- Email: [email protected]
The future of neurotechnology innovation
Epilepsy & Behavior 15 (2009) 120–122
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Technological Approaches to the Scientific Explorations of Epilepsy and Behavior
The future of neurotechnology innovation Zack Lynch Neurotechnology Industry Organization, 315 30th Street, San Francisco, CA 94131, USA
a r t i c l e
i n f o
Article history: Received 23 March 2009 Accepted 23 March 2009 Available online 25 April 2009
a b s t r a c t Advances across several areas of neurotechnology research including stem cells treatments, new imaging technologies, drug delivery technologies and novel neuromodulation platforms promise to accelerate the development of treatments and cures for brain-related illnesses. Ó 2009 Elsevier Inc. All rights reserved.
Keywords: Neurotechnology Neuromodulation Optogenetics Neuroimaging Stem cells Blood brain barrier Nanowires Economic burden Neurological disease Psychiatric illness
1. Introduction Neurological diseases and psychiatric illnesses account for more hospitalizations, long-term care, and chronic suffering than nearly all other health conditions combined. Beyond the untold human suffering, the annual economic burden of brain-related illnesses has reached more than $1 trillion in the United States [1]. Critical unmet medical needs remain in almost every area of brain and nervous system disorders, including: Alzheimer’s disease, addiction, anxiety, depression, epilepsy, multiple sclerosis, obesity, pain, Parkinson’s disease, sensory disorders, spinal cord injury, stroke, schizophrenia, sleep disorders, and traumatic brain injury. An increasing awareness of this growing economic problem and the corresponding market opportunity of nearly 2 billion people worldwide are stimulating both public and private funding in neurotechnology including new drugs, medical devices, and diagnostics for brain and peripheral nervous system disorders. Recent advances in neuroscience have dramatically expanded our understanding of the basic biological and behavioral components of brain-related illnesses. In particular, an increasing number of neurotransmitters, neurotransmitter receptors, ion channels, and other proteins critical for normal brain functioning have been identified and characterized [2,3], genetically engineered animal models have improved
E-mail address: [email protected] 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.03.030
target validation [4] and neuroimaging techniques have made it easier to study what occurs in the injured and healthy brain [5]. Although great strides have been made over the past decade, technological advances across several areas of research and development hold promise for the development of even more efficacious treatments and, for the first time, cures for brain and peripheral nervous system disorders. These areas include stem cell treatments, new imaging technologies, drug delivery technologies, and novel neuromodulation platforms. 2. Stem cells and neuroregeneration The brain has extremely limited capabilities to repair itself, but new strategies are emerging to improve the brain’s ability to regenerate lost neurons and to facilitate the incorporation of implanted stem cells into brain circuitry. There are currently at least eight private and three public companies developing neuroregeneration cell transplant therapies. More than $450 million in venture funding has been invested in companies working on cell replacement and stem cell therapies for brain and spinal cord disorders. There are significant challenges to overcome when considering the use of implanted cells for neurological diseases. For example, inducing a cell to differentiate into a skin cell or a liver cell is likely to be easier than inducing it to form precise connections with another area of the brain. The chemical signals for forming the appropriate connections in the brain may be present only during certain
Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122
times of development [6]. Additionally, the character and connections of these new cells must be stable. Despite these complexities, stem cell therapies offer the potential for outright cures to some neurological diseases. Recently, we have seen progress in bringing these treatments into human trials. A California company has been in clinical testing of fetal stem cells to treat Batten’s disease since 2005 and expects to complete their Phase I study in early 2009. In December 2008, they received FDA approval to begin trials in a second disorder, Pelizaeus–Merzbacher disease (PMD), a fatal brain disorder that affects mainly young children. In February 2009, the first embryonic stem cell trial for spinal cord injury treatment was also approved. These are slow and precautious steps, centering on untreatable disorders, but cell-based therapeutic candidates for amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and stroke will soon follow. 