6

Energy

INTRODUCTION

The U.S. health care industry representing approximately $3 trillion of annual expenditures1 and employing roughly 15 million people2 comprises one of the largest sectors of the national economy. Our nation boasts the most technologically advanced, and the most costly, health care system in the world: almost 20 cents of every dollar is spent on health care. To remain the world leader in developing and introducing innovative medical instrumentation while improving and bringing down the cost of health care will require continued investment in research and development. Photonics technology plays a key role in providing the most effective, lowest-cost approaches for diagnosing, treating, and preventing disease and maintaining a healthy U.S. citizenry.3 In the nearly 15 years since the publication of the National Research Council’s (NRC’s) Harnessing Light: Optical Science and Engineering for the 21st Century,4 advances in photonics technologies and developments

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1 Centers for Medicare and Medicaid Services. 2012. “National Health Expenditures 2010 Highlights.” Available at http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData/Downloads/highlights.pdf. Accessed August 1, 2012.

2 SelectUSA. 2012. “The Health and Medical Technology Industry in the United States.” Available at http://selectusa.commerce.gov/industry-snapshots/health-and-medical-technology-industry-unitedstates. Accessed August 1, 2012.

3 For a more detailed description of the optics and photonics in the service of health and medicine, see the full description in Appendix C of this report.

4 National Research Council. 1998. Harnessing Light: Optical Science and Engineering for the 21st Century. Washington, D.C.: National Academy Press.



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6 Health and Medicine INTRODUCTION The U.S. health care industry representing approximately $3 trillion of annual expenditures1 and employing roughly 15 million people2 comprises one of the largest sectors of the national economy. Our nation boasts the most technologically advanced, and the most costly, health care system in the world: almost 20 cents of every dollar is spent on health care. To remain the world leader in developing and introducing innovative medical instrumentation while improving and bringing down the cost of health care will require continued investment in research and development. Photonics technology plays a key role in providing the most effec- tive, lowest-cost approaches for diagnosing, treating, and preventing disease and maintaining a healthy U.S. citizenry.3 In the nearly 15 years since the publication of the National Research Council’s (NRC’s) Harnessing Light: Optical Science and Engineering for the 21st Century,4 advances in photonics technologies and develop- 1  Centers for Medicare and Medicaid Services. 2012. “National Health Expenditures 2010 High- lights.” Available at http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and- Reports/NationalHealthExpendData/Downloads/highlights.pdf. Accessed August 1, 2012. 2  SelectUSA. 2012. “The Health and Medical Technology Industry in the United States.” Available at http://selectusa.commerce.gov/industry-snapshots/health-and-medical-technology-industry-united- states. Accessed August 1, 2012. 3  For a more detailed description of the optics and photonics in the service of health and medicine, see the full description in Appendix C of this report. 4  National Research Council. 1998. Harnessing Light: Optical Science and Engineering for the 21st Century. Washington, D.C.: National Academy Press. 163

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164 Optics and Photonics: Essential Technologies for O u r N at i o n ments in the field of biophotonics have created many opportunities for significant improvements in the quality of health care as well as for substantial reductions in the overall cost. The discipline of biophotonics deals with the interaction of light, or electro- magnetic radiation, with living organisms and biologically active macromolecules: proteins (hemoglobin), nucleic acids (DNA and RNA), and metabolites (glucose and lactose). Light interacts with biological material and organisms in many diverse ways, depending primarily on the energy or color of the photon. At both high (x ray) and low (radio frequency [RF]) energies the body is mostly transparent, thus allowing the non-invasive imaging of the internal structure of organs and bones. In contrast, certain colors or wavelengths in the infrared (IR) and ultraviolet (UV) regions are absorbed strongly by biological tissues. The intense, focused light of lasers with these colors can be used for a wide variety of unique therapeutic inter- ventions: making incisions, cauterizing and sealing wounds, and selectively heating or even vaporizing specific regions of organs and tissues. In the visible region of the spectrum, some biologically active macromolecules naturally absorb specific photon energies or colors. The amount of this intrinsic absorption can be used to determine the physiological health of an organ—for example, whether the tissue is getting sufficient oxygenated blood flow. Non-absorbing macromolecules can be labeled using specifically engineered dyes that selectively bind to macromolecules. These dyes or biomarkers can be used in conjunction with visible and near-infrared light to highlight specific cell and tissue types, such as metastatic cancer cells cir- culating in the bloodstream. Modern biomedical instrumentation takes advantage of this wide range of interactions between photons and biological materials and provides a remarkably broad set of tools for the physician and life scientist. HISTORICAL OVERVIEW OF THE IMPACT OF TECHNOLOGY ON MEDICINE Prior to the modern age of medicine, physicians primarily used their five senses directly to determine the causes of ill health.5 For example: • The color of a person’s eyes was studied to detect jaundice and possible liver failure. • The urine of patients was tasted for sweetness, to detect the presence of glucose and diagnose diabetes. • An ammonia-like odor in urine implied possible kidney failure. 5  Berger, D. 1999. A brief history of medical diagnosis and the birth of the clinical laboratory. Part 1—Ancient times through the 19th century. Medical Laboratory Observer 31(7):28-30, 32, 34-40.

