Another in the series: “What Drives Research in the Field of Biomaterials?”
The amazingly complex system of the brain, and its network of many different cell types interacting and functioning together, has always been “top of mind” – pardon the pun – for many researchers. It is just a little over 10 years since Professor Karl Deisseroth introduced “optogenetics,” a novel technique to study the brain and nervous tissue. Optogenetics combines optics and genetics to develop a monitoring tool based on the observations from simple micro-organisms such as unicellular algea, which have light sensitive proteins to guide them through the depths of the ocean. (You can learn more about this innovative technique by reading my Right Turn on this topic here). In 2010, optogenetics was named as “method of the year” in the journal Nature Methods.
Knowing different types of light sensitive proteins and their genetic codes, scientists have used adenoviruses as genetic transporters and successfully produced these proteins inside different populations of cells. The cells can then be activated or deactivated using light. When used in brain cells, this gives neuroscientists a valuable tool to modulate cell activity and directly study the functions of various cellular populations.
While visiting California, I had the chance to talk to Professor Jin Hyung Lee, an assistant professor of Neurology and Neurological Sciences, Bioengineering and Neurosurgery at Stanford University and former postdoctoral fellow in the Deisseroth lab. She is an Electrical Engineer by training with a passion for neuroscience who has won multiple honors and awards. She obtained her Bachelor’s degree from Seoul National University and Masters and Doctoral degrees from Stanford University. Her lab uses an innovative combination of optogenetics and functional MRI (fMRI) techniques to analyze the circuitry of the human brain in physiological settings of health and disease. It was an absolute pleasure talking to her.
What does it mean to study the brain on a global scale?
The brain is a circuit of millions and millions of neural cells that not only are connected microscopically and macroscopically, but function together. When we study the connectivity of the neurons in the brain as a whole, we call it the global scale. In my lab we are interested in studying the brain circuitry and how a certain population of cells in the brain interacts with the rest of it. This will help us understand the underlying mechanisms that, for instance, drive a normal hand movement, and how those change in the case of a patient with Parkinson’s. We believe the molecular mechanisms of a disease, whether it is Alzheimer’s, Multiple Sclerosis or something else, change the functionality of this circuit. This change determines the different phenotypes seen in the disease.
Can you explain a little more about your research and how you use optogenetics?
My lab works on a lot of technical development to measure and image the changes that happen in brain circuitry as a whole. We use a novel technique that combines optogenetics and fMRI to produce high-resolution, high throughput images and link the different scales of information for us. We try to understand how a normal brain circuits functions and then we utilize this knowledge to study the differences in various disease settings. Knowing these differences, we can design therapeutics that help treat these functional changes in the brain. Currently, we are investigating stem cells as potential regenerative agents in the diseased brain.
When you integrate stem cells into a treatment strategy for the brain, you want them to replace a certain group of malfunctioning cells. Thus, you will need to know what these cells really do inside the brain. Up until now, the only way to know this after transplanting the cells has been to look at the behavioral changes observed in test animals. You would have to slice up the brain to check for the cells’ survival and whether they really integrated into the circuit or not. And if they did, were they really functional neurons producing action potentials and interacting with other neurons? Or were they simply providing supportive trophic factors (helper molecules that allow a neuron to develop and maintain connections with its neighbours) for the rest of the tissue?
In this context, we engineered stem cells that are optogenetically excitable and transplanted them into lab animal brains in hopes that we would be able to control them. This way, any resulting modulation of the brain activity would definitely be caused by these cells. Our final goal is to visualize these activities. This allows us to observe what the transplanted cells do in a live state. Then, we will be able to troubleshoot our stem cells and optimize them to treat a certain disease.
What does it mean to use optogenetically excitable cells?
A neuron is similar to an electric wire and, similar to how an electric current passes through a wire, information passes through neural cells via an “action potential.” Traditionally, when you want to artificially create action potentials or “excite neurons” in the brain, you put in an electrode and apply electric current through it. But there are many different neural cell types in the brain that are spatially intermingled and you won’t be able to control each one of the cell types separately. So, if you put a current through, you don’t really have control over which ones you are exciting. It is like when you have a really thick finger and you want to press the individual buttons on a phone; it will not work.
Now with optogenetics, you can selectively express light sensitive proteins in only the cell types that you are interested in. So when you apply light, only those cells become excited or vice versa. In my lab, we engineer the stem cells to be selectively excitable by light and then transplant them to the brain tissue. When the light hits the brain and you observe function in the brain via fMRI, it means the activity came from the cells that you put in.
Is it only through shining a certain light-wave that the cells become active?
The cells are functional, but their activity can be increased or decreased depending on the wavelength you use. In other words, you are able to selectively modulate the cells that you transplant and directly measure their activity.
This all sounds really fascinating. Have you started doing experiments in animal models?
We want to study the brain as it functions so these are all in vivo studies in animal models. The next step is to observe whether we can translate similar techniques to humans and eventually have some clinical trials.
Your background is in electrical engineering. How did you become interested in pursuing a career in bioengineering and neuroscience?
As someone who loved math and physics, I went to a competitive science and engineering high school in Seoul, South Korea. I remember falling asleep while trying to solve a math problem and then waking up with a clear idea of the solution. This peaked my interest in the human brain and it was always at the back of my head to figure out how it functions. Initially, I wasn’t quite sure how I could contribute to the science on the brain.
When you have an interest in something, eventually you’ll find a way. For me it was during my PhD in imaging technology that I took neuroscience courses. I realized that there was a need for a circuit analysis tool to understand how the neural circuits of the brain function. Now, in my lab, we apply the systems and circuit engineering perspective to develop new techniques for studying the brain.
Can you tell us a little about challenges that you face in your research?
I can answer this question from two perspectives. From the perspective of research in an academic setting, the main challenge is the slow pace. You might have many interesting ideas, but you will not be able to pursue them without any funding. The application and the processing time for funding can sometimes be quite slow, which can be frustrating at times.
From the perspective of research in neuroscience, one of the biggest challenges is that the whole field is mainly organized based on binary hypothesis testing. Binary questioning is a very valuable tool with its own limitations and when you are trying to reverse engineer a system, it is going to be very challenging. When you ask: “what do these cells do in the brain and how do they communicate with other parts of the brain?” you are exploring and trying to come up with a systematic description of how the brain functions. Therefore, you need to have a more comprehensive approach to understand the system.
In such a setting, being open to different approaches, tools and new ways of thinking becomes very important. However, sometimes the scientific community is not as receptive to different ideas and we end up with new challenges. I think accepting and seeing the need for different ways of thinking is very important for neuroscience to move forward.
As a researcher, in a novel field of work, do you have any message for young researchers and entrepreneurs?
I think it is very important for the up-and-coming younger generation of scientists to be really open-minded. When you go to graduate school, it is good to know your plan and know where your passion lies. However, you don’t necessarily know what will come your way. I think it is important to have a solid background in your field, but at the same time be flexible in approaching a problem. Try to have this sentence nailed in your mind: “If you want to solve a problem, you need to keep an open mind, since there are many different types of solutions.” I think this way you will have a proper perspective while having the end goal in mind.
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