From Optogenetic Technologies to Neuromodulation Therapies

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Science Translational Medicine  20 Mar 2013:
Vol. 5, Issue 177, pp. 177ps6
DOI: 10.1126/scitranslmed.3003100


The field of optogenetics has provided new insight into neuronal communication and complex brain function. Now, scientists eagerly anticipate clinical application of this technology, with the hope that it will help improve treatments for various neurological disorders. However, the translational hurdles are high. In this Perspective, we highlight the technical, practical, and regulatory hurdles that lie ahead along the path towards making optogenetic neuromodulation therapies a reality in the clinic.


Optogenetics has emerged as a powerful new paradigm for uncovering how neurons communicate and give rise to more complex brain function. The technique involves the genetic integration of light-activated channels into cells’ membranes to confer light-based, optical control (activation or deactivation) of physiological processes. The rapid scientific progress of the optogenetics field has led to a somewhat optimistic view that direct clinical application of this technology is imminent and potentially will lead to improved treatments for various neurological disorders. This view has to be tempered with the reality of the technical, practical, and regulatory hurdles that lie ahead in translating this approach to the clinic.

The goal of a clinical neuromodulation system is to alter the information flow within a neural circuit for therapeutic benefit. Existing examples of these systems include deep brain stimulators for the treatment of Parkinson’s disease and tremor, spinal cord stimulators for pain, and sacral nerve stimulators for incontinence (1). Although these techniques do help the intended patient populations, neuromodulation nevertheless faces several major challenges that may be solved by emerging optogenetics technology. These challenges include improving the specificity of modulation and providing dynamic titration of stimulation on the basis of an individual patient’s needs. Although industry is actively exploring technical approaches for closed-loop sensing and algorithm-enabled neuromodulation devices, there is also a strong interest in improving the specificity of treatment and exploring novel stimulation patterns, namely through the use of optogenetics technologies.


Optogenetics—through opsin expression—has the potential for high specificity in the types of cells activated or inhibited. This specificity is potentially useful in aiding the information flow problem. It provides an alternative to electrode design and further miniaturization, perhaps freeing bioengineers from the electro-geometrical constraints of predicate systems. In addition, optogenetic methods can bias neural circuits in new ways, including simultaneous excitation and direct inhibition from the same device. From an engineering perspective, the enhanced selectivity and physiological modulation schemes are potentially disruptive to the design of therapy strategies. However, to fully translate these opportunities, other practical constraints must be addressed. These include requirements for patient safety, therapeutic efficacy, as well as understanding the economic value of the solution compared with established “gold standard” practices. Such practical (and ethical) constraints are at risk of being overlooked in the excitement of a promising new technology.

To properly frame the problem, the design of a therapy requires attention to the entire care continuum, by analyzing the potential “therapy system.” Engineers often break the design analysis into three key components: management of interfaces, management of energy, and management of information flow. A systems model of optogenetics within this framework is illustrated in Fig. 1: Opsins are embedded into target cells to provide the interface between physiology and the device, and a device then provides the light energy to actuate the network. From a therapy system perspective, optogenetics offers several exciting opportunities in the management of such interfaces and information. For example, the interface of the device in Fig. 1 to the nervous system is nonconducting, which can provide practical advantages for real-world challenges such as magnetic resonance imaging (MRI) safety and compliance, device survival in the presence of electrocautery or defibrillation, and potentially reduced cross-contamination to sensing modalities such as biopotential amplification. As with any implantable system, the interface across the skin barrier must also be considered (Fig. 1) because in the case of optogenetic therapy, both power and information (telemetry) may need to be transferred. Still, a great deal of engineering is needed for a practical implant system to meet stringent regulatory and safety requirements (

Fig. 1

The idealized optogenetic neuromodulation system. An envisioned neuromodulation system based on optogenetic technologies would be multifaceted, including viral or cell-based therapy, fluidic delivery, optical delivery, power, and telemetry.



The challenge of building an optogenetic system might seem deceptively simple: embedding opsins into the desired component of a neural circuit, piping in sufficient light, and illuminating a volume of tissue with the proper pattern. Each of these steps, however, presents distinct translational challenges.

Embedding opsins. The majority of current scientific approaches to optical neural control involve delivery of opsin genes to cells by means of transfection through a viral vector (Fig. 1) or creation of new animal lines through transgenic techniques. Although the creation of a transgenic human application involving germline modification is not viable, the use of optogenetics through viral delivery in a gene therapy setting is a potential clinical application of this technology (2). For some, gene therapy trials have received a negative connotation because of adverse events experienced in some of the early trials (3).

