Interview with Optogenetics pioneer Dr Ofer Yizhar from Stanford Karl Deisseroth lab

DR OFER YIZHAR | Synaptic Organization in Neural Circuits, Department of Neurobiology, Weizmann Institute of Science 

Dr. Ofer Yizhar is one of Israel’s pioneers in the field of optogenetics – a breakthrough neuroscientific method based on light-specific activation (or suppression) of neurons in the brain. Dr. Yizhar has recently returned to Israel from Stanford University, where his expertise in optogenetics gathered traction during his postdoctoral work. He now heads the optogenetics lab at Weizmann Institute, which is currently being set up to accommodate the revolutionary research likely to make Israel one of the world’s leading optogenetic hubs in the near future. 

Utilizing optogenetic methods, Dr. Yizhar’s lab is studying a specific part of the brain – the prefrontal cortex, where processes such as memory generation and goal-directed behavior take place, and which is home to an array of widely studied psychiatric disorders, such as schizophrenia and autism.

OPTOGENETICS

Several brain exploration methods are currently in use in labs throughout the world, and perhaps to best grasp the beauty of optogenetics as a brain research tool it is necessary to introduce other techniques in the field. Below is a brief recap of some of the most common neuronal mapping approaches used in the lab.

One rather straight-forward technique used to visualize individual neurons and synapses in the cortical column is, literally, brain carving. A team of researchers at Harvard, led by prominent brain explorer Dr. Lichtman, have been working towards creating the most efficient contraption for slicing off pastrami-thin slices of mouse brain and observing them under a powerful electron microscope. Theoretically, this process may yield a complete 3D cellular reconstruction of a brain, but it would require creating and aligning thousands, if not millions, of brain slices.

Amongst other, less brute-force neuronal visualization technique is the Clarity Project, which helps visualize neurons in brains of live mice. The Clarity project revolves around scientists' ability to chemically produce completely transparent brains (or other organs) in mice--a technique which was recently developed by Prof. Karl Deisseroth and his team at Stanford, where, incidentally, Dr. Yizhar carried out his post-doctoral work. The chemical treatment strips away lipids which normally block the passage of light using the detergent SDS.

To help them through the treacherous cranial terrain scientists at Dr. Lichtman's and Dr. Diesseroth's labs utilize fluorescent staining of neurons, which helps isolate single cells spanning a number of brain areas. The staining produces colorful images, termed BrainBows.

But certainly the most compelling technique developed at Deisseroth's lab is optogenetics - a research tool which revolves around a gene discovered in 2002, encoding light-gated ion channels, or Channelrhodopsins, found in unicellular green algae. Upon activation with a specific-frequency light, the channels open, causing an ion influx into the cell much akin to the mechanism which causes our neurons to fire. Using a different color of light can also activate a different set of channels—the Halorhodopsins which will cause a negative ion influx into the cell and thus inhibition of the neuron. For algae, this mechanism’s function is to orient the cells towards or away from light. But this mechanism can also be applied to mammalian cells.

Channelrhodopsin activation using 470 nm light frequency will cause a positive ion influx into the cell, whilst Halorhodopsin activation using 580 nm light frequency will initiate a negative ion influx

Image source: John Carnett /Popular Science

In recent years scientists succeeded in engineering rhodopsins from algae into nerve cells of lab animals, either grown externally or, in fact, in perfectly alive animals. In essence, genes encoding these channels can be “injected” into very specific areas of the brain, which will render those areas light-sensitive. By shining a light with the use of optic cables into those areas, scientists can trigger very specific neurons, and examine the animal’s behavior, thereby demonstrating the role of the specific neurons they are studying. 

A WORD WITH DR. OFER YIZHAR

What was your inspiration to become involved in the field of neuroscience?

