of animal and human cases would significantly improve epidemiological surveillance of infectious disease. This process requires cooperation at multiple levels to ensure that the logistics and public support for these initiatives is ongoing and effective. Additionally, educating people about the nature of zoonotic pathogens is crucial to fostering the dialogue and action necessary to secure the good health of animals, producers, and consumers.

References

1. John’s Hopkins Center for a Livable Future: Industrial Food Animal Production in America. Fall 2013. http://www.jhsph.edu/research/centers-and-institutes/johns-hopkins-center-for-a-livable-future/_pdf/research/clf_reports/CLF-PEW-for%20Web.pdf (accessed Oct 24, 2013).
2. Cleaveland, S. et al. Phil. Trans. R. Soc. B. 2001, 356, 991.
3. Watanabe, M. E. BioScience 2008, 58, 680.
4. Burnet, F. M. Biological Aspects of Infectious Disease. Macmillan: New York, 1940.
5. Centers for Disease Control and Prevention: Avian Flu and Humans. http://www.cdc.gov/flu/avianflu/h5n1-people.html. (accessed Oct 12, 2013)
6. Cumulative number of confirmed human cases of avian influenza A(H5N1) reported to WHO. http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/ (accessed March 14, 2013)
7. Chan, M. World Now at the Start of the 2009 Influenza Pandemic. http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/ (accessed March 14, 2013).
8. Ma, W. et al. J. Mol. Genet. Med. [Online] 2009, 3, 158-164.
9. Mathew, A. G. et al. Foodborne Pathog. Dis. 2007, 4, 115-133.
10. DeWaal, C. S.; Grooters, S. V. Antibiotic Resistance in Foodborne Pathogens. http://cspinet.org/new/pdf/outbreaks_antibiotic_resistance_in_foodborne_pathogens_2013.pdf (accessed March 14, 2014).
11. Shames, L. Agencies Have Made Limited Progress Addressing Antibiotic Use in Animals http://louise.house.gov/images/user_images/gt/stories/GAO_Report_on_Antibioic_Resistance.pdf. (accessed Jan 20, 2014).