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3 Human Performance Modification as a Biological Problem Several technologies that can affect human biological systems are fertile ground for exploration of how human performance can be modified. These include tissue engineering, methods for combating fatigue related to the operational cycles of the human body, and issues associated with nutrition. Because nutrition was explicitly excluded from its task, the committee has restricted its discussion to human tissue engineering and fatigue research. TISSUE ENGINEERING The modification of the cellular aspects of humans is a subject of active inquiry throughout the world. The types of tissues that are being researched range from muscles (e.g., to increase strength) to organs (e.g., to create replacement organs). The research is being conducted in sports- medicine laboratories, genetic-engineering laboratories, and rehabilitative-surgery centers. The committee found tissue engineering to be one of the most difficult subjects to review because it is so vast, so varied, and so complex. Further, because the topic involves direct interference in the human body, there are widely differing views around the world as to what kinds of research are considered morally acceptable. Tissue engineering can be defined as the use of cells, engineering, materials, and suitable biochemical and physiochemical factors to improve or replace biological functions. Success has been achieved in tissues that are thin membranes, that are avascular, or that have high regeneration potential. For example, tissue-engineered skin, cartilage, bone, and corneas have been used clinically (Khademhosseini et al., 2009). There have been three approaches to tissue engineering: the conductive approach, using a material to provide the structural framework for cell infiltration; the inductive approach, using soluble materials to promote cell infiltration; and the cell-replacement approach, providing either an allograft (from a donor) or an autologous graft (from the patient) to repair a tissue. Those approaches have been successfully used clinically to improve regeneration. Tissue engineering can be used to speed recovery and to improve the quality of the generated tissue. In the case of cell-replacement therapies, the cell source is of great importance. With a shortage of donor organs and available cells, stem cells are the primary alternative to isolating cells from a patient’s tissue (Doss et al., 2004). Human embryonic stem cells, which have the capacity to differentiate into all cell types, have resulted in the formation of teratomas1 when implanted in vivo (Thomson et al., 1998; Caspi et al., 2007). Adult stem cells, which can 1 A teratoma is a “multi-layered benign tumor that grows from pluripotent cells injected into mice with a dysfunctional immune system. Scientists test whether they have established a human embryonic stem cell (hESC) line by injecting putative stem cells into such mice and verifying that the resulting teratomas contain cells derived from all three embryonic germ layers.” National Institutes of Health, U.S. Department of Health and Human Services. 2011. Stem Cell Information. Available at http://stemcells.nih.gov/info/glossary. Accessed August 10, 2012. 23
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24 HUMAN PERFORMANCE MODIFICATION: REVIEW OF WORLDWIDE RESEARCH differentiate into several but not all cell types, have been in use for decades. Hematopoietic2 and mesenchymal3 stem cells are commonly used but have limited capacity. Primary cells, or terminally differentiated cells, lack the capacity to regenerate numerous times, and often cell quality decreases with each passage. Today, most tissues are too complex to be replicated. First, the ability to create a vascularized tissue remains a fundamental challenge in the field. Mass-transport limitations governing nutrients and waste affect the function and viability of a tissue (Allen et al., 2001; Sachlos and Auguste, 2008). Microfluidic, capillary-like systems exhibit high resistance and require substantial pressures to produce continuous flow. Second, the ability to organize cells in three dimensions is limited. Hydrogel-based and scaffold-based matrices offer little help in the assembly of cellular networks, which are important for cell–cell communication. For example, the heart and muscles must contract synchronously. Discontinuities within the cell organization can result in loss of function or abnormal gene expression, which can lead to a diseased state. Thus, cell organization, mechanics, and electric signals must all be linked to produce a viable, functional tissue. Focused efforts have tried to repair tissue by mimicking 3-D tissue architecture, extracellular matrix, and cell organization. For example, organ printing was established as a bottom-up approach that uses 100- to 500-μm aggregates of cells, known as tissue spheroids, as building blocks to make 3-D tissue constructs (Ruei-Zeng and Hwan-You, 2008). Robotic bioprinting of hydrogel droplets containing cells can be used to dispense or digitally spray tissue spheroids to achieve multicellular structures (Wang et al., 2006). Cells then self-assemble within and between spheroids to form larger, integrated structures. However, mass-transport limitations hinder the advancement of this technology. In summary, the ability to enhance tissue performance is limited by (1) the need to obtain adequate and substantial numbers of viable cells, (2) mass-transport characteristics that dictate cell viability, and (3) the need to recapitulate the tissue architecture and cell organization that are required for tissue function. Tissue-engineering methods are focused on clinical repair, and current methods are unable to surpass the functioning of healthy tissue. Worldwide Research Tissue engineering has commercial applications in ligament repair and replacement, and epidermal constructs. The committee found that the countries with companies that provide products in this field include Australia, France, Italy, Germany, the United States, the United Kingdom, Switzerland, Japan, and Korea. Research on organ regeneration and bone replacement is also under way. FATIGUE: JUDGMENT AND DECISION MAKING Good human–machine system design exploits human strengths (such as pattern recognition and decision making) and protects against human weaknesses. “The human operator brings much more performance variability to a system than one finds in [reliable] software and modern hardware. . . . Once an operator has been trained and is current in system operation, the greatest 2 “Hematopoietic stem cells are immature cells that develop into all types of blood cells including white blood cells, red blood cells and platelets.” National Institutes of Health, U.S. Department of Health and Human Services. 2011. Stem Cell Information. Available at http://stemcells.nih.gov/info/glossary. Accessed July 31, 212. For more information on hematopoietic stem cells, see http://stemcells.nih.gov/info/basics/basics4.asp. Accessed July 31, 2012. 3 Mesenchymal stem cells are “rare cells mainly found in the bone marrow that can give rise to a large number of tissue types such as bone, cartilage (the lining of joints), fat tissue and connective tissue (tissue that is in between organs and structures in the body).” Texas Heart Institute. 2009. Available at http://texasheart.org/Research /StemCellCenter/Glossary.cfm. Accessed July 31, 2012.