Nevertheless, gene therapy trials continue to push forward owing to the potential to have great impact on various areas of clinical medicine. To this end, new delivery methods that improve gene therapy safety, such as self-regulating and self-inactivating vectors or nonviral genetic delivery packages, have been developed. Conversely, some viral vectors, such as adeno-associated virus, are now considered generally safe by regulatory bodies, so that the safety issues remaining concern the transgenes delivered by use of them, rather than the viral delivery vectors themselves (4). The nervous system has been an early target for gene therapy applications, and there are several gene therapy trials for the treatment of Parkinson’s disease currently under way ( identifiers NCT00195143, NCT01621581, and NCT00985517) (5). These trials, if successful, will pave the pathway for using gene therapy strategies as potential vehicles for delivering opsins to the nervous system.

An alternative to viral or nonviral vectors for delivery of opsins to targeted cells is to directly transplant human cells that have already been modified to include optogenetic functionality. A similar strategy has been explored in the use of genetically altered cells as chronic drug delivery vehicles (6). This strategy has been particularly attractive for brain disorders such as Parkinson’s disease, in which systemic delivery of synthetic dopamine has been the standard clinical treatment. There are several current research thrusts primarily focused on Parkinson’s disease that use transplanted and reprogrammed induced pluripotent stem cells (7). In the case of an optogenetic cell transplantation application, there is the additional burden that the delivered cells have to functionally integrate into the local neural circuitry. Weick et al. showed that an immortal human stem cell–derived neural line can integrate the gene that encodes channelrhodopsin-2 protein (ChR2) and, when transplanted into an immunocompromised animal, may functionally connect with the surrounding neural populations (8).

Recent work further demonstrates the potential clinical utility of optogenetics—but in nonneuronal cells—to perform light-triggered GLP-1 expression, resulting in production of insulin, as a treatment for diabetes (9). This most recent study by Ye et al. highlights what is likely to be another challenge in trying to decide which opsin to use and how many should be used. There are many different opsins that are currently available, including excitatory, inhibitory, and G protein–coupled varieties (2, 10). Compounding this problem is the rapid development of subclasses of opsin variants that have altered excitation wavelength or channel kinetics. As with the development of viral vectors, in which the discovery of new serotypes has occurred more rapidly than can the work needed to allow their use in clinical trials, the rapid growth of the opsin library might actually delay decisions about when to begin necessary translational work. There is always the possibility that a newer, better, faster, more efficient protein may be right around the corner.

Providing proper illumination. The greatest challenge in the engineering of an optogenetic system is the management of energy. This includes both the generation of appropriate photon densities and practically piping those photons to the target tissue (Fig. 1). Compared with electrical stimulation, optogenetics is incredibly inefficient at stimulating cellular activity. Opsins used in today’s research require power expenditure up to 1000-fold more than electrical modulation to affect an equivalent volume of tissue; indeed, many optical stimulation systems include a cooling system in order to maintain acceptable temperature excursions in the vicinity of the tissue or place the optical generation far from the biological preparation isolated by a fiber.

Temperature fluctuations are not the only concern. Large energy requirements often lead to excessive device size or shorter implant lifetimes that lower the effective economic value of the device; for a rechargeable system, the increased burden might limit patient acceptance. Because there is a very strong mandate on temperature control in brain implants (11), and device size and longevity are critical economic considerations, the challenge of opsin inefficiency must be addressed. The most likely solution will require a combination of more sensitive opsins, the use of secondary pathways that amplify the impact of a single event, and the application of opsins that hold their state with relatively low duty cycles of optical stimulation (10).

Sweating the small stuff. In addition to these fundamental challenges, there are several practical issues that must be addressed before optogenetic translation will be possible. New devices and delivery methods will be needed. Delivering vectors to the human brain often involves targeting regions that are not as neat and tidy as they are in the rodent or primate. For example, the human putamen is banana-shaped, not nice and round. Once the opsins are placed, a stable optical system must be embedded in the body (Fig. 1). Assuming that the optical source is internal to the body, a method of placing the light source into a hermetic environment and illuminating the target is a major challenge (12). Foreign bodies placed in the body tend to be encapsulated, which could block a simple window to the neural circuit. Devices that use a fiber to place the light source need to be rigid during placement and then highly flexible in order to comply with mechanical stress. Existing electrical systems have solved this with insertion stylets embedded in highly flexible electrodes; similar optical routing and anchoring methods will need to be designed and tested. The challenges of implementing an implantable optical source perhaps bias the most immediate translational opportunities to hybrid systems, leveraging external illumination methods, such as treatments for eye disease (2, 13).

Beyond science and technology, the macroeconomic, regulatory, and clinical barriers to optogenetics must also be considered. Implementing a therapy will most likely require both a biologic and a device, invoking special considerations from a regulatory standpoint similar to combination therapies, such as those in programmable infusion systems—for example, the Medtronic SynchroMed programmable infusion system for intrathecal drug delivery. Clinical acceptance and training are also potential hurdles (14).

