Podcast Summary
Revolutionizing Neuroscience with Optogenetics: Dr. Carl Desarath's groundbreaking optogenetics research uses light to activate specific neurons, opening new avenues for understanding the human mind and potentially treating mental health issues like depression, anxiety, and autism.
Dr. Carl Desarath, a professor at Stanford, has revolutionized neuroscience through optogenetics - a tool that uses light to activate specific neurons through genetic engineering. This groundbreaking research has opened new avenues for understanding the human mind, leading to numerous scientific awards, including the prestigious Lasker Award. Dr. Desarath's work, which focuses on mental health issues like depression, anxiety, and autism, has the potential to significantly impact our understanding and treatment of these conditions. His recent book, "Projections," offers a personal and poetic exploration into mental illness. With so much ground left to cover, we look forward to having Dr. Desarath back on the podcast for further discussions.
Background in Biochemistry, Theoretical Physics, and MD-PhD program shaped career goals: Academic background and experiences influenced career choice, leading to a unique perspective in neurosurgery through MD-PhD program
The interviewee's academic background and experiences, specifically being part of the MD-PhD program and having a strong foundation in biochemistry and theoretical physics, played a significant role in shaping their career goals and eventual decision to pursue both clinical medicine and research. Their early interest in understanding the brain at the cellular level and the emotional expression of humans led them to medical school with a focus on neurosurgery, where they could directly interact with the human brain. The MD-PhD program allowed them to keep both clinical and research threads alive, ultimately leading to a unique and valuable perspective in their field.
Fit between medical students and specialty residents impacts experience and interest: Personal experiences and fit play a crucial role in shaping medical students' interest in specialties. Neurosurgery, with its direct impact on patients and complex nature, can be appealing despite demanding training.
The fit between a medical student and the residents of a specific specialty during clinical rotations significantly influences their experience and potential interest in that field. The speaker shared their personal experience of disliking pediatric oncology due to not fitting in, but later discovering a passion for neurosurgery despite initial reluctance. Neurosurgery, although complex, has a unique appeal due to its direct interaction with the brain and the potential to make a significant impact on patients' lives. However, the demanding nature of the specialty leaves little time for philosophical contemplation, and residents' willingness to engage in deep thought declines as they progress through their training.
Unexpected experiences in medicine lead to career shifts: An open mind and new experiences can lead to unexpected career opportunities in medicine, even in seemingly less desirable areas like psychiatry.
The field of medicine offers unexpected experiences and opportunities, even in areas that may initially seem less desirable or less measurable. The speaker shares his experience of observing an awake brain surgery during his general surgery rotation, which left him in awe and led him to consider neurosurgery. However, his plans changed when he completed a psychiatry rotation in a locked ward at a VA hospital. Despite his initial expectations, he was struck by the purity and consistency of psychiatric disorders in this setting and the profound expression of symptoms. This experience ultimately influenced his career choice. The speaker also highlights the unique challenges of psychiatry, such as the lack of measurable biomarkers for diagnoses. Overall, this discussion underscores the importance of keeping an open mind and being open to new experiences in the field of medicine.
Transformative experience with a patient's mental illness: Encountering a patient's mental illness can inspire a healthcare professional to pursue a career in psychiatry and deepen their understanding of the human mind.
Direct exposure to the profound suffering and mystery of a patient's mental illness, despite the lack of immediate solutions or tools, can be a transformative and inspiring experience for a healthcare professional. This encounter challenged the speaker's expectations and led him to reevaluate his career goals, ultimately steering him towards psychiatry. The mystery of the human mind and its ability to create emotions and feelings from a collection of cells fascinated him, and he saw it as a burden shared by humanity that needed to be understood. The experience instilled in him a strong desire to figure out the nature of mental illness and to help in any way possible, even if the tools were limited at the time.
Balancing Psychiatry and Neuroscience Residencies: Despite the challenges of balancing clinical training and research in psychiatry and neuroscience, it's possible with the right support and determination.
Pursuing a career in both psychiatry and neuroscience, while challenging, is possible. During Carl's residency, he faced the difficult decision of prioritizing his clinical training or his research. The choice was particularly difficult due to the demanding nature of residencies and the rapid pace of scientific discoveries. However, with the help of a research track psychiatry residency and a supportive mentor, Carl was able to balance both worlds, effectively completing a combined postdoctoral fellowship and psychiatry residency at the same time. This experience was unique and not without its challenges, especially as a single parent at the time. Nevertheless, Carl's determination and perseverance allowed him to make it work and make significant contributions to both fields.