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HUMAN PERFORMANCE MODIFICATION AS A BIOLOGICAL PROBLEM 25 contributor to variability in that person’s performance is cognitive fatigue,” especially during night work (Folkard and Tucker, 2003; Miller 2005, 2010). The human body has complex operational requirements, one of which is adequate rest. During rest periods, such as sleep, vital functions occur (Matthews et al., 2012). When the body is deprived of rest, specifically sleep, those functions do not occur, and the ability of the person to perform degrades predictably. The effect is noticeable in both cognitive and muscular performance. Sleep deprivation also causes substantial physiologic changes, such as increases in blood pressure (Conquest, 1991; Matthews et al., 2012; Chan et al., 1993). The need for sleep is complicated by the reaction of the human body to light and dark. Sleep during periods of light is not as effective in operational restoration of the human mechanism as sleep during periods of darkness. Research has shown that job effectiveness, as measured in terms of the speed and accuracy of trained workers, is highest between 7 a.m. and 7 p.m. and lowest during the predawn hours (Fokard and Tucker, 2003; Office of Technology Assessment, 1991). Physical fatigue in people is manifested in deteriorated dexterity, decreased eye–hand coordination, tremors, discomfort, and loss of strength and endurance. It is often not only how long a person works or how much rest and sleep he or she receives, but also the type of physical and mental workload that the person is subjected to while awake that determines whether fatigue is present (Chaffin et al., 2006). System design can play an important part in improving or optimizing the performance of human elements in the overall system (Costa, 2001). Conversely, human performance can be degraded by taking advantage of perturbations to normal operational cycles (for example, attacking before dawn) (Gunzelman et al., 2012). Some research in the various aspects of human fatigue is focusing on how human performance can be modified—improved or degraded—through fatigue-related elements of system design and performance (Matthews et al., 2012). Research tends to be focused on working situations in which altered sleep patterns are necessary, such as military movements or shift-work environments (Hull, 1990; Office of Technology Assessment, 1991; West et al., 2007; Samaha et al., 2007). It is clear that fatigue-inducing situations degrade human performance. They can lead to dangerous situations, such as when a transport worker’s decision-making ability is degraded because of fatigue. Research has shown that fatigue has serious effects on the human brain (Reeves et al., 2006, 2007). But research results are mixed as to how to optimize human sleep needs in operational environments that demand 24-hour activity, such as in medical facilities, prisons, manufacturing plants, and telecommunications facilities (Costa, 2001). The optimization of length and staggering of shift assignments are being studied, but no clear picture of a “right” answer has emerged. Each environment has a different type of worker and different operational requirements, and this may explain why the research findings are mixed. Some technologies can affect fatigue. For example, there has been a revolution in the science and technology of light-induced human performance modification. The use of spectrum-tuned light sources can wake people up or cause them to become drowsy. Examples are the recent identification of the melanopsin-pigmented retinal ganglion cell system, which is exquisitely sensitive to 460- to 480-nm blue light, and the use of blue-light filtering (in Canada) and blue- light treatment (in Europe) to affect human performance in 24/7 operations. The energy in that narrow window—6 percent of the total visual light spectrum—can duplicate the effects of the energy of the total light spectrum. These developments can be expected to influence the design of lighting systems, computer display screens, and eyewear. For example, Casper (at the University of Toronto) has shown that filtering out 460- to 480-nm light dramatically improves vigilance and performance in the circadian nadir (Rahman et al., 2011); it reverses the nocturnal dip in performance and provides users an enormous advantage in nighttime and early-morning operations.
