Brain research has been accelerating rapidly in recent decades, but the translation of our many discoveries into treatments and cures for brain disorders has not happened as many expected. We do not have cures for the vast majority of brain illnesses, from Alzheimer’s to depression, and many medications we do have to treat the brain are derived from drugs produced in the 1950s—before we knew much about the brain at all. Tackling brain disorders is clearly one of the biggest challenges facing humanity today. What will it take to overcome it? Nicole Rust takes readers along on her personal journey to answer this question.
What inspired you to write Elusive Cures?
Nicole C. Rust: I am a brain researcher, and I was concerned that discoveries about the brain have been piling up for some time, but they haven’t been translating into new treatments for brain disorders — at least not at the rate that many hoped. I wanted to better understand why, and what the brain research community plans to do about it. The descriptions you find in modern textbooks of how we plan to create new treatments (for, say, schizophrenia) are outdated and do not reflect what’s happening in the field today; it’s time for an update.
Brain research is in the middle of a transformation, following breakthroughs that allow us to measure the brain in ways we’ve never been able to before, along with new artificial intelligence to help us sift through all that new data. In Elusive Cures, I describe the throughline between those breakthroughs and the end goal of treating the most formidable brain disorders, from Alzheimer’s to psychosis.
You thread the personal stories of individuals with brain and mental disorders throughout your book. Why was that important to you?
NR: Those stories help us comprehend what’s at stake in our quest to understand the brain. The book opens with the story of Carol Jennings, a remarkable woman who helped researchers find the genetic mutation that causes Alzheimer’s in her family. That discovery shaped Alzheimer’s research for the next 30 years and led to the first drugs that slow the progression of the disease. Those drugs are a step forward, but they don’t slow decline by a lot, and they fall short of what we need to help individuals, including Carol’s family. Carol spent 30 years advocating for individuals with Alzheimer’s, and absent a cure, she refused to get tested for the gene herself. She inherited it, and we could not help her, despite her contributions to the gene’s discovery. Carol died from Alzheimer’s last year. As her husband, Stuart, says, “It’s the kids we are fighting for now.” Personal stories like Carol’s motivate us to fight.
As you describe, the brain is the most complicated thing in the universe. Will non-experts be able to understand and enjoy your book?
NR: What a great question. It’s true, the brain is complicated. But the answer to the question, “What’s so complicated about it?” is not. The brain is complicated because it’s chock-full of feedback loops, where causes (like brain activity) trigger effects (like our behavior) that feed back as causes (to shape how our brains are wired up; that’s learning). We know that systems like that can get really complicated — the weather and ecosystems are two examples. Ultimately, the answers to “What’s been holding back progress in brain research?” are more conceptual than technical, and I shaped the book around those concepts. I wrote it for non-experts to understand (and I hope they enjoy it).
In Elusive Cures, you trace the discovery stories behind many of the therapies we have to treat brain disorders. Did that history surprise you?
NR: It did indeed. Before the research for Elusive Cures, I did not realize how many of the drugs we have today were serendipitously discovered long ago, before we understood much about the brain at all. The first antidepressant is a great example — it was discovered during clinical trials for a drug to treat the lung-infecting bacteria tuberculosis. The patients who received the drug were joyous and dancing around, and researchers realized it had a different purpose. Another example is the class of antipsychotic drugs — there are 26 of them in total, and they all work in the same way as the first, serendipitously discovered drug.
At the same time, truly novel therapies also exist, and I was surprised by how much is involved in creating a new one. In the book, I trace the development story behind the new insomnia drug suvorexant, which began with the decades-long discovery of a new way brain cells communicate and its role in sleep. Next, the pharmaceutical industry spent a decade developing the drug, including a screen of over 2 million chemicals to find the right one, followed by multiple stages of clinical trials to ensure the drug is effective and safe. What’s involved in creating a novel therapy from “the bench to the bedside” is epic.
Your book covers brain disorders of many types. Focusing on one, what do we know about depression? What are we struggling to understand?
NR: Depression is heartbreaking. As the novelist William Styron describes his own experience, “Most physical distress yields to some analgesia, not so depression. Psychotherapy is of little use to the profoundly depressed, and antidepressants are, to put it generously, unreliable. Even the soothing balm of sleep usually disappears.” Around 15% of adults will suffer from depression, and for half of those who decide to try antidepressant medication, it will not help.
There’s so much we don’t understand about depression. Like other psychiatric conditions, depression is diagnosed based on symptoms (like sadness and insomnia) rather than biological markers (like brain scans or blood tests). This is because we still don’t understand what’s happening in the brain of someone who is experiencing a depressive episode or even how antidepressants work, when they do. We don’t even understand how our brains drive our everyday moods.
After decades of research, we now know that explanations of depression in the brain will not be simple. For instance, a predisposition for depression cannot be tied to a single gene — it’s tied only weakly to hundreds of them. Likewise, there’s no single part of the brain that can be linked to depression, and that is why we still cannot decipher from a brain scan whether someone is experiencing a depressive episode.
Fortunately, this is a new era for mood and depression research. In fact, I am so excited about the next steps for understanding it that I’ve decided to redirect my entire research program to study the neuroscience of mood on the other side of writing this book. Elusive Cures describes what those next steps are.
The arc of Elusive Cures captures your transformation from pessimism to optimism about the future of treatments and cures for brain disorders. What caused that shift?
NR: Yes, that’s true. I was motivated to write Elusive Cures because I couldn’t see the throughline between what was happening in brain research and the end-goal of treating brain disorders. I also couldn’t find descriptions of that throughline written down anywhere in a way that left me hopeful. So I decided to figure it out for myself, focusing on the question, “What’s it going to take to understand the brain in the way that we need to treat brain disorders?” It was clear from the outset that something needed to change in terms of how brain researchers (including myself) were going about things.
While writing the book, I realized that the changes that need to happen are already happening. That’s the source of my newfound optimism. In broad strokes, we’ve been oversimplifying the brain as something like a domino chain of causes that lead to effects, assuming that the causes of brain disorders are broken dominoes (like mutated genes or brain areas with aberrant activity). For many disorders — from Alzheimer’s to depression — that hasn’t been working. We’ve known all along that the brain is chock-full of feedback loops, but it’s only due to recent breakthroughs that we are able to measure and model the brain that way. In a brain with those loops, the causes of brain disorders can manifest in ways that are different from “broken dominos.” There’s good reason to think those loops are key to what we’ve been missing. I am hopeful that this shift in how we think about the brain will be meaningful for reaching the end goal of treatments and cures. It’s a new era!
About the Author
Nicole C. Rust is professor of psychology at the University of Pennsylvania. Recipient of the Troland Award from the National Academy of Sciences, she is a contributing editor at The Transmitter, a leading brain research news magazine.