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H e a lt h and Medicine 165 • The chest was struck or thumped and the resulting sound analyzed to iden- tify the presence of fluid in the lungs, implying tuberculosis or pneumonia. • The abdomen and breasts were palpated to detect cancerous lumps. Currently biomedical technology extends and enhances the senses of the physi- cian and thus dramatically increases the ability of the physician to diagnose disease. Considering that the primary sense used by physicians in diagnosis was sight, it is understandable that optics and imaging have played a critical role in improving health care. Over the past 100 years, optics and imaging have allowed the clinician to see the previously unseen. For example, observation of bacteria and microbial parasites led to the development of antibiotics, and direct imaging of skeleton and organs with x ray aided in observing and setting bone fractures and diagnosing traumatic injuries to other organs. For example, laser-based flow cytometers pro- vide detailed quantification of critical blood cell types, which is one of the primary tools for diagnosing and monitoring the treatment of AIDS patients.6 In addition to allowing the physician to see what could not be seen unaided, state-of-the-art optical technologies increase the sensitivity and specificity of mea- surements far beyond the physician’s sense of taste, smell, hearing, and touch.7 Photonics plays a major role in many modern molecular diagnostic instruments. Optical technologies now provide precise measurements of blood serum chemistry for maintaining safe glucose levels in patients with diabetes, replacing urine taste tests.8 Kidney function tests rely on accurate optical measurements of the glo- merular filtration rate (GFR) rather than smelling a patient’s urine. Lung diseases such as emphysema, lung cancer, and tuberculosis are detected using computed tomography (CT) and chest x ray imaging. In addition, these imaging modalities provide more complete diagnosis of potential tumors detected by palpation. During the 20th century, improvements in medical technology have doubled the life expectancy9 of individuals in high-income countries, changing the primary causes of death for a typical individual. One hundred years ago, infectious diseases often killed most individuals before the age of 50, whereas today the typical indi- vidual in a high-income country lives until the age of 80. Optics and photonics have been essential technologies leading to this dramatic increase in life expectancy. For example, the microscope was the key technology allowing discoveries in microbi- 6  Hazenberg, M.D., S.A. Otto, B.H. van Benthem, M.T. Roos, R.A. Coutinho, J.M. Lange, D. H ­ amann, M. Prins, and F. Miedema. 2003. Persistent immune activation in HIV-1 infection is asso­ ciated with progression to AIDS. AIDS 17(13):1881-1888. 7  Bynum, W.F., and Roy Porter, eds. 1933. Medicine and the Five Senses. Cambridge, Mass.: C ­ ambridge University Press. 8  For more information, see Appendix C in this report. 9  See, for example, the CIA’s World Factbook, available at https://www.cia.gov/library/publications/ the-world-factbook/. Accessed December 1, 2011.

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166 Optics and Photonics: Essential Technologies for O u r N at i o n FIGURE 6.1  Life expectancy: 2011 estimates by CIA World Factbook. SOURCE: CIA. 2011. World Factbook. Available at https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html. ology which determined that germs are the underlying cause of most infectious diseases, leading to the development of effective antibiotic drugs. The primary causes of death today (heart disease, cancer, diabetes, and neuro- degenerative diseases) are diseases that are more prevalent at older ages. The success of modern medicine has therefore created a series of new challenges, requiring further innovation. Many of these challenges are being met using optics and photonics instrumen- tation, which is providing scientific insights into the underlying molecular biology causing these diseases as well as quantitative new diagnostic instruments to help steer effective interventional therapies. In low-income countries, infectious diseases, such as tuberculosis, malaria, and AIDS, remain leading causes of death. This is due in large part to the absence of low-cost diagnostic tests that can detect these diseases at an early stage when the infections can be more easily contained and cost-effective intervention strategies can be employed. (See Figure 6.1.) OPTICS AND PHOTONICS IN MEDICAL PRACTICE TODAY A patient entering the emergency room (ER) with chest pains or a severe headache almost invariably receives a high-resolution, three-dimensional scan us- ing CT or magnetic resonance imaging (MRI) as an initial diagnostic screening, which can assist in the diagnosis of a heart attack, pulmonary embolism, or stroke. CT and MRI both use photons with wavelengths for which the human body is very

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H e a lt h and Medicine 167 transparent, creating comprehensive, high-resolution, three-dimensional images of the anatomy: CT uses x-ray photons and MRI uses RF photons.10 Stroke and heart attack can lead to sudden death, but effective interventions exist if the condi- tions can be diagnosed swiftly. If a nonresponsive patient comes to the ER with an unlabeled prescription in his or her pocket, how can the ER attendant determine whether or not the patient’s drugs have contributed to his or her condition? New technology using lasers has the potential to provide a fast method for identifying drugs by exposing the pills to laser light and observing the spectra emitted in re- sponse to the laser excitation. The colors emitted by the sample provide a unique fingerprint, which can be compared with a database of more than 5,000 common pharmaceuticals to determine the precise makeup of the patient’s prescription and to determine quickly whether these drugs contributed to the patient’s condition.11 In the surgical suite, brain damage occurs in less than 5 minutes in anesthetized patients during surgery if sufficient oxygen levels are not maintained. During the early and mid-20th century, the monitoring of blood oxygen levels required taking a blood sample and sending it to the hospital laboratory for analysis. This process typically took tens of minutes to complete, presenting significant hazards to the patient with such slow feedback. These procedures were revolutionized by opti- cal pulse oximeters, developed in the 1980s, which precisely measure the ratio of the absorption levels of the blood at two wavelengths, using convenient, low-cost, disposable optical probes based on light-emitting diodes (LEDs) and inexpensive solid-state detectors.12 In the past, mortality rates of 1 in 2,000 to 1 in 7,000 were reported in developed countries, and many patients suffered brain damage owing to oxygen deprivation during surgery;13 today such deaths and injuries have es- sentially been eliminated. Surgery almost always results in some unavoidable trauma to the patient. Minimizing the size of the surgical incision reduces this trauma and can dramati- cally speed recovery. Modern optical endoscopes provide a close-up view of organs and a method for implementing laser surgery, utilizing incisions of less than a few centimeters. In addition, endoscopic visualization is now the standard of care for screening for colon cancer and for diagnosing esophageal cancer. Commonly used today in orthopedic surgery for repairing injuries in almost all of the major joints 10  For more information about developments in CT instruments, see Appendix C. 11  Gendrin, C., Y. Roggo, and C. Collet. 2008. Pharmaceutical applications of vibrational chemi- cal imaging and chemometrics: A review. Journal of Pharmaceutical and Biomedical Analysis 48(3): 533-553. 12  For more information about O saturation measurements, see Appendix C in this report. 2 13  World Health Organization (WHO). 2008. Global Pulse Oximetry Project. Background docu- ment. First International Consultation Meeting. WHO Headquarters, Geneva, CH. Available at http://www.who.int/patientsafety/events/08/1st_pulse_oximetry_meeting_background_doc.pdf. Ac- cessed August 1, 2012.