Motivated by unsatisfied scientific understanding during residency: The speaker's personal experience during residency sparked her curiosity and led her to pursue a research career in mental health treatments for more precise causality and deeper scientific understanding.
During her psychiatry residency, the speaker was deeply involved in clinical work and gained a thorough understanding of available treatments for mental health conditions. However, she was unsatisfied by the lack of scientific understanding behind these treatments, as they were all nonspecific and did not target particular cells or psychiatric symptoms. This context motivated her to pursue a research career in order to gain more precise causality and deepen the scientific understanding of mental health treatments. The speaker's son, who is now an MSTP student, went through this transformation with her and has since grown into a talented individual with interests in guitar, computer science, and medicine.
Understanding the complex structure of the human brain: The human brain, with its 90 billion neurons and intricate synapses, is a complex system that has evolved over millions of years to give humans advanced cognitive abilities
The human brain is an incredibly complex and intricate system, made up of approximately 90 billion neurons, each with the ability to generate electricity and transmit information through electrochemical signals. These neurons are organized into various layers in the brain, with the outer cortex being the most advanced in humans, consisting of six layers of cells. The wiring between these cells, or synapses, is also incredibly complex, with information flowing through electricity and chemicals. Over millions of years of evolution, our brains have scaled up these structures and added new layers and functions, leading to the advanced cognitive abilities unique to humans. Understanding the neuroanatomy and neurophysiology of the brain is essential to grasping the depth and breadth of the discoveries and mysteries yet to be uncovered.
Exploring the ancient and conserved structures of the brain: Neuroscientists study the ancient, conserved structures of the brain, like the hypothalamus and brainstem, while also investigating unique surface structures and complex signaling processes involving multiple neurotransmitters and neurochemicals.
The deep structures of the brain, such as the hypothalamus, are ancient and conserved among all vertebrates, while the surface structures are more complex and unique to each species. The brainstem, which handles essential functions like breathing, is highly conserved across fish, mice, and humans. Neurons can release multiple neurotransmitters and neurochemicals, adding complexity to the signaling process. Studying these shared and conserved structures, as well as the differences, can help us understand the intricacies of the brain. Historically, neuroscientists faced challenges in establishing causality between brain stimulation and responses. They used electrodes to listen in and stimulate specific regions of the brain, affecting all electrical cells near the electrode, not just the intended ones. However, this provided a foundation for understanding brain function. Recent advancements include the discovery that neurons can release multiple neurotransmitters and neurochemicals, adding complexity to the signaling process. Additionally, different cells have various receptors for these chemicals, leading to diverse responses. By studying these shared and conserved structures, as well as the differences, we can continue to unravel the mysteries of the brain.
The discovery of microbial opsins revolutionized neuroscience with optogenetics: Microbial opsins enabled optogenetics, providing a solution for turning off cells and testing necessity in neuroscience research and clinical applications.
The discovery of microbial opsins, a class of light-activated electricity generators, revolutionized the field of neuroscience by enabling optogenetics, a technology that brought cell type specific causality and digital switches to single neurons. This discovery was made possible by the convergence of several threads, including the known existence of these proteins and advancements in gene introduction techniques. However, despite the foundational work in neuroscience and the discovery of dopamine neurons, there were uncertainties and limitations, such as the lack of a specific way to turn off cells and test necessity. This situation persisted both clinically and in research, and the discovery of microbial opsins provided a solution to this challenge.
Using viruses to introduce genes into neurons: Viruses are used to deliver foreign genes into neurons for various applications, including creating optogenetics tools for neuroscience research.
Viruses are used as vehicles to introduce foreign genes into cells, including neurons. DNA, the instruction manual for making proteins, is encoded in genes, which are made up of nucleotides. To get a gene into a cell, viruses are often used due to their ability to effectively deliver genetic material. Some viruses work with DNA, while others use RNA as their genetic material. The use of viruses to introduce genes into neurons is a relatively recent development, and it was a race among researchers to publish the first paper on the subject in the mid-2000s. The technology has since become widely adopted due to its potential for various applications, including the creation of optogenetics tools for neuroscience research.
