PERSPECTIVE The neurology clinic needs monkey research COLLOQUIUM PAPER Michael E. Goldberga,b,c,1 Edited by Robert H. Wurtz, National Institutes of Health, Bethesda, MD, and approved August 2, 2019 (received for review May 4, 2019) This report discusses how a number of currently incurable diseases might be treated by advances developed as the result of current ongoing research on monkeys. The diseases discussed include Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, and stroke. Finally, the report discusses the devastating effect the animal rights movement and adverse publicity can have on basic neurobiological research on monkeys. neurological diseases | monkey research | needed therapies Neurological and psychiatric diseases present an im- nucleus, two structures within the basal ganglia. As mense public health burden in the United States and reviewed by Jerrold Vitek in his chapter, the current throughout the world. One estimate is that they com- state-of-the-art treatment is electrical stimulation of prise 19% of all disability-adjusted life years (1). In the subthalamic nucleus. This approach was devel- neurology, although our diagnostic capacity has grown oped as the result of years of basic neurophysiological significantly in the past 50 y, therapeutic strategies lag research by Mahlon DeLong and his colleagues, who far beyond diagnosis and are still limited to very narrow sought to understand the role of the basal ganglia in niches, such as the first 4.5 h after a stroke begins (2). the generation of normal movement. DeLong began Medical diseases, like heart or kidney failure, have a by studying the normal physiology of the basal gan- number of treatment modalities, like drugs, surgery, glia, including the substantia nigra (3), the globus or, when all else fails, transplant. Unfortunately, the pallidus, and subthalamic nuclei (4). brain or even the spinal cord cannot be transplanted. In 1976, a chemistry graduate, trying to synthesize In this review, I will describe a number of neurological desmethylprodine (MPPP), an opioid, injected himself diseases and discuss how basic research on nonhu- with his product and suddenly developed a parkin- man primates could help develop useful therapeutic sonian syndrome. His MPPP had been contami- approaches. nated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which the Kopin laboratory at the National ’ Parkinson s Disease Institute of Mental Health showed caused a similar ’ Parkinson s disease, a neurodegenerative disease that parkinsonian syndrome in rhesus monkeys (5). Delong’s attacks an area of the brain known as the basal gan- group (6) studied the activity of the subthalamic nucleus glia, is perhaps the most successful therapeutic tri- in rhesus monkeys who had been treated with MPTP, umph arising from research on monkeys. It is a disease showing that subthalamic neurons were hyperactive in characterized by motor tremor, slowness, and rigidity, the MPTP monkeys. They then discovered that stim- and is typified by the degeneration of a particular class ulation of the subthalamic nucleus ameliorated the of neurons that contain dopamine and project from symptoms of MPTP-induced parkinsonism in the mon- the substantia nigra pars compacta to the caudate keys (6). Although there are a number of successful drug aZuckerman Mind, Brain and Behavior Institute, Department of Neuroscience, Columbia University, New York, NY 10027; bZuckerman Mind, Brain and Behavior Institute, Department of Neurology, Columbia University, New York, NY 10027; and cNeurohospitalist Division, Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032 This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Using Monkey Models to Understand and Develop Treatments for Human Brain Disorders,” held January 7–8, 2019, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. NAS colloquia began in 1991 and have been published in PNAS since 1995. From February 2001 through May 2019 colloquia were supported by a generous gift from The Dame Jillian and Dr. Arthur M. Sackler Foundation for the Arts, Sciences, & Humanities, in memory of Dame Sackler’s husband, Arthur M. Sackler. The complete program and video recordings of most presentations are available on the NAS website at http://www.nasonline.org/using-monkey-models. Author contributions: M.E.G. wrote the paper. The author declares no conflict of interest. This article is a PNAS Direct Submission. Published under the PNAS license. 