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168 Optics and Photonics: Essential Technologies for O u r N at i o n (knee, elbow, hip, wrist), this technology has allowed many surgeries to become outpatient procedures, eliminating hospital stays and greatly reducing health care costs. Besides being ubiquitous in the hospital, optical methods and instruments are also used in monitoring chronic conditions and in many outpatient surgical proce- dures.14 The most pervasive use of optics and lasers in surgery is in ophthalmology. Laser treatments are standard therapy for treating blindness due to diabetes as well as age-related degenerative disease. One of the most common laser cosmetic surgeries today is the correction of focus of the eye lens by the precise shaping of the cornea, a procedure that has been performed on tens of millions of patients. Lasers and optics are also used in many outpatient elective cosmetic procedures, such as skin resurfacing and hair and tattoo removal. Almost everyone has had blood drawn and sent to the clinical laboratory for blood tests, but few people are aware that these blood samples are analyzed using lasers and optical imaging to provide the measurements characterizing the status of the patient’s blood and circulatory system. Many types of blood cells have distinct shapes and unique internal structures, which can be detected by illuminating the cells with a laser beam and analyzing the transmitted and scattered laser light. The laser-based instruments used for these purposes can count many thousands of cells per second and are used to measure with great precision the different types of cells present in the bloodstream. A doctor detecting a suspicious lump in a patient will often order an explor- atory biopsy, which is sent to the pathology laboratory. High-resolution imaging of the excised tissue and analysis of the size and shape of the cells provide the most precise diagnosis of tumor malignancy and aggressiveness. These images also can help determine the boundaries between healthy and diseased tumor tissue, provid- ing a surgeon with guidance about how much tissue needs to be removed to fully excise a tumor. ADVANCES IN TECHNOLOGY PROVIDING THE OPPORTUNITY FOR NEW APPLICATIONS OF PHOTONICS New optical technology has accelerated the translation of remarkable new capabilities into medical practice. As an example, just 30 years ago the standard technique for sequencing genes involved the radioactive labeling (using a radioac- tive isotope of phosphorous) of the gene bases, gel electrophoresis to separate the gene fragments by size, and the overnight exposure of an optical film placed in close proximity to the gel. This laborious and time-consuming process allowed the se- quencing of only several hundred bases during a typical day. With the introduction of optical methods in the 1980s, including four-color sequencing and optical scan- 14  For more information, see Appendix C.

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H e a lt h and Medicine 169 ning of the gel, the speed of sequencing increased by a factor of 10. The develop- ment of superior separation technologies, including capillary electrophoresis and better optical designs using confocal laser scanning, increased sequencing speed by about another factor of 10. Recently, single molecular fluorescence detection dur- ing single-strand DNA synthesis, synthesis-based sequencing (SBS), has replaced electrophoresis. Low-noise, high-resolution charge-coupled device (CCD) imaging devices allow the simultaneous sequencing of millions of individual DNA strands. These technologies have increased the speed of sequencing by a factor of 1,000. (See Figure 6.2.) Not only has the speed increased by 100,000-fold, but the cost of sequencing the genome has decreased from billions of dollars to under $1,000. Data collected during 1 day in a typical sequencing laboratory in 1970 would fill approximately half of a single page in a lab notebook. In 1990, the technology produced enough data to fill a chapter of a lab book, or about 20 pages in a single day. In the year 2000, a single day’s data would fill a whole lab book. Present-day technology, driven by advances in laser sources, nanophotonics, and detectors, generate enough data in 1 hour to fill the contents of 10, 24-volume encyclopedias. ADVANCES IN TECHNOLOGY PROVIDING THE OPPORTUNITY FOR FUTURE APPLICATIONS OF PHOTONICS Continuing advances in several critical areas of technology have dramatically increased the capabilities of biomedical optical instrumentation and herald a new era of innovation in biomedical optics, leading to improvements in treating many types of diseases. New optical sources and materials, imaging devices, microfluidic technologies, and detection methods will provide remarkable increases in speed, sensitivity, and precision for biomedical optical instrumentation. Nucleic Acid Sequence Detection and Mutation Detection Predilections for many diseases are the result of the specific makeup of an in- dividual’s inherited genetic code. Specific alterations in certain genes can dramati- cally increase the likelihood of cancer, cognitive impairment, and severe allergic reactions to certain types of food. Early identification of these inherited tendencies allows preventive strategies to be in place before the disease causes significant dam- age. With the advent of rapid and much-lower-cost methods for whole genome sequencing, many of which rely on optical methods, the possibility exists that a wide range of correlations between genetic makeup and disease predilection can be detected earlier, and appropriate interventions put in place.15 Today, sequencing a complete human genome costs less than $5,000; it is 15  For more information, see Appendix C.