When I was about to hand in my PhD thesis, I was looking for my next step and I came across the 2005 paper where Ed Boyden and Karl Deisseroth showed how channelrhodopsin can be expressed in neurons and used for light-based activation of these cells. I was immediately fascinated with this technique and decided to try to learn more about it. During my time as a postdoc at Stanford, the field virtually exploded and more and more labs were adopting the technique, which made our work very exciting. 

Regarding neuroscience in general, I was fascinated with the brain, I felt that neuroscience is a huge challenge and I had some amazing teachers during my undergraduate studies (such as Idan Segev and Micha Spira), who conveyed the passion for neuroscience. I guess it caught on.

Personally, what are your most profound interests in the sphere of neuroscience?

I was always fascinated by synaptic connections, the places where neurons communicate with each other. These connections provide the brain with the stability at which it can continuously represent lasting memories, but are also remarkably plastic, allowing us to rapidly generate new memories and recover from trauma. Recent genetic studies of mental disorders show that these disorders are often associated with mutations that change the molecules of synaptic connections. My goal is to understand how these genetic changes lead to altered structure and function in neural circuits. The optogenetic tools provide us with a whole new experimental ground in which we can address these questions.

What is the focus of your current research?

Our goal is to uncover some of the basic properties of the prefrontal cortex, and elucidate the mechanisms that lead to impaired function in this part of the brain associated with neuropsychiatric disorders. The tools I developed at Stanford are in use in the lab, but we are also working on expanding the optogenetic toolkit to allow new types of light-based modulation of neural circuits.

What recent noteworthy discoveries in optogenetics have there been?
The field is constantly changing, being only several years old. Developments in optics that allow exquisite single-cell resolution at which we can probe the function of neural circuits, techniques for wireless optical stimulation and recording of neural activity, and continuous molecular engineering of new tools with unique properties, are all pushing the technology forward at a really fast pace. I think these are all things that make optogenetics so exciting at the moment.

Which neuro-research tools that you are aware of are in most direct competition with optogenetics?

I don’t really see it as a competition. All of these tools are out in the open and scientists are just picking and choosing among the different techniques to answer the scientific questions they are working on. There have been excellent papers recently combining optogenetics, calcium imaging and pharmacogenetic tools (“designer receptors” that can be expressed genetically and respond only to synthetic ligands, allowing pharmacological activation or inactivation of specifically defined cells). 

You recently returned from Stanford and began work at Weizmann Institute. How would you say the two environments compare or differ?

Weizmann is an amazing place to work in. It’s not the same scale at Stanford, but it’s a first grade research institute and I can see many parallels between the two places. The emphasis on scientific excellence, the collaborative spirit and the vibrant scientific atmosphere are all part of that. Another thing that I think makes Weizmann similar is its ability to draw excellent students who are excited about science. In neuroscience we have a unique challenge of bringing together people with very diverse specialties. We are trying to recruit students with engineering, computer science, biology and psychology backgrounds – this is just because of the multidisciplinary nature of the work. At Stanford we had a program called “Bio-X” which tries to do exactly that and I think that the brain sciences program at Weizmann is very successful in attracting this type of diversity of students.

As optogenetics gathers momentum many people are beginning to wonder whether this tool can ever be applied on humans. Can you comment on that?

I think it might be possible at some point, but several things need to happen before that – the first is that we have a strong indication of a therapeutic target for modulation using optogenetics with good pre-clinical results. The second is extensive safety testing of the method of gene delivery and of the outcome of expression of opsins in mammalian or primate neurons for years. Since viral vectors are currently being used in numerous clinical trials (for example using AAV-based vectors), I think this is not such a far-fetched goal. 

Do you intend to have any commercial projects underway in your field of research? Do you believe there is a commercial aspect to optogenetics? 

At the moment my research is purely basic in nature. I think that one of the crucial steps in the potential translation of optogenetic techniques to the clinic is the discovery of good therapeutic targets (neural circuits that when modulated with optogenetics might lead improvement in symptoms). This type of discovery can only arise from a detailed understanding of pathophysiological mechanisms.