1Email: [email protected]. First published December 23, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1907759116 PNAS | December 26, 2019 | vol. 116 | no. 52 | 26255–26258 Downloaded by guest on September 24, 2021 therapies for Parkinson’s disease, such as L-DOPA, which work by on a respirator, with a trach and a PEG. For much of that time, he augmenting the activity of dopamine in the basal ganglia, deep was able to communicate with lip and eye movements. His wife brain stimulation of the subthalamic nucleus is the best treatment and children could understand him. When New York City had a modality when drugs fail (7). blackout that lasted for a day, Wayne’s backup batteries lasted However, there are nonmotor symptoms of Parkinson’s dis- until the lights came back on. He lived for 5 y with a trach and a ease as well. Patients with Parkinson’s disease develop apathy, PEG, but ultimately, the process of ALS invades much more of the sleep disorders, impulse control disorders, and ultimately dementia. brain than the motor system, and he died. He and his daughter These symptoms do not respond to current treatment modalities Ingrid wrote a book together while Wayne was on the respirator, for Parkinson’s disease but are equally devastating. Patients with Math Coach, a guide to teaching your children math. It is still in Parkinson’s disease often have degeneration of cells in the frontal print and available from Amazon. cortex, and it is not known whether the nonmotor symptoms arise Monkey research can help patients with ALS in a number of from frontal degeneration, from degeneration of nonnigral dopa- ways. A prosthetic arm can help a patient do some of the activities mine neurons [for example, neurons in the ventral tegmental area, of daily living, like typing on a keyboard and, for patients who do which also degenerate in MPTP monkeys (8)], or from dysfunction of not need the PEG, feed themselves. The chapters by Richard the projection of the substantia nigra pars compacta to the non- Andersen and Andrew Schwartz describe how several laboratories motor regions of the caudate nucleus. Studies on parkinsonian and have developed prosthetic arms and even hands that quadriple- normal monkeys may well provide a key to these disorders and gic humans can control with their own brain activity, recorded by enable successful therapies. More importantly, the current multielectrode arrays implanted in their brains. The dramatic therapies for Parkinson’s disease are network therapies: Rather success of brain–machine interfaces came about because of work than attacking the cause of the disease, they help the damaged on the activity of neurons in the cerebral cortex of rhesus mon- network perform better. The real cure for Parkinson’s disease will keys, which began with the pioneering work of Edward Evarts (10), arrive after we understand why the dopaminergic cells in the who developed the techniques for studying the activity of neurons substantia nigra pars compacta that project to the caudate in the brain of awake, behaving monkeys. He then studied the nucleus degenerate. Monkey models of Parkinson’sdisease activity of neurons in the motor cortex of monkeys who were that have the same mechanism for cell degeneration as human performing conditioned voluntary movements (11). After years of Parkinson’s disease will have to be used to screen candidate research on the neurophysiology of the normal cerebral cortex of treatments. awake, behaving monkeys by many laboratories (12–16), it be- came possible to develop brain–machine interfaces. In order to Amyotrophic Lateral Sclerosis (or “Lou Gehrig’s Disease”) show that a human prosthesis was possible, it was necessary to Amyotrophic lateral sclerosis (ALS) is a disease that destroys spinal show that a monkey could control a cursor on a screen (17, 18) and motor neurons, the neurons in the spinal cord that directly control ultimately a robotic arm with thought alone, monitored by multi- the action of muscles, and the cortical neurons that directly control ple electrodes implanted in its brain (18–20). The monkeys could the spinal motor neurons (9). It is called Lou Gehrig’s disease control the robots with thought alone, without actually making because it killed the famous Columbia University and New York movements. Research on the basic science of movement control Yankee baseball player at the age of 38. ALS begins insidiously, as in monkeys has enabled the idea of a prosthetic arm to move from the patients begin to notice slight weakness of their arms or legs, a dream to an engineering problem. or slight difficulty with swallowing. As the disease progresses, they Although most ALS patients are cognitively normal, they can become weaker and weaker, until they can no longer breathe. Lou communicate only with great difficulty. A first step has been to Gehrig died 2 y after he first noticed that he was becoming weak. use the knowledge accumulated from monkey neurophysiology There is currently no known mechanism for the neuronal de- to allow paralyzed humans to communicate by typing through a generation in the disease. There are a number of genetic causes brain–machine interface (21). Recently, Nima Mesgarani and of ALS, which make up a total of 5–10% of the cases, the most coworkers (22) have shown that it is possible to decode activity common of which are a hexanucleotide repeat in gene C90RF72, from the brain of human patients speaking numbers with elec- and mutations in the enzyme superoxide dismutase (SOD1).