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170 Optics and Photonics: Essential Technologies for O u r N at i o n (a) FIGURE 6.2 Technologies have increased the speed of s ­ equencing by a factor of 1,000. Time to sequence a sin- gle human genome with (a) pre-laser DNA sequencers (1970s), (b) 1990s laser-based DNA sequencers, and (c) second-­ eneration laser-based DNA sequencers. SOURCE: g (b) C ­ ongressional briefing by Thomas Baer, Executive Director, Stanford Photonics Research Center, Stanford University, Palo Alto, Calif. November 30, 2010. Available at http://portal.acs. org/preview/fileFetch/C/CNBP_026401/pdf/CNBP_026401. pdf. Accessed November 8, 2012. (c)

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H e a lt h and Medicine 171 projected that the next generation of instruments will reduce the cost to $1,000 over the next few years.16 The new generation of SBS sequencers (see Box 6.1 and Figure 6.3) combines nanotechnology with photonics to achieve this remarkable increase in speed.17 To reach their full potential, these instruments will require fur- ther investment in research to develop higher-speed and -sensitivity CCD cameras, more efficient labeling dyes, high-speed software to extract quantitative informa- tion from large, high-resolution images, and nanophotonic structures optimized to localize the fluorescent signals from the individual DNA strands. Proteomic Analysis Through Protein and Tissue Arrays Detecting cancer recurrence early, determining the most appropriate drug therapy to slow tumor growth, and detecting and/or diagnosing a number of deadly infectious diseases are all examples of diagnostic tests that rely on measuring specific proteins in the blood serum. Recent advances in protein detection using photonics technology platforms are providing dramatic increases in sensitivity and specificity. Microfluidics and robotics combined with optics provide the technology to create arrays of tissue samples on slides that can be automatically laser scanned and analyzed after exposure to fluorescently labeled antibodies which attach to tumor-specific proteins. These tissue arrays are analyzed using laser scanners and automated image analysis of the digital images. Drug interactions and molecular structures can be studied across hundreds of diseased and healthy patient samples all located on a single slide. This technology has the potential for greatly accelerat- ing the drug development process and reducing development costs. These protein-measuring instruments use automated, high-resolution micros- copy, wide-field-of-view, low-noise imaging devices, and quantitative fluorescence microscopy. The performance of these instruments will improve greatly with ad- vances in the areas of optics and photonics technology. High-Throughput Screening The development of new drugs based on small molecules is often limited by the rate at which candidate molecules can be screened for their therapeutic effect on target cell cultures. In recent years, optical technology has been combined with 16  Bio-ITWorld Staff. 2011. “Illumina Announces $5,000 Genome Pricing.” Available at http:// www.bio-itworld.com/news/05/09/2011/Illumina-announces-five-thousand-dollar-genome.html. Accessed August 1, 2012. 17  Margulies, M., M. Egholm, and W.E. Altman, et al. 2005. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376-380.

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172 Optics and Photonics: Essential Technologies for O u r N at i o n BOX 6.1 Nucleic Acid Synthesis-Based Sequencing The first human genome was sequenced using technology based on electrophoresis, a process by which molecules of different sizes and chemical makeup are separated spatially in special gelatins by running an electric current through the gel. This process allowed different nucleic acid sequences to be isolated and the genetic code to be read out using fluorescent tags and laser scanners. The newest approaches to gene sequencing use a radically different approach—called synthesis- based sequencing (SBS)—which relies on several key photonics technologies. A sample containing a quantity of DNA molecules with unknown sequences is placed in a special microfluidics chamber. In this chamber separate strands of DNA are captured in different locations and then are copied by special enzymes. As the copy is created, each added base is incorporated into the growing DNA strand along with a fluorescent dye. Each of the four bases is coupled to a different-colored dye. The addition of each new base is detected by exciting the fluorescence dye with a laser and detecting the color of the fluores- cence using a high-resolution, high-sensitivity CCD (charge-coupled device) camera. After the dye color is detected and the added base is identified, the dye molecule is enzymatically cleaved from the DNA strand. This process is repeated until the all of the bases have been added and identified and the DNA sequence has been determined. This synthesis of copies of the various DNA molecules in the sample takes place simultaneously in hundreds of thousands of distinct locations, all of which can be monitored in parallel by high-sensitivity cameras that can detect signals as low as a single photon from each synthesis site. This approach has increased the speed of the sequencing of nucleic acids by many orders of magnitude. Currently, a single instrument can sequence the 3 billion base pairs in a human genome in less than a day. In contrast, the hu- man genome project employed many hundreds of instruments and took more than 10 years to complete.   SOURCE: Fuller, C.W., L.R. Middendorf, S.A. Benner, G.M. Church, T. Harris, X. Huang, S.B. Jovanovich, J.R. Nelson, J.A. Schloss, D.C. Schwartz, and D.V. Vezenov. 2009. The challenges of ­ ­ equencing by synthesis. Nature Biotechnology 27(11):1013-1023. s robotics to provide the ability to screen hundreds of thousands of drug candidates per day, dramatically accelerating the drug discovery process. This high-throughput screening technology relies on robotic sample-handling automation for the precise and rapid parallel processing of multiple samples as well as on optical technology for high-speed quantitative data collection. Optical methods, including fluores- cence, bioluminescence, and colorimetry, are used to identify and count viable and nonviable cells affected by the candidate compounds, determine activated molecular pathways in target cells, and detect the overall cellular response to po- tential small-molecule drugs. An example of an approach that allows very low con- centrations of proteins to be detected by actually counting the protein molecules individually is seen in Figure 6.4. More recently, by combining microfluidics with microscopic imaging to enhance protein quantification, researchers have increased sample throughput by 1,000-fold, to an astounding 10 million samples per day,