3. Neuroimaging and disease treatment Brain and nervous system illnesses are exceptionally difficult to research and diagnose, partly because changes in the local environment of the brain are difficult to assess within the confines of the skull. Although diagnostic tests for diseases like cancer and diabetes are common and can use samples from blood, urine, or tissue, diagnostic tests for many brain-related illnesses are only beginning to emerge. Neuroimaging is revolutionizing the diagnosis and treatment of brain-related illness. It is difficult to imagine treating patients with brain tumors, cerebrovascular disorders, or epilepsy without current imaging tools. Several decades of neuroimaging research have contributed enormously to our understanding of structural and functional differences in people with neurological and psychiatric disorders. For example, PET scans have been shown to be 93% accurate in detecting Alzheimer’s disease about 3 years before the conventional diagnosis of ‘‘probable Alzheimer’s” [7]. Imaging now offers insights into the mechanisms of action of drugs used to treat schizophrenia and the causal mechanisms that may be at the root of many disorders [8]. Diagnosis of mental illness and differential treatment selection is one of the most difficult aspects of psychiatric treatment, yet this is where neuroimaging will add tremendous value in the years ahead. On the neurofeedback front, a private company, in conjunction with Stanford University, is using real-time functional MRI (rtfMRI) to train patients in pain management techniques by monitoring the ongoing activity of their brains. Within a 13-minute session, patients can learn to control activity in different parts of their brain and alter their sensitivity to painful stimuli, allowing them to better control pain. Patients watched their brain’s level of activity as seen by rtfMRI and were trained to decrease pain intensity through mental exercises, such as focusing on a part of the body where they did not have pain. In years to come, rtfMRI has the potential to add an entirely new treatment option for a whole host of brain-related illnesses including depression, addiction, and dementia. 4. Crossing the blood–brain barrier Dozens of private companies are currently developing or commercializing neurodrug delivery methods and devices that will bring life to old and new compounds alike. These technologies include: Implantable devices: Implantable pumps bypass the blood– brain barrier (BBB) and deliver highly accurate amounts of drugs to specific sites in the brain or spinal cord.
121
Expression systems: A French company is circumventing the BBB using encapsulated cell technology (ECT), a polymer implant containing cells that provide continuous, long-term release of the therapeutic protein to the brain or eye [9]. Receptor-mediated transport: Receptors that transport nutrients to the brain from the blood can be tricked into transporting therapeutic chemicals, peptides, and proteins across the BBB. Insulin, transferrin, and lipoproteins, for example, cross the BBB by facilitated transport, and can be combined with therapeutic proteins or other molecules to promote access to the brain [10]. Cell-penetrating peptides: During the past decade, several arginine-rich peptides have been described, such as SynB vectors, which allow for intracellular delivery and BBB transport [11]. The mechanism for this transport is unknown. A Swiss company is using cell-penetrating peptides to develop treatments for stroke and myocardial infarction. Focused ultrasound: Some research shows that focused ultrasound can temporarily open the BBB in a targeted area for a window of time [12]. A seed stage company is working to commercialize this technology and improve it for use in humans. Nanoparticle formulations: Nanoparticle formulations refer to therapeutics encapsulated in nanoscale particles that can pass the BBB [13]. Although there is great interest in using nanotechnology to improve neuropharmaceutical delivery to the brain, it will take some time to overcome challenges of this platform, including the need for intravenous delivery, manufacturing, and clearance by the liver. 5. Novel neuromodulation platforms Adaptation of pacemaker technology has led to major advances in neurodevice development, allowing for stimulation of discrete brain areas and nerves for the treatment of Parkinson’s, essential tremor, epilepsy, and even obsessive–compulsive disorder. Novel device platforms for neuromodulation will allow for less invasive and more responsive therapies in the future. Optogenetics, for example, is an emerging field combining optics and genetics to probe neural circuits on the millisecond time scale [14]. In early development, delivery of genes tied to cell-specific promoters has been used to make certain neurons light sensitive. Then highly targeted light-emitting hardware such as fiberoptics is used to activate or deactivate that specific cell type. One startup in this area is developing an optogenetic neuromodulation system that may one day enable the blind to see. Leveraging this technology will yield entirely new levels of control over specific cell types in the brain, making it possible to treat illnesses that emerge as a result of malfunctioning neuronal circuits. Another exciting example of the future of neurodevice development relates to the development of conducting polymer nanowires, which will make it possible to monitor and modulate individual brain cells. The wires can be threaded through the circulatory system into the brain, without the need for invasive brain surgery. They do not block normal blood flow or interfere with the exchange of gases and nutrients through the blood vessel walls. Looking forward, it will be possible to connect an entire array of nanowires to a catheter tube that could then be guided through the circulatory system into the brain. Once there, the wires would branch out into tinier blood vessels until they reached specific locations. Each nanowire would then be used to record the electrical activity of a single nerve cell or small groups of them. Nanowire sensors could greatly improve doctors’ ability to pinpoint damage from injury and stroke, localize the epileptogenic zone(s) of seizures, and detect the presence of tumors and other brain abnormalities. Beyond that, nanowires that could deliver electrical impulses have the potential to transform the entire field of neuromodulation, dramatically expanding the potential scope of treatable conditions.