Despite documented, peer-reviewed clinical success and economic value, neuromodulation still faces modest acceptance as a clinical therapy. Two key reasons for this are the perceived complexity of stimulation therapies from the clinician’s perspective and the innate fear of an implant from the patient’s point of view. Compounding these concerns with the addition of transgenic activation of tissue will only make the barrier to clinical and patient acceptance higher during initial introduction. Additionally, as with any disruptive technology, there is the potential for a “wait and see” attitude among both clinicians and patients, both wondering if there is yet another breakthrough right around the corner. Addressing these issues will require substantial investments in physician training and patient education, made particularly difficult owing to the highly complex nature of the potential treatment. Guidance on these issues may be found in other intricate treatments, such as stem cell transplantation, for which expectations of patients and physicians varied widely (15). Compounding this problem is the lack of current research on the long-term effectiveness as well as potential chronic complications associated with optogenetic technology. In a companion Perspective in this issue of Science Translational Medicine, Chow and Boyden address some of the challenges associated with trying to translate recent findings in animal studies in which long-term issues of safety and efficacy have not yet had time to mature (2). Additionally, they look at the specific challenges of many of the current optogenetic research tools, which have been derived from nonmammalian opsins.


Each of these challenges can—and probably will be—addressed with suitable scientific, engineering, and clinical investment. Nevertheless, translation represents a confluence of multiple technologies, thus making time-to-implementation hard to predict. Looming large, however, is the motivation for making the initial leap into the clinic in the first place. Choosing the wrong initial clinical target, if unsuccessful, has the potential to be a major setback to follow-on therapies. Perhaps most importantly, the need for clearly defining the “killer application” that truly leverages the benefits of optogenetics still remains (2). Although the field has largely considered central nervous system disorders as the first likely targets, perhaps the peripheral nervous system could be a more tractable initial entry point. For example, the application of optogenetic stimulation to selectively block chronic pain sensation or relieve muscle spasticity might have immediate clinical applications. If improvements in optical delivery technology and optogenetic varients (2) could allow for the targeting of more superficial structures through the skin, then managing the challenges of the skin barrier (Fig. 1) would be much different. These types of applications could leverage more peripheral approaches to minimize invasiveness while maximizing potential benefits. Accordingly, the use of optogenetics in nonneuronal tissue holds promise for early adoption of this technology in the clinic, such as in cardiac applications that are accessible through minimally invasive techniques.

Any potential application is ultimately a balance of risk and effort versus the ultimate reward, both to the patient and those that champion it. The field has yet to show any relative benefit of optogenetic technology over existing electrical stimulation systems in a neuromodulation application. So, although the technology is promising, the optogenetic risk-benefit ratio is still largely unknown, and the effort required to clear the clinical translational hurdles is large, with the pathway to an initial clinical optogenetic system still unclear.

Although direct application of optogenetics in humans is far off, research in animal models has led to a better understanding of the mechanisms underlying current clinical treatments. For example, Gradinaru et al. explored the use of optogenetic techniques to help uncover the mechanisms of action of deep brain stimulation (DBS) for Parkinson’s disease (16). This type of approach (using optogenetics as a tool for understanding mechanism) may well prove to have the most direct impact of optogenetics on clinical care, rather than using optogenetics itself to treat disease. If studies using optogenetics in rodents or primates reveal that there is an optimal location and rate of stimulation that most effectively ameliorates the symptoms of Parkinson’s disease, then this would have an immediate impact on clinical care. In this case, DBS surgeries and treatment protocols could be modified effectively without much burden from either device development or regulatory hurdles. Boyden et al. outline how optogenetics might have similar clinical impact through the identification of new molecular- and circuit-level targets, including providing new in vivo screens for therapeutic targets (2).

Approaches such as that of Gradinaru and others have the potential to affect implantable neural device development efforts. Many new devices show great initial promise in preclinical models but are challenged to define the appropriate positive and negative controls that are needed to push them forward past preclinical testing and into humans. Optogenetic animal models, particularly ones in primates, may offer the ideal preclinical testbed for the development of new techniques and technologies (17).


As with any disruptive technology, hurdles can mask opportunities. Although the current trend in optogenetics research has been toward new functionality and scientific exploration, there should always be an awareness of both the clinical issues and opportunities that lie on the horizon. The emerging field needs to be cognizant of the translational issues so that opportunity is not lost when the time is right to introduce this technology in the first clinical demonstration. Along the way, the clinical field needs to stay abreast of the new science that is continually emerging from this technology, so that new findings can come to bear on clinical treatments. Correspondingly, device technologists should be vigilant in exploring and understanding optogenetic technologies, where appropriate, to help validate and improve therapies. Longer term, they will be called on to deliver the practical solutions that will bring optogenetics to a clinical reality.

References and Notes

  1. Acknowledgments: The authors thank B. Kaemmerer for his review and guidance on this manuscript.Competing interests: T.D. is an employee and stockholder of Medtronic, which makes implantable devices for treatment of neurological disease. T.D. has patents filed on optogenetic therapy devices. J.C.W. has patents related to implantable neural devices.
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