Revolutionizing Neuroscience Research with Viral Technologies: Viral technologies allowed researchers to precisely control individual neurons by introducing genes and generating large currents, overcoming challenges of specificity and invasiveness with microbial options.
The development of viral technologies for introducing genes into specific neurons was a major advancement in neuroscience research. Francis Crick had long advocated for this technology, suggesting that light could be used for its non-invasive properties and great specificity. With viral technologies, researchers could introduce genes into multiple cells and get hundreds or more copies per cell, resulting in much bigger currents than with microbial options. However, a major challenge was directing the virus to exactly the cells of interest, which was achieved by concentrating the virus and doing a focal injection into the desired region. Despite the initial small currents generated by a single opsin, expressing large numbers of options per cell allowed researchers to reach the necessary levels for controlling neurons. Overall, viral technologies revolutionized neuroscience research by enabling precise control of individual neurons.
Exploiting unique promoters for specific cell types in optogenetics: Researchers used unique promoters near genes to create a virus that only infects and expresses the opsin gene in specific neurotransmitter-producing cells, enabling optogenetics to effectively control neural activity in those cells.
The development of optogenetics, a technique used to control neural activity with light, required finding a way to make the production of opsin cells specific to certain cell types. Early attempts at this involved engineering the virus capsid to target specific cells based on their surface proteins, but this approach was not practical due to the lack of a comprehensive understanding of the proteins expressed by each cell type and the potential for cross reactivity. A more successful approach involved working with the DNA near genes, specifically the promoters and enhancers, which attract transcription factors and determine whether a gene is expressed. By exploiting the promoters that are unique to specific neurotransmitter-producing cells, researchers were able to create a virus that would only infect and express the opsin gene in those cells, providing the specificity needed for optogenetics to be effective.
Gene editing in the brain with immune privilege: Researchers used gene editing to target dopamine neurons in the brain, leveraging immune privilege to avoid detection, leading to new insights into animal behavior and neurochemistry.
Carl and his team were able to use a gene editing technique to selectively target and modify dopamine neurons in the brain, leveraging the immune privilege of the brain to avoid detection by the immune system. This breakthrough allowed them to answer long-standing questions in neurobiology and neurochemistry, such as the role of dopamine neurons in animal behavior, with unprecedented precision. By introducing a light-sensitive protein into dopamine neurons and observing the animals' preferences based on light exposure, they were able to demonstrate that dopamine neurons play a key role in animal behavior. This groundbreaking research opened up new possibilities for understanding the complex workings of the brain and paved the way for further advancements in neuroscience.
Understanding animal preferences through conditioning place tests: Animals spend more time in environments linked to dopamine neuron activation, revealing their positive association and shedding light on mood regulation, memory, feelings, and thoughts.
The conditioning place preference test in animals, which involves associating a particular environment with a pleasurable or unpleasant experience, can reveal the animal's subjective valence towards that experience. This test, which can be used to investigate the role of dopamine neurons in reward and motivation, has shown that animals will spend a significant amount of time in environments associated with dopamine neuron activation, suggesting a positive association. The test has been used to investigate various rewards and aversions, and even more advanced versions involve the animal actively working to receive the reward. The discovery of this tool has given scientists a profound sense of optimism, as it provides a way to ask long-standing questions about mood regulation, memory, feelings, and thoughts. Ten years ago, the appreciation for this tool in the scientific psychiatry community was immediate, as psychiatrists, who deal with the clinical manifestations of these questions every day, recognized its potential value.
From promising concept to widely adopted neuroscience method: Optogenetics, a neuroscience technique for precise, causal manipulation of neural activity, went from a promising concept in 2004 to a widely adopted method by 2009, leading to numerous discoveries in various fields of neuroscience research, including anxiety studies.
The development of optogenetics, a revolutionary neuroscience technique, went from a promising concept in 2004 to a widely adopted and generalizable method by 2009. During those years, researchers faced challenges in making the technique precise, causal, and applicable to various cell types and neurotransmitters. With the support of various funding institutions and private donors, they managed to overcome these challenges, leading to numerous discoveries and applications in various fields of neuroscience research. One significant area of interest was studying anxiety, a common theme in psychiatric disorders like depression and autism spectrum disorders, in a precise and causal manner using optogenetics. Anxiety, which can range from normal to pathological, is a complex emotion that can severely impact social and occupational functioning, making it a crucial area of study. The technique's ability to target specific cell types and manipulate their activity provided new insights into the underlying mechanisms of anxiety and its relation to other psychiatric disorders.