122
Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122
When looked at separately, each of these technological innovations will dramatically improve disease diagnosis and therapeutic effectiveness. But looking at them separately is a mistake. To understand the breakthrough treatments that will truly transform neuromedicine in the years to come, we need to consider what will emerge as the new technologies converge and create multiplier effects with each other, thus opening up entirely new avenues for treating and curing the brain-related illnesses that impact the daily lives of so many across the planet. References [1] Lynch Z, Lynch C. The Neurotechnology Industry 2008 report: drugs, devices and diagnostics for the brain and nervous systems. NeuroInsights 2008. [2] Baumann CR, Basseti CL. Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter. Sleep Med Rev 2005;9:253–68. [3] Ferré1 S, Ciruela F, Woods A, Lluis C, Franco R. Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends Neurosci 2007;30:440–6. [4] Cozzia J, Fraicharda A, Thiam K. Use of genetically modified rat models for translational medicine. Drug Discovery Today 2008;13:488–94. [5] Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 2008;9:58–65.
[6] Mriganka S, Rubenstein JL. Patterning and plasticity of the cerebral cortex. Science 2005;310:805–10. [7] Mosconi L, Brysa M, Glodzik-Sobanskaa L, De Santia S, Rusineka H, de Leona M. Early detection of Alzheimer’s disease using neuroimaging. Exp Gerontol 2007;42:129–38. [8] Brunet-Gouet E, Decety J. Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res Neuroimaging 2006;148(2–3):75–92. [9] Sieving PA, Caruso RC, Tao W, et al. CNTF for human retinal neurodegeneration: Phase I trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. Proc Natl Acad Sci USA 2006;103(10):3896–901. [10] Demeule M, Currie JC, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem 2008;106:1534–44. [11] Abulrob A, Sprong H, Van Bergenen Henegouwen P, Stanimirovic D. The blood– brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 2005;95:1201–14. [12] Hynynen K, McDannold N, Vykhodtseva N, et al. Focal disruption of the blood– brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg 2006;105:445–54. [13] Tsuji J, Maynard A, Howard P, et al. Research strategies for safety evaluation of nanomaterials: part IV. Risk assessment of nanoparticles. Toxicol Sci 2006;89:42–50. [14] Admantidis AR, Zhang F, Aravanis AM, Deisseroth K, Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007;450:420–4.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Technological Approaches to the Scientific Explorations of Epilepsy and Behavior
The future of neurotechnology innovation Zack Lynch Neurotechnology Industry Organization, 315 30th Street, San Francisco, CA 94131, USA
a r t i c l e
i n f o
Article history: Received 23 March 2009 Accepted 23 March 2009 Available online 25 April 2009
a b s t r a c t Advances across several areas of neurotechnology research including stem cells treatments, new imaging technologies, drug delivery technologies and novel neuromodulation platforms promise to accelerate the development of treatments and cures for brain-related illnesses. Ó 2009 Elsevier Inc. All rights reserved.
Keywords: Neurotechnology Neuromodulation Optogenetics Neuroimaging Stem cells Blood brain barrier Nanowires Economic burden Neurological disease Psychiatric illness
1. Introduction Neurological diseases and psychiatric illnesses account for more hospitalizations, long-term care, and chronic suffering than nearly all other health conditions combined. Beyond the untold human suffering, the annual economic burden of brain-related illnesses has reached more than $1 trillion in the United States [1]. Critical unmet medical needs remain in almost every area of brain and nervous system disorders, including: Alzheimer’s disease, addiction, anxiety, depression, epilepsy, multiple sclerosis, obesity, pain, Parkinson’s disease, sensory disorders, spinal cord injury, stroke, schizophrenia, sleep disorders, and traumatic brain injury. An increasing awareness of this growing economic problem and the corresponding market opportunity of nearly 2 billion people worldwide are stimulating both public and private funding in neurotechnology including new drugs, medical devices, and diagnostics for brain and peripheral nervous system disorders. Recent advances in neuroscience have dramatically expanded our understanding of the basic biological and behavioral components of brain-related illnesses. In particular, an increasing number of neurotransmitters, neurotransmitter receptors, ion channels, and other proteins critical for normal brain functioning have been identified and characterized [2,3], genetically engineered animal models have improved
E-mail address: [email protected] 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.03.030