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H e a lt h and Medicine 173 FIGURE 6.3  The Pacific Biosciences PacBio RS platform is used for single-molecule sequence data. SOURCE: © Pacific Biosciences. Reprinted with permission. FIGURE 6.4  Showing single occupancy: reaction wells approximately 5 microns in diameter contain a single bead coated with antibodies that trap a single target protein molecule. This single protein in turn binds a fluorescent enzyme that creates a fluorescent signal localized in the well, which is detected by laser scanning the well array. This approach allows very low concentrations of proteins to be detected by actually counting the protein molecules individually. SOURCE: Subbaraman, N. 2010. “Detecting Single Cancer Molecules.” Technology Review. Available at http://www.technologyreview. com/biomedicine/25462/. Reprinted with permission.

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174 Optics and Photonics: Essential Technologies for O u r N at i o n and radically reduced the sample volume and the time required for analysis.18 These instruments utilize and will benefit from improvements in high-sensitivity, quantum-limited imaging detectors and new, compact, long-lived laser sources. Flow Cytometry Mass Spectrometry Although essential to survival, the human immune system also is a key factor in a number of common diseases, such as rheumatoid arthritis, childhood or Type I diabetes, and arteriosclerosis. Understanding the complex processes that make up an immune response requires the simultaneous monitoring of the activity and con- centration of dozens of immune-system cell types. Lasers have traditionally been used in flow cytometer instruments to evaluate patient blood samples, identifying and counting the immune-system cell types. These instruments were limited in the past to quantifying only a few different cell types simultaneously. A new generation of flow cytometry instruments combines optical detection with mass spectrometry. This new technology promises to allow a status check of a patient’s immune system by simultaneously quantifying all of the major cellular constituents. When com- bined with other advanced proteomic technologies, including tissue microarrays and protein mass spectrometry, the CyTOF instrument (see Figure 6.5) will provide the most complete understanding of the immune system to date.19 Identifying immune cell types along with their associated functions in affected tissues—that is arthritic joints, inflammatory tissues, and pancreatic islets—will allow the most complete understanding of the local and systemic processes that underlie many degenerative diseases such as rheumatoid arthritis, diabetes, Alzheimer’s disease, and heart disease.20 Ophthalmology Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two of the leading causes of blindness, particularly in older patients.21 Laser-based surgical and drug therapies can slow the disease progression, particularly if the disease is detected prior to major damage to the retina. Early detection is difficult because the disease primarily impacts tissue beneath the surface of the retina, which 18  Agrestia, J.J., E. Antipov, A.R. Abate, K. Ahn, A.C. Rowat, J.-C. Baret, M. Marquez, A.M. Klibanov, A.D. Griffiths, and D.A. Weitz. 2009. Ultrahigh-throughput screening in drop-based microfluidics for directed evolution. Proceedings of the National Academy of Sciences of the United States of America 107(9):4004-4009. 19  Cheung, R.K., and P.J. Utz. 2011. Screening: CyTOF—the next generation of cell detection. Nature Reviews Rheumatology 7(9):502-503. 20  For information about use in HIV status, see Appendix C. 21  For more information, see the section on “Ophthalmology” in Appendix C.

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H e a lt h and Medicine 175 (a) (b) FIGURE 6.5  (a) A CyTOF instrument, which extends the capability of multi-parameter flow cytometry by atomic mass spectrometry to measure up to 100 biomarkers simultaneously in single cells at a rate of 1,000 cells per second; (b) data: 138-178 segment of mass spectrum for a homogeneous sample of several enriched isotopes of lanthanides. SOURCE: DVS Sciences, Inc. Available at http://www. dvssciences.com/index.html. Reprinted with permission.

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176 Optics and Photonics: Essential Technologies for O u r N at i o n is not easily observed in the early stage. New optical methods employing optical coherence tomography (OCT), a type of microscopic laser radar imaging that can probe beneath the surface of the retina, provide a method for precise subsurface imaging. OCT provides a high-resolution, three-dimensional image of the interior of the eye, allowing subsurface structures to be resolved down to a depth of about 1 millimeter below the surface of the retina. This capability allows early diagnosis and early intervention, which can stop or slow down the disease progression, provid- ing the potential for many additional years of visual acuity to affected individuals. The number of cases of AMD and DR has increased greatly due to the aging of the population and the obesity epidemic.22 Early detection and intervention with new anti-angiogenesis drugs have proven to be remarkably effective in treating AMD. Moreover, the efficacy of new drugs currently under development can be quantitatively assessed and compared using the three-dimensional OCT images, which accurately define the volume of the lesions in the retina caused by AMD. Changes in the lesion volumes provide a direct measure of the drug efficacy and can help determine effective and safe dosage levels. OCT also provides the capability for the accurate mapping of the lens and sur- rounding tissue capsule, which can be measured with great precision in all three dimensions. This information, when combined with laser surgery using ultrafast lasers, has the potential to revolutionize the protocol for treating cataracts. Using OCT guidance, femtosecond lasers can be precisely focused on the capsule and automatically cut close to perfectly round incisions in the capsule. These precise incisions greatly assist in locating and centering the replacement lens. The same ultrafast pulsed laser can also be used to segment the original occluded lens, which can then be much more easily extracted from the patient’s eye. This combination of OCT for precise measurement of eye morphology, along with precision fem- tosecond ultrafast laser machining, is setting a new standard for quality in these ophthalmic procedures, as seen in Figure 6.6.23 Image-Guided Surgery For most solid tumor cancers, surgical excision is often the optimal interven- tion strategy when it is feasible. Most often it is very important to balance the 22  AMD Alliance International. 2011. Increasing Understanding of Wet Age-Related Macular Degen- eration (AMD) as a Chronic Disease to ensure that all patients have access to early intervention, regular proactive treatment, and integrated care, and that research is ongoing for improved treatment options. Available at http://www.amdalliance.org/user_files/documents/AMD_ChronicDiseasePolicy_M03_ NoCrops_Low_Res.pdf. Accessed August 1, 2012. 23  Friedman, N.J., D.V. Palanker, G. Schuele, D. Andersen, G. Marcellino, B.S. Seibel, J. Batlle, R. Feliz, J.H. Talamo, M.S. Blumenkranz, and W.W. Culbertson. 2011. Femtosecond laser capsulotomy. Journal of Cataract and Refractive Surgery 37(7):1189-1198.

