Delve into the mind of Adam Cohen as he sheds light on the remarkable world of bioelectrical imaging. Discover how this cutting-edge technology is unlocking the secrets of neural communication, revolutionising disease treatments, and shaping a brighter future for understanding the brain. Explore the intersection of biology and optics in Cohen’s groundbreaking work.
Which wall does your research break?
Bioelectrical signals are ubiquitous throughout life, from regulating antibiotic resistance in bacteria to carrying the chatter of the ~100 billion neurons in a human brain. Bioelectrical signals are also dysregulated in many diseases of the brain, heart, and other organs. Yet cell voltage has been notoriously difficult to measure: the traditional approach required a researcher to insert a fine probe into a single cell. Such probes only revealed the voltage at a single point in space, not the full three-dimensional dance across interacting cells and tissues. Also, many cells and tissues are completely inaccessible to physical probes: for example, the cell walls in bacteria, plants, and fungi prevent measurements on their bioelectrical signals. For more than 50 years, scientists have sought to develop a means to convert bioelectrical signals into light, which can be detected in a microscope. The ability to image bioelectrical signals in neurons opens a door to developing new treatments for diseases of the nervous system. In diseases such as epilepsy and pain, dysregulation of neuronal ion channels causes aberrant firing patterns. Due to the complex interactions among different types of ion channels, simply blocking a single channel-type is rarely enough to treat the disease. By applying voltage imaging in cell-based disease models, one can probe in detail how candidate therapeutics affect cell excitability. These insights can reveal disease mechanisms and can predict drug efficacy in humans.
What inspired or motivated you to work on your current research or project?
As a child, I was fascinated by electronics and electrical circuits. I spent hours disassembling and modifying radios and televisions I retrieved from the garbage. When I grew older, I hoped to tinker in a similar way with the bioelectrical circuits of life. The key tools for the electronics hobbyist are a function generator and oscilloscope, for introducing and recording electrical signals at different parts of a circuit. Yet introducing and recording electrical signals in biological circuits is extraordinarily difficult. It takes a skilled person typically one hour to attach a physical probe and to record from a single cell, and ideally one would like to stimulate and record simultaneously from dozens or even hundreds of cells. Thus the idea of building a neuro-optical interface was attractive. One could pattern light of one color (e.g. blue) to stimulate neurons in near-arbitrary patterns of space and time, and one could simultaneously map the bioelectrical responses with light of a different color (e.g. red). Based on my lab’s biophysical studies on microbial rhodopsin proteins, I hypothesized that these molecules might serve as the key link between bioelectricity and light. In the wild, these proteins absorb sunlight, and convert that energy into a membrane voltage which their host microorganisms use to power their metabolism. I hypothesized that one might run these tools in reverse: to convert changes in membrane voltage into an optical signal one could detect. After some searching, we identified a gene derived from an archaeal microorganism in the Dead Sea which, when transferred to neurons, caused the neurons to fluoresce when they fired. This discovery opened the door to bioelectrical imaging in the nervous system and beyond. Almost everybody knows somebody who has suffered a disease of the nervous system; yet in most cases treatment options are limited or nonexistent. Soon after we found a way to visualize bioelectrical signals, we realized that this capability could be the key to developing improved medicines for diseases of excitable tissues, including the brain and heart. Some molecules which were selected in part based on our voltage-imaging measurements are now in clinical trials for Amyotrophic Lateral Sclerosis (ALS). Other molecules are in development for pain and epilepsy. Advancement of bioelectrical imaging combines basic biophysics, physiology and neuroscience with the potential to impact human health. I love that all this can emerge from a gene found in a humble microorganism in the Dead Sea.
In what ways does society benefit from your research?
Bioelectrical imaging is changing the way many people develop medicines. Whereas previous efforts relied either on indirect surrogate measurements, or extremely labor-intensive and low-throughput manual electrophysiology, with voltage imaging one can now directly observe the bioelectrical signals which are dysregulated in many diseases. Some areas where these tools are now being applied are:
- Non-addictive treatments for pain: inflammation causes pain-sensing neurons to become hyperexcitable. Even a gentle touch can be excruciatingly painful. We and others are developing compounds that can selectively reverse this hyperexcitability. • Targeted treatments for epilepsies: there are thousands of different genetic mutations which can cause a patient to experience epilepsy. By making stem cell-derived neurons from epilepsy patients, we can re-create a model of the disease in a dish. These patient-derived models are being used to test targeted epilepsy therapeutics.
- New approaches to treating ALS: Motor neuron hyperexcitability is implicated in the pathogenesis of ALS. Voltage-imaging assays have been used to find potassium channel activators that can quiet these hyperexcitable neurons. Some of these drugs are now in clinical trials.
- Testing drugs for cardiac safety and efficacy: A major risk in developing any new drug is that it might interfere with heart function, a possibly fatal side-effect. By testing candidate drugs on human stem cell-derived cardiomyocytes, we and others are evaluating safety profiles earlier in the development pipeline than was previously possible. These same assays can be used to test new candidate anti-arrhythmic drugs.
- Understanding uterine excitability: The uterus is one of the least-understood human organs. It is active throughout the estrus cycle and during delivery, but we do not know the spatial structures or biophysical triggers of uterine contractions. We are using voltage imaging to map these signals in mice, as a first step toward ultimately developing therapeutics for disorders of uterine contraction. More broadly, we and others are using voltage imaging tools to study the basic function of the nervous system: how does the brain encode memories? How does it regulate attention? How does it represent the complex barrage of sensory inputs? An improved understanding of these fundamental processes is the first step toward developing treatments for corresponding disorders.
Looking ahead, what are your hopes or aspirations for the future based on your research or project?
I hope that the combination of recent advances in voltage imaging, spatial transcriptomics, and stem cell biology will allow us to connect the dots from genetics to neuronal biophysics, to circuit function, and ultimately to behavior. Equipped with these connections, we will finally have a map of the complex landscape which relates genetics and environment to diseases of the nervous system. Having such a map is the first step toward developing cures.