target validation [4] and neuroimaging techniques have made it easier to study what occurs in the injured and healthy brain [5]. Although great strides have been made over the past decade, technological advances across several areas of research and development hold promise for the development of even more efficacious treatments and, for the first time, cures for brain and peripheral nervous system disorders. These areas include stem cell treatments, new imaging technologies, drug delivery technologies, and novel neuromodulation platforms. 2. Stem cells and neuroregeneration The brain has extremely limited capabilities to repair itself, but new strategies are emerging to improve the brain’s ability to regenerate lost neurons and to facilitate the incorporation of implanted stem cells into brain circuitry. There are currently at least eight private and three public companies developing neuroregeneration cell transplant therapies. More than $450 million in venture funding has been invested in companies working on cell replacement and stem cell therapies for brain and spinal cord disorders. There are significant challenges to overcome when considering the use of implanted cells for neurological diseases. For example, inducing a cell to differentiate into a skin cell or a liver cell is likely to be easier than inducing it to form precise connections with another area of the brain. The chemical signals for forming the appropriate connections in the brain may be present only during certain
Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122
times of development [6]. Additionally, the character and connections of these new cells must be stable. Despite these complexities, stem cell therapies offer the potential for outright cures to some neurological diseases. Recently, we have seen progress in bringing these treatments into human trials. A California company has been in clinical testing of fetal stem cells to treat Batten’s disease since 2005 and expects to complete their Phase I study in early 2009. In December 2008, they received FDA approval to begin trials in a second disorder, Pelizaeus–Merzbacher disease (PMD), a fatal brain disorder that affects mainly young children. In February 2009, the first embryonic stem cell trial for spinal cord injury treatment was also approved. These are slow and precautious steps, centering on untreatable disorders, but cell-based therapeutic candidates for amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and stroke will soon follow. 3. Neuroimaging and disease treatment Brain and nervous system illnesses are exceptionally difficult to research and diagnose, partly because changes in the local environment of the brain are difficult to assess within the confines of the skull. Although diagnostic tests for diseases like cancer and diabetes are common and can use samples from blood, urine, or tissue, diagnostic tests for many brain-related illnesses are only beginning to emerge. Neuroimaging is revolutionizing the diagnosis and treatment of brain-related illness. It is difficult to imagine treating patients with brain tumors, cerebrovascular disorders, or epilepsy without current imaging tools. Several decades of neuroimaging research have contributed enormously to our understanding of structural and functional differences in people with neurological and psychiatric disorders. For example, PET scans have been shown to be 93% accurate in detecting Alzheimer’s disease about 3 years before the conventional diagnosis of ‘‘probable Alzheimer’s” [7]. Imaging now offers insights into the mechanisms of action of drugs used to treat schizophrenia and the causal mechanisms that may be at the root of many disorders [8]. Diagnosis of mental illness and differential treatment selection is one of the most difficult aspects of psychiatric treatment, yet this is where neuroimaging will add tremendous value in the years ahead. On the neurofeedback front, a private company, in conjunction with Stanford University, is using real-time functional MRI (rtfMRI) to train patients in pain management techniques by monitoring the ongoing activity of their brains. Within a 13-minute session, patients can learn to control activity in different parts of their brain and alter their sensitivity to painful stimuli, allowing them to better control pain. Patients watched their brain’s level of activity as seen by rtfMRI and were trained to decrease pain intensity through mental exercises, such as focusing on a part of the body where they did not have pain. In years to come, rtfMRI has the potential to add an entirely new treatment option for a whole host of brain-related illnesses including depression, addiction, and dementia. 4. Crossing the blood–brain barrier Dozens of private companies are currently developing or commercializing neurodrug delivery methods and devices that will bring life to old and new compounds alike. These technologies include: Implantable devices: Implantable pumps bypass the blood– brain barrier (BBB) and deliver highly accurate amounts of drugs to specific sites in the brain or spinal cord.