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H e a lt h and Medicine 177 FIGURE 6.6  Excised and stained lens capsule samples from (top) a manual capsulorhexis and (bot- tom) a laser capsulotomy with clearly improved boundaries of lens capsule cutting with optical coher- ence tomography (OCT)-guided femtosecond laser surgery. SOURCE: Reprinted with permission from Friedman, N.J., D.V. Palanker, G. Schuele, D. Andersen, G. Marcellino, B.S. Seibel, J. Batlle, R. Feliz, J.H. Talamo, M.S. Blumenkranz, and W.W. Culbertson. 2011. Femtosecond laser capsulotomy. Journal of Cataract and Refractive Surgery 37(7):1189-1198. need to remove the tumor completely versus the desire to maintain the integrity and function of the surrounding tissue. This is of particular importance in organs such as the brain, liver, and pancreas. Currently many surgical procedures require the excision of a sample portion of the affected organ, which is then sent to the pathology lab for analysis to determine the tumor boundaries, which then help guide the surgeon’s decision as to how much tissue to remove. This process is time-consuming and is typically performed while the patient is anesthetized. New optical techniques are being developed24 that provide real-time images of the tu- mor boundaries. These techniques employ fluorescent biomarkers (see Figure 6.7), which selectively bind to the tumor cells, providing a clear demarcation between the healthy and diseased tissues that can be visualized directly by the surgeon during the operation. Similar techniques can be used to highlight nearby nerves 24  For additional information, see Appendix C.

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178 Optics and Photonics: Essential Technologies for O u r N at i o n FIGURE 6.7  Comparisons highlighting different fluorescent biomarkers. (a) White light reflectance only used in (a-c); (b) Cy5 fluorescence (pseudocolored cyan, overlaid on reflectance) image high- lighting deeply buried nerve (long-stemmed arrow); (c) yellow fluorescent compound (YFP) fluores- cence (pseudocolored yellow, overlaid on reflectance) image highlights additional branches (large arrowhead); (d) white light reflectance only used in (d-f); (e) FAM fluorescence (pseudocolored cyan, overlaid on reflectance) image highlighting a stained buried nerve branch (large arrowhead); (f) Cy5 fluorescence (pseudocolored green, overlaid on reflectance) image highlighting a tumor (small arrow- heads). SOURCE: Reprinted with permission from Whitney, M.A., J.L. Crisp, L.T. Nguyen, B. Friedman, L.A. Gross, P. Steinbach, R.Y. Tsien, and Q.T. Nguyen. 2011. Fluorescent peptides highlight peripheral nerves during surgery in mice. Nature Biotechnology 29:352-356. and lymph nodes that may need to be carefully avoided or excised as part of the operational procedure.25 Dual Energy CT and Quantitative Image Analysis The primary causes of death in the United States today are heart disease, cancer, and pulmonary disease, such as emphysema.26 In all of these modern ailments, early detection is the key to effective intervention. Since, in their early stages, these diseases often develop with minor or no symptoms, appropriate routine screen- ing of at-risk populations must be implemented to detect disease in apparently healthy individuals. These screens must be low-cost, minimally invasive, and have low false-positive results in order to prevent unnecessary follow-on procedures. Imaging methods can provide a very effective approach to meeting these criteria. Recent large-scale clinical trials have demonstrated the ability of low-dose x ray CT scanning as a very effective method to screen for lung cancer tumors, 25  For information about the use of optic and photonics in biopsies, see Appendix C. 26  Centers for Disease Control and Prevention (CDC). 2012. “Leading Causes of Death.” Available at http://www.cdc.gov/nchs/fastats/lcod.htm/. Accessed August 1, 2012.

