191 - Revolutionizing our understanding of mental illness with optogenetics

KEYPOINTS

• 01

  A psychiatry rotation changed his career.

  Karl Deisseroth, a Stanford psychiatrist and bioengineer and Attia's former medical school classmate (he was in the highly selective MD-PhD Medical Scientist Training Program), planned on neurosurgery until a rotation on a locked psychiatric unit, with patients who were a danger to themselves or others, convinced him psychiatry was where the greatest need and mystery lay. He trained before 80-hour week limits, with a young son born in 1996.

• 02

  Psychiatry in 2004 lacked causal tools.

  When he set up his lab in 2004, treatments like drugs, electroconvulsive therapy and vagus nerve stimulation worked for some patients but without precise understanding. The brain has about 90 billion neurons, each forming 10,000–100,000 synapses, and earlier tools (lesions, electrodes, drugs) couldn't control specific cell types with precise timing.

• 03

  Optogenetics borrows light-sensitive proteins from microbes.

  Microbial opsins were discovered in 1971 by Dieter Oesterhelt and Walther Stoeckenius at UCSF; these single-component proteins pump or pass ions when light hits them. In principle someone could have put them into neurons in the late 1980s or 1990s, but the currents were thought far too small: neurons need about 100–200 picoamps to fire. Deisseroth's lab published its paper in summer 2005, and several other papers followed within six months.

• 04

  Viruses made targeting specific cells possible.

  The opsin gene (such as channelrhodopsin) is packaged into a virus that delivers it, paired with cell-type-specific genetic elements, into neurons; it can even be given systemically in some settings, though focal injection is cheaper. Deisseroth says the method wasn't really 'solved' until about 2009, after years of work on light delivery, viral vectors and generalizable targeting.

• 05

  Optogenetics established causality for dopamine and reward.

  In 2009, his group selectively fired dopamine neurons, not nearby GABA or serotonin cells, and showed it was sufficient to drive preference. With typical rewards like sugar water or social contact, animals prefer the stimulated side about 70–30 or 80–20; dopamine stimulation produced similar effects.

• 06

  Anxiety's components can be split apart.

  In 2013, his lab found separate, nearby cell populations controlling distinct features of anxiety: breathing changes, risk-avoidance behavior (like avoiding exposed spaces) and the negative internal state. Too little anxiety is also dangerous, as people who don't perceive threat take extreme risks.

• 07

  Anxiety links autism and depression.

  Deisseroth emphasizes that anxiety can be crushing and becomes pathological when it exceeds the normal range; it's a common thread in autism spectrum disorders, depression and other conditions. Optogenetics has been used to study social behavior and states like parenting (work at Harvard in 2018 used the same tools).

• 08

  Depression involves discounting effort.

  Where a manic person thinks anything's possible, a depressed person thinks nothing is, devaluing effort and leading to hopelessness and sometimes suicidality. Anhedonia, the absence of pleasure, is so central that major depressive disorder can be diagnosed without depressed mood. In fish and mice, 'giving up' can be adaptive in truly hopeless situations, which suggests depression is a misfiring of a useful circuit.

• 09

  Severe psychiatric illnesses are highly heritable.

  Genetic contributions run about 50% for depression and up to 50–80% for schizophrenia, autism and bipolar disorder. Hypomania may be unusually prevalent in North America, possibly because of who emigrated. Early-life trauma has clear, lasting psychiatric effects, including on personality disorders like borderline, seen in animals too.

• 10

  Optogenetics is a discovery tool first.

  Deisseroth stresses that the immediate value of optogenetics is in identifying which cells and projections cause which behaviors, insights that can then guide treatments using other methods, such as drugs, brain stimulation or psychedelic-assisted therapy (ketamine, psilocybin, LSD and MDMA are all of interest to him and Attia). Psychiatrists grasped its importance quickly because they knew better than anyone how much specificity their field lacked.

• 11

  Projections uses patient stories to explain the science.

  Deisseroth wrote Projections from about 2017 to 2020, blending clinical stories with circuit science and working with language in ways atypical for a scientist. He received the Lasker Award for optogenetics. Self-harm ranks among the 10 leading causes of death, and higher if overdoses are included, which is why the stakes are so high.