121
Expression systems: A French company is circumventing the BBB using encapsulated cell technology (ECT), a polymer implant containing cells that provide continuous, long-term release of the therapeutic protein to the brain or eye [9]. Receptor-mediated transport: Receptors that transport nutrients to the brain from the blood can be tricked into transporting therapeutic chemicals, peptides, and proteins across the BBB. Insulin, transferrin, and lipoproteins, for example, cross the BBB by facilitated transport, and can be combined with therapeutic proteins or other molecules to promote access to the brain [10]. Cell-penetrating peptides: During the past decade, several arginine-rich peptides have been described, such as SynB vectors, which allow for intracellular delivery and BBB transport [11]. The mechanism for this transport is unknown. A Swiss company is using cell-penetrating peptides to develop treatments for stroke and myocardial infarction. Focused ultrasound: Some research shows that focused ultrasound can temporarily open the BBB in a targeted area for a window of time [12]. A seed stage company is working to commercialize this technology and improve it for use in humans. Nanoparticle formulations: Nanoparticle formulations refer to therapeutics encapsulated in nanoscale particles that can pass the BBB [13]. Although there is great interest in using nanotechnology to improve neuropharmaceutical delivery to the brain, it will take some time to overcome challenges of this platform, including the need for intravenous delivery, manufacturing, and clearance by the liver. 5. Novel neuromodulation platforms Adaptation of pacemaker technology has led to major advances in neurodevice development, allowing for stimulation of discrete brain areas and nerves for the treatment of Parkinson’s, essential tremor, epilepsy, and even obsessive–compulsive disorder. Novel device platforms for neuromodulation will allow for less invasive and more responsive therapies in the future. Optogenetics, for example, is an emerging field combining optics and genetics to probe neural circuits on the millisecond time scale [14]. In early development, delivery of genes tied to cell-specific promoters has been used to make certain neurons light sensitive. Then highly targeted light-emitting hardware such as fiberoptics is used to activate or deactivate that specific cell type. One startup in this area is developing an optogenetic neuromodulation system that may one day enable the blind to see. Leveraging this technology will yield entirely new levels of control over specific cell types in the brain, making it possible to treat illnesses that emerge as a result of malfunctioning neuronal circuits. Another exciting example of the future of neurodevice development relates to the development of conducting polymer nanowires, which will make it possible to monitor and modulate individual brain cells. The wires can be threaded through the circulatory system into the brain, without the need for invasive brain surgery. They do not block normal blood flow or interfere with the exchange of gases and nutrients through the blood vessel walls. Looking forward, it will be possible to connect an entire array of nanowires to a catheter tube that could then be guided through the circulatory system into the brain. Once there, the wires would branch out into tinier blood vessels until they reached specific locations. Each nanowire would then be used to record the electrical activity of a single nerve cell or small groups of them. Nanowire sensors could greatly improve doctors’ ability to pinpoint damage from injury and stroke, localize the epileptogenic zone(s) of seizures, and detect the presence of tumors and other brain abnormalities. Beyond that, nanowires that could deliver electrical impulses have the potential to transform the entire field of neuromodulation, dramatically expanding the potential scope of treatable conditions.
122
Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122
When looked at separately, each of these technological innovations will dramatically improve disease diagnosis and therapeutic effectiveness. But looking at them separately is a mistake. To understand the breakthrough treatments that will truly transform neuromedicine in the years to come, we need to consider what will emerge as the new technologies converge and create multiplier effects with each other, thus opening up entirely new avenues for treating and curing the brain-related illnesses that impact the daily lives of so many across the planet. References [1] Lynch Z, Lynch C. The Neurotechnology Industry 2008 report: drugs, devices and diagnostics for the brain and nervous systems. NeuroInsights 2008. [2] Baumann CR, Basseti CL. Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter. Sleep Med Rev 2005;9:253–68. [3] Ferré1 S, Ciruela F, Woods A, Lluis C, Franco R. Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends Neurosci 2007;30:440–6. [4] Cozzia J, Fraicharda A, Thiam K. Use of genetically modified rat models for translational medicine. Drug Discovery Today 2008;13:488–94. [5] Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 2008;9:58–65.
[6] Mriganka S, Rubenstein JL. Patterning and plasticity of the cerebral cortex. Science 2005;310:805–10. [7] Mosconi L, Brysa M, Glodzik-Sobanskaa L, De Santia S, Rusineka H, de Leona M. Early detection of Alzheimer’s disease using neuroimaging. Exp Gerontol 2007;42:129–38. [8] Brunet-Gouet E, Decety J. Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res Neuroimaging 2006;148(2–3):75–92. [9] Sieving PA, Caruso RC, Tao W, et al. CNTF for human retinal neurodegeneration: Phase I trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. Proc Natl Acad Sci USA 2006;103(10):3896–901. [10] Demeule M, Currie JC, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem 2008;106:1534–44. [11] Abulrob A, Sprong H, Van Bergenen Henegouwen P, Stanimirovic D. The blood– brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 2005;95:1201–14. [12] Hynynen K, McDannold N, Vykhodtseva N, et al. Focal disruption of the blood– brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg 2006;105:445–54. [13] Tsuji J, Maynard A, Howard P, et al. Research strategies for safety evaluation of nanomaterials: part IV. Risk assessment of nanoparticles. Toxicol Sci 2006;89:42–50. [14] Admantidis AR, Zhang F, Aravanis AM, Deisseroth K, Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007;450:420–4.