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H e a lt h and Medicine 179 cardiovascular disease, and early signs of emphysema. High-resolution CT scans of the chest provide data sets that allow precise measurement of the size of lesions in the lung and allow tracking of changes in the size of these lesions, which is a very specific indication of malignancy. These CT data sets can also provide measures of occlusions or obstruction in cardiac vasculature (early indication of heart attack risk) and assessment of pulmonary function (indicative of emphysema). CT imaging is a fast (a scan takes less than 10 seconds), non-invasive, and low-cost method for obtaining critical data that can be used to determine effec- tive early intervention, preventing disease progression and greatly reducing the cost of treatment and improving the quality of life for the patient. To achieve the full potential of this technology will require new approaches to data analysis and quantitative feature extraction. For example, to deploy effective screening services, more precise methods for quantifying tumor size, determining the level of calcifi- cation in cardiac vasculature, and extracting measures of lung expiration capacity must be developed. The critical contributions of optical technology to CT instrumentation (and other imaging platforms such as MRI and ultrasound) are often overlooked. Fun- damentally, CT devices are optical instruments, employing photons chosen with wavelengths for which the body is partially transparent to precisely image the inter- nal physiology of the patient. The x ray photon sources, the optics for focusing the x rays, and the detectors used to detect the x ray photons are designed employing many of the same techniques developed for the design of imaging instruments using visible light. Similarly, the mathematical methods for analyzing the raw trans- mitted x ray data, for reconstructing and visualizing three-dimensional models of internal anatomy, are almost identical to comparable techniques employed in other imaging modalities using visible or infrared light. Thus advances in detector technology, image reconstruction models, and techniques for quantitative feature extraction from large three-dimensional data sets will greatly enhance the perfor- mance of CT, MRI, and ultrasound imaging platforms.27 In general, advances in developing quantitative imaging data analysis pro- cedures are hindered by the inability of the scientific community to access com- mon data sets useful for comparing the performance of automated computerized methods to analyze the data. Establishment of the infrastructure to support public access to large data sets of image data and open-source software tools to extract clinically significant features from these data should be a national priority. Such an infrastructure is vital to accelerating advances in many different imaging modali- ties, including OCT, CT, MRI, ultrasound, x ray, diffuse optical imaging, and others. 27  Baer, T.M., J.L. Mulshine, and J.J. Jacobs. 2007. Biomedical Imaging Archive Network. Skeletal Radiology 36(9):799-801.

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180 Optics and Photonics: Essential Technologies for O u r N at i o n Biomedical Optics in Regenerative Medicine One of the most active frontiers of modern medicine is in the field of stem cell research. As more is learned about the fundamental processes behind how progeni- tor cells differentiate and develop into cell types that make up specific tissues and how tissue expands and develops into organs, the potential arises for using this knowledge to repair or replace organs that are damaged due to aging or traumatic injury. Time-lapse microscopic imaging of stem cells as they differentiate into dif- ferent cells types is playing a key role in identifying specific stages that characterize both normal and abnormal growth pathways. These data can potentially be used to determine which cells are safe to transplant into patients and which may be give rise to tumors.28 Biomedical Optics in Research Advances in technology and the application of new instruments often provide the basis for further insights and discoveries that lead to a deeper understanding of the causes and the molecular basis of diseases. Significant improvements in optical technology have dramatically increased the ability to measure and study biological processes in both in vitro and in vivo environments. The past few years have witnessed the birth and genesis of a whole new field of biophotonics called optogenetics.29 (This field was declared the Method of the Year in 2010 by the journal Nature Methods.30) As defined by Carl Deisseroth, one of its primary developers: “Optogenetics is the combination of genetic and optical methods to achieve gain or loss of function of well-defined events in specific cells of living tissue.”31 This technique has seen primary application in neuroscience, where the function of single neurons or groups of neurons can be monitored and controlled by specific wavelengths of light. Neurons in live, behaving animals can be genetically programmed to fire or be prevented from firing by exposure to dif- ferent colors of light. Moreover, the active or inactive state of the neuron can be detected by observing fluorescence from the neuron. This provides neuroscientists with tools very analogous to those used by engineers to study electronic circuits: specific neural circuits can be activated or deactivated, and the overall circuit re- 28  Wong, C.C., K.E. Loewke, N.L. Bossert, B. Behr, C.J. De Jonge, T.M. Baer, R.A. Reijo Pera. 2010. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nature Biotechnology 28:1115-1121. 29  For additional information, see Appendix C. 30  Nature Methods. 2011. “Method of the Year 2010.” Editorial. Available at http://www.nature.com/ nmeth/journal/v8/n1/full/nmeth.f.321.html. Accessed July 27, 2012. 31  Lin, S.-C., K. Deisseroth, and J.M. Henderson. 2011. Optogenetics: Background and Concepts for Neurosurgery. Neurosurgery 69(1):1-3.

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H e a lt h and Medicine 181 sponse to these changes and the changes to information flow through the neuronal circuit can be monitored in real time. All of these types of measurements have been performed in a wide variety of alert, active animals. These remarkable capabilities are made possible by the combination of the development of new forms of bioengineered, light-sensitive proteins and the ap- plication of two photon imaging instruments that allow the subsurface probing of neural anatomies. These new bioengineered materials and optical techniques have revolutionized the field of neuroscience and provide, essentially for the first time, the possibility of reverse engineering and modeling of the neural circuitry of complex brains in live animals. One of the fundamental principles of imaging that has limited the size of ob- jects that can be resolved is the diffraction limit. In essence, objects smaller than the wavelength of light used to illuminate the sample cannot be imaged clearly. Over the past 10 years, several techniques have been developed that allow the pre- cise location of single molecules to be determined to a fraction of a wavelength of light. These approaches allow startlingly vivid images illustrating the locations of proteins and small molecules in organelles and other structures within cells, providing a new capability for gaining insight into the mechanisms and functions of proteins within cells. Several other areas of biophotonics are in early stages of development but show great promise. These include the use of free electron laser coherent x ray sources to probe the structure of membrane bound proteins in situ. These proteins are often key drug targets, since they control signaling pathways within the cell that are in- volved with a number of diseases. Laser tweezers and atomic force microscopy are being used to measure what the impact of localized forces on cell membranes is and how these forces can initiate biochemical signaling within the cell. This research has important ramifications on the engineering of tissue structures to support the appropriate growth of specific cell types for organ transplantation. FINDINGS Key Finding: Many chronic, debilitating, and often fatal degenerative diseases impacting the aging population are mediated or exacerbated by the patient’s own immune system. Understanding and controlling the immune system are thus among the major challenges facing modern medicine today. Optical instrumenta- tion will continue to be the principal enabling technology allowing advances in the understanding of the immune system. Key Finding:  Stem cell science is advancing rapidly, providing great insight into how cells progress from progenitor cells (capable of transforming into any tissue type) to cells of a phenotype characteristic of a specific tissue. Controlling these