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26 HUMAN PERFORMANCE MODIFICATION: REVIEW OF WORLDWIDE RESEARCH The practical applications of such technologies are being explored in various situations, such as military deployments and long-haul trucking (Paul et al., 2007). Paul and his Canadian colleagues have successfully countered jet lag and shift lag by timing light treatments in conjunction with timing ingestion of sustained-release melatonin. Light treatments are also being used in the treatment of seasonal affective disorder. The physiologic mechanisms are still being explored (Boivin and James, 2005; James et al., 2004). A combination of the technologies with pharmacologic agents, such as caffeine or melatonin, and structured changes in sleep patterns can assist people who must move between time zones (Piérard et al., 2001). Most fatigue researchers point out that the solutions to worker fatigue include the participation of workers’ organizations, managers, and supervisors. Fatigue is difficult for people to manage successfully apart from their work environments. Enormous strides have been made in the design, development, and implementation of fatigue-risk management systems (FRMSs). Regulations and laws have been passed that require FRMSs, as discussed in the comprehensive FRMS guidance statement published by the American College of Occupational and Environmental Medicine (Lerman et al., 2012). Interestingly, some people are naturally fatigue-resistant (Aeschbach et al., 2003; He et al., 2009; King et al., 2009). There might be an identifiable genetic component of that attribute that has not yet been discovered. If such a genetic component is identified, it might be a useful target for experimentation to help workers or soldiers to become fatigue-resistant. Knowledge about the nature of fatigue associated with many kinds of specific jobs may be used to optimize operational plans. International working-time regulations may affect military or contractor duty periods during training. The accident and incident risks associated with fatigue may be documented and quantified, and the results may inform operational planning. In the next 5 years, 12-hour shifts may come to dominate 24/7 operations because of the flexibility they provide workers to structure their off-duty time. Technologies for ambient light treatment in the nighttime workplace have been deployed commercially and may be used to enhance nighttime work performance. Readiness-for-duty testing technologies have been deployed minimally in the commercial world (Axelsson et al., 1998; Bloodworth et al., 2001; Campolo et al., 1998; Dwyer et al., 2007; Laundry and Lees, 1991; McGettrick and O’Neill, 2006; Richardson et al., 2007; Smith et al., 1998; Tucker et al., 1998; Williamson et al., 1994). In the next 5-10 years, fatigue-risk modeling will become common in 24/7 operations. Modafinil may be approved as an over-the-counter stimulant to be used somewhat like caffeine. Top-down FRMSs will be common in 24/7 operations, and the practice of removing sleep debt before critical operations will also be common. In the next 10-15 years, pretravel adjustment of the circadian rhythm will become common, and on-duty napping during 24/7 and nighttime operations will become an accepted practice. In the next 15-20 years, rapidly rotating and flexible shift plans will be used in support of 24/7 operations, and more care will be taken to ensure that enough personnel will be available to support four- and five-crew solutions to meet 24/7 work demand (Axelsson et al., 1998; Bloodworth et al., 2001; Campolo et al., 1998; Dwyer et al., 2007; Laundry and Lees, 1991; McGettrick and O’Neill, 2006; Richardson et al., 2007; Smith et al., 1998; Tucker et al., 1998; Williamson et al., 1994). There are some indications that physiological stimulation of the human body can interfere with sleep biology (De Groen, 1979). At the crudest level, such stimulation might be a physical nudge. At the most sophisticated level, it might be brain stimulation (Dimitrov and Ralev, 2009). It is well within the realm of imagination to consider the potential of implants, such as electrodes, that might provide such stimulation if a series of warning indicators were detected. Alerts based on measurement of ocular movements and blinks have been used successfully to reduce impairment caused by drowsiness in real time in equipment-operating tasks (Johns et al., 2007).4 4 Fletcher, Adam. 2012. “Technologies for Fatigue Detection and Management.” Presentation to the committee, March 8.
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HUMAN PERFORMANCE MODIFICATION AS A BIOLOGICAL PROBLEM 27 The alerts have been effective temporarily, but additional research is needed to assess their full impact on fatigue. Recent advances in integration of computing power into personally wearable devices, such as smart wristwatches, will probably contribute to advances in the ability to measure and respond to physiologic changes that indicate fatigue. Worldwide Research The committee found that open research in human fatigue is being conducted in several countries: Belgium, Australia, the Netherlands, Germany, Canada, Japan, the United Kingdom, the United States, Kuwait, Italy, France, Poland, and Singapore.