Identifying cells controlling anxiety components: Optogenetics helps identify specific brain cells controlling anxiety's physiological, behavioral, and emotional aspects, paving the way for targeted interventions without addictive properties or side effects
Anxiety is a complex mental health condition with various components, including physiological changes, behavioral responses, and negative emotional experiences. These components are likely controlled by different cells in the brain. While medications like Valium, Xanax, and Adivan can effectively treat anxiety by acting on the GABA receptor, they come with addictive properties and side effects. Optogenetics, a research technique that uses light to control neural activity, has helped identify specific cells that control different features of anxiety, opening up new possibilities for targeted interventions.
Understanding Anxiety and Autism through Neurobiology: Neurobiology reveals that anxiety in autism arises from brain processing differences, and optogenetics offers new possibilities for understanding and treating this complex condition.
The brain's complex states, such as anxiety and parenting, can be broken down into their sub-features, and understanding how these features are assembled from cells can provide valuable insights into various neurological conditions, including autism. Anxiety is a common symptom in individuals with autism, and it arises due to the overwhelming nature of social interactions. The human social world is complex and fraught with possibilities for misunderstanding, making it an anxiety-provoking situation for individuals with autism. Neurobiologically, this information overload might occur due to differences in brain processing. Optogenetics, a technique used to control neuronal activity with light, is providing a window into the potential 10-year timescale of autism treatment. Despite the significant genetic component of autism, the lack of a single gene or protein target has hindered the development of effective treatments. However, the advancements in optogenetics offer new possibilities for understanding and treating this complex condition.
Understanding social interactions and mental health through optogenetics: Optogenetics, a research tool to manipulate neuronal activity with light, reveals specific cells responsible for mental health conditions like depression, mania, and eating disorders, paving the way for targeted therapies.
Social interactions, like in the case of mice, involve both motivation and cognition, and these aspects can be influenced by different cells in the brain. Optogenetics, a research tool used to manipulate neuronal activity with light, has been instrumental in understanding the cellular basis of social interaction and various mental health conditions such as depression, mania, and eating disorders. While it may not be the primary mode of treatment, it serves as a crucial discovery tool, paving the way for targeted therapies by revealing the specific cells responsible for various aspects of mental health. The recent success of conferring sight to a blind person with optogenetics highlights its potential as a transformative treatment in certain cases. Overall, the future of mental health treatment lies in the understanding of cellular causality, which optogenetics provides, and the subsequent development of targeted therapies based on this knowledge.
Exploring Altered States Through Writing: Carl Zimmer's 'Projections' offers a unique perspective on mental illness, using engaging writing to help readers understand and feel various altered states, drawing on his personal experiences and scientific expertise.
Carl Zimmer's book "Projections" is a remarkable achievement that breaks the mold of typical scientific texts. Zimmer, who is already renowned for his scientific accomplishments, demonstrates his gift for writing as well. His goal was to help readers understand and feel various altered states, from mania to grief, using writing that matches the feelings. He worked diligently on the project for several years, finding joy in the process despite its challenges. The book also explores the evolutionary basis for mental illness, offering unique insights into conditions like mania and grief. Zimmer's personal connection to the topic, as he himself has dealt with mental health issues, adds depth to the text. Overall, "Projections" is a testament to Zimmer's versatility and passion for sharing knowledge with a wide audience.
Mania in bipolar disorder: Evolutionary benefits and ethical dilemmas: Mania, a component of bipolar disorder, has potential benefits such as increased creativity and charisma, but also causes serious problems. Its genetic link is strong, and ethical implications of treatment are complex.
Mania, a key component of bipolar disorder, may have evolutionary benefits, particularly in the context of recent immigrants. Mania is a state of elevated mood and increased energy, which can be valuable for taking risks and making significant life changes. The genetic link to mania is strong, with bipolar type 1 disorder being highly genetically determined. While mania can cause serious problems, it also has positive aspects, such as increased creativity and charisma. However, the ethical implications of treating mania are complex, as there are cases where mania may be beneficial. The discussion also touched upon the strong genetic links to various psychiatric disorders, including bipolar disorder, autism, and depression.