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182 Optics and Photonics: Essential Technologies for O u r N at i o n processes in vivo and developing confidence that once the cells are transplanted into a patient they will continue to develop normally, present a major remaining challenge that must be overcome before stem cells can be used broadly in regen- erative medicine. Microscopic imaging technologies will provide key non-invasive methods to monitor the growth process of stem-cell-derived tissues and help en- sure their safety and efficacy for transplantation. Finding:  Optical techniques using solid-state light sources and detectors com- bined with microfluidics are the ideal technology base for automated, low-cost, portable devices that can be operated by personnel without their needing extensive training. In high-income countries the primary causes of death and patient mor- bidity are degenerative diseases due to longer life expectancy; in contrast, in low- income countries the infectious diseases remain leading causes of death. One of the primary challenges for infectious diseases in low-income countries is to develop low-cost diagnostic methods that can identify disease in its pre-symptomatic and pre-infectious early stage. Additionally, diseases such as malaria and tuberculosis have different phenotypes that can be identified using optically based diagnostic methods and thus help determine the most effective course of therapy. Finding:  The current generation of imaging instruments (CT, MRI, OCT, and ultrasound) provides unprecedented resolution, allowing spectacular three-dimen- sional, non-invasive images of human anatomy. These data sets contain informa- tion that will allow early diagnosis of many potentially fatal diseases, including lung cancer, heart disease, emphysema, and Alzheimer’s disease. Early detection often provides the opportunity for the most effective intervention. However, these images contain an enormous amount of information, at times overwhelming the ability of the radiologist or clinician to effectively evaluate and digest all the information available from the raw images. Similar challenges are faced by ophthalmologists in- terpreting three-dimensional data sets generated by OCT instruments, and likewise by pathologists dealing with large data sets generated by the automated scanning of large tissue sections imaged with subcellular resolution. Automated image-analysis software can provide reliable quantitative measurement of key features from these complex data sets, improving the diagnostic reliability, decreasing the amount of time required, and lowering cost. Clearly all of these new image approaches have many challenges in common and could benefit from a centralized infrastructure for sharing data and image-analysis software algorithms. Finding:  A person’s genes determine, in part, that person’s tendency to succumb to specific diseases. Developing more cost-effective methods to sequence human genomes could lead to effective identification of an individual’s risk factors and potentially to effective early intervention and preventative strategies. Almost all of

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H e a lt h and Medicine 183 the most recent generation of high-throughput sequencing instruments are based on optical methods. RECOMMENDATIONS Key Recommendation:  The U.S. optics and photonics community should develop new instrumentation to allow simultaneous measurement of all immune-system cell types in a blood sample. Many health issues could be addressed by an improved knowledge of the immune system, which represents one of the major areas requir- ing better understanding. Key Recommendation:  New approaches, or dramatic improvements in existing methods and instruments, should be developed by industry and academia to in- crease the rate at which new pharmaceuticals can be safely developed and proved effective. Developing these approaches will require investment by the government and the private sector in optical methods integrated with high-speed sample- handling robotics, methods for evaluating the molecular makeup of microscopic samples, and increased sensitivity and specificity for detecting antibodies, enzymes, and important cell phenotypes. Recommendation:  The U.S. health care diagnostics industry, in cooperation with academia, should prioritize the development of low-cost diagnostics for extremely drug-resistant and multi-drug-resistant TB, malaria, HIV, and other dangerous pathogens, and low-cost blood-serum- and tissue-analysis technology to poten- tially save millions of lives per year. Recommendation:  The U.S. health care industry, in cooperation with academia, should prioritize the development of new optical instruments and integrated incu- bation technology capable of imaging expanding and differentiating cell cultures in vitro and in vivo, to provide important tools for predicting the safety and efficacy of stem-cell-derived tissue transplants. Recommendation:  The U.S. software and information technology industry, in cooperation with academia, should prioritize the development of new software methods automating the extracting, quantifying, and highlighting of important features in large, two- and three-dimensional data sets to optimize the utility of the latest generation of imaging instruments. Recommendation:  The U.S. life science instrumentation industry, in cooperation with academia and the federal government, should prioritize the development of the next generation of super-high-throughput sequencing devices, required for

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184 Optics and Photonics: Essential Technologies for O u r N at i o n lowering the cost of sequencing down to the target cost of $1,000 per genome. This will require advances in high-sensitivity, low-noise, high-resolution CCD cameras, high-efficiency laser sources, and nanophotonic devices integrated with microfluidics and automated systematic analysis. Recommendation:  The U.S. government should expand investment in multidis- ciplinary centers (e.g., at universities with medical and engineering schools) at which critical developments combining medical and engineering discoveries can be efficiently fostered. Recommendation:  The U.S. government, in cooperation with scientific and medi- cal societies, should facilitate the creation of an information technology infra- structure for sharing large amounts of medical and clinical data (e.g., quantitative imaging and molecular data) and open-source analysis tools.