Understanding the Complexity of Mental Health Disorders: Bipolar disorder involves mania and depression, which may be necessary for recharging after significant life shifts. Anxiety disorders are common and underappreciated, significantly impacting daily life. Depression, a mystery clinically, is being studied through advancements like optogenetics to understand its components.
The human condition, as expressed in mental health disorders like bipolar, exists on a spectrum. Mania and depression are two extremes, but the ability to sustain an elevated energy state for weeks, months, or even years is crucial for those who undertake significant life shifts, like immigrating to a new country. The pairing of mania and depression in bipolar disorder may be necessary for recharging after the discharge of emotional and physical energy. Anxiety disorders, which are the most common psychiatric disorder when grouped together, are often underappreciated and can significantly impact a person's daily life. Depression, which is also common, remains a mystery clinically, and scientific advancements, such as optogenetics, offer insight into the various components of depression, including anhedonia, the absence of pleasure.
Understanding Anhedonia and Hopelessness in Depression through Optogenetics: Optogenetics reveals overactive prefrontal cortex can suppress dopamine neurons, causing anhedonia. Excessive frontal cortex activity also suppresses positive and negative experiences, leading to anhedonia in rodents. Hopelessness can be studied in animals and optogenetics provides insights into its neural mechanisms.
Optogenetics, a research technique that uses light to control brain cells, has provided valuable insights into the neural mechanisms behind anhedonia, a key symptom of depression. Researchers have found that overactivity in the prefrontal cortex can suppress the ability of dopamine neurons to recruit reward circuitry, leading to anhedonia. Optogenetics has also shown that the frontal cortex can suppress both positive and negative experiences, and excessive frontal cortex activity can cause anhedonia in rodents. Additionally, hopelessness, another depression symptom, can be studied in animals by observing their response to challenging situations, and optogenetics can provide insights into the neural mechanisms behind hopelessness as well. The evolutionary basis for depression is less clear, but the prevalence of depression suggests that it may serve some adaptive function, possibly related to energy conservation or risk assessment.
Depression as a potential adaptive response: Depression may have evolved as a coping mechanism to help organisms conserve energy during tough times, despite its negative aspects.
Depression may have evolved as a passive coping mechanism, akin to hibernation, to help organisms conserve energy during difficult times. This theory, while speculative, suggests that depression's negative aspects, such as low energy and lack of motivation, may have provided some adaptive value at the population level. Depression is genetically determined and common, and understanding its evolutionary origins could help us better comprehend this complex mental health condition. Regarding non-human primates, they too can exhibit maladaptive states that resemble depression, particularly in response to bereavement. However, there is no evidence of true suicide or suicidal behaviors in animals, likely due to the cognitive complexity involved in understanding the concept of ending one's own life.
Impact of Early Childhood Trauma on Animal and Human Mental Health: Early life experiences, including trauma, can shape an individual's mental health and brain development, potentially leading to long-term behavioral and genetic effects.
While animals may have complex minds like humans, they don't have the ability to express deep concepts in the same way we do due to the lack of certain physical capabilities. Trauma, particularly during early childhood, can have lasting effects on mental health, including depression, and these effects can be both behavioral and potentially epigenetic. The brain is highly tunable during young ages, and early life experiences can shape an individual's expectations and reactions to the world. The lasting impact of trauma may not be due solely to neural circuitry changes but could also be genetic or epigenetic. Emotional tears, a uniquely human trait, can reveal deep emotions and elicit a strong desire to help from others.
Emotions and physiology: Close proximity in brainstem: Emotions can trigger involuntary expressions and behaviors due to brainstem's emotional and physiological control regions proximity. Carl Zimmer's work delves deeper into this concept and explores personality disorders and therapeutic benefits of psychedelics.
Emotional changes can trigger involuntary expressions and social behaviors in humans, potentially leading to the evolution of new systems. This is due to the close proximity of emotional and physiological control regions in the brainstem. The concept of a "storehouse of tears" in projections, which was brought up during the conversation, highlights this idea. Carl Zimmer's work, including his book "She Has Her Mother's Laugh," explores these ideas further. The discussion also touched upon the significance of personality disorders and the potential therapeutic benefits of psychedelics. For more in-depth content on these topics and access to exclusive podcast content, consider joining Peter Attia's membership program.
