CAMBRIDGE, MASS. — Inside a fifth-floor lab at the Massachusetts Institute of Technology, a 76-year-old neuroscientist is helping to reinvent psychiatry by hotwiring the brains of mice.
Susumu Tonegawa has figured out how to reverse symptoms of depression in moody male rodents by reactivating the happy memories they created days earlier during a bit of sexual frolicking with female mice. He injects a modified, light-sensitive gene into those happy-memory cells, then uses fiber optics to switch on the memories with a stream of blue light. The depressed mice perk up in seconds. When he turns the light off, their lethargy rapidly returns. Another flip of the switch, and they're active again.
"We cured their depression," he says.
Tonegawa's approach in creating and manipulating memory cells has drawn praise from a normally staid academic community. Beyond those institutional confines, the potential of a radical new tool to treat one of the most complex mental illnesses could be a game-changer in psychiatry.
This is where Thomas Insel, the former director of the National Institute of Mental Health, hoped to push scientists when he announced in 2013 that the agency was refocusing its research to intensify the hunt for the physiological signs of mental diseases and disorders: the biomarkers, or concrete measurements of mental illness that many expect will move the field into the 21st century. After four decades of virtually no major advances in the treatment of mental illness, a profound shift was imperative, Insel thought.
There have already been small but significant successes in identifying depression biomarkers. Scientists at Duke University found that the stress response of the amygdala, an almond-shaped structure in the brain that is linked to fear and pleasure, can predict a person's vulnerability to developing depression as much as four years into the future.
And Northwestern University researchers were able to pinpoint 11 genetic blood markers that distinguished teenagers who were depressed from those who weren't.
Then in 2014, a Northwestern neurobiologist used molecular markers in RNA - the messengers that carry out the DNA's instructions - to develop a blood test for depression in adults that would confirm a physiological basis for patients' symptoms.
"The thinking is changing as the technology changes. . . . This test brings mental health diagnosis into the 21st century and offers the first personalized medicine approach to people suffering from depression," said Eva Redei, a professor of psychiatry and behavioral sciences at Northwestern's Feinberg School of Medicine, who developed the test.
The need has never been more acute. Depression is already the leading cause of disability on the planet, affecting 350 million people of all ages, according to the World Health Organization. Despite its prevalence, the disorder is extremely difficult to study because it is so variable - which is why genetic research has so often failed. One psychiatrist likens it to looking for the genetic risk factors for fever.
Medication and psychotherapy remain the first-line treatments for major depression, though they help less than 40 percent of patients achieve remission of their symptoms. The state of the art in psychopharmacology remains the selective serotonin reuptake inhibitors, drugs such as Paxil, Prozac and Zoloft, which were first patented nearly 50 years ago. These SSRIs target the neurochemicals that carry information between neurons in the brain, but no one knows exactly how or why they work, and because the medications can't lock in on specific neurons or regions of gray matter, they are more blunt instrument than precision tool.
That shortcoming is one major reason why scientists have shifted from neurochemicals to neurocircuits - the networks of cells that are activated every time we think, feel or move - to unravel the mysteries of depression.
At MIT, where he directs the Center for Neural Circuit Genetics, Tonegawa was ready.
Because he had trained as a molecular biologist, he already had a leg up on traditional neuroscientists. Because he was used to crossing disciplines - in 1987 he won the Nobel Prize in Physiology or Medicine for lifting the veil on antibody diversity - he already had the creativity necessary for discoveries. And because he continues to battle his own depression since the suicide of his teenage son more than four years ago, he understands better than most the importance of his potential breakthrough.
"My interests are very narrow now," he admits. "I can't enjoy many things."
It was perhaps inevitable that Tonegawa's research in memory would lead him to this current work. Over the past four years, he and his lab have shown that the physical traces of memories are not stored in the synapses, or connections, between cells, as previously thought, but in discrete circuits of cells, called memory engrams. Tonegawa then upended the common belief that the loss of long-term memory, which can result from a brain injury or disease such as Alzheimer's, is not necessarily the result of damaged memory cells but of a damaged memory-retrieval system.
The first step was to identify and label happy-memory cells with the light-sensitive gene, then to stress those male mice with close confinement until they exhibited symptoms of depression - which meant, for instance, a lack of interest in sugar water. When reactivation of the positive memory neurons lessened the depression, Tonegawa wondered whether simply re-exposing those males to females to create new happy experiences would lift their depression. It did not, which didn't surprise him at all.
"Depressed patients, they don't seek pleasure. That's a hallmark of depression. Enjoyable experiences don't register anymore," he said.
Tonegawa even found the curative sweet spot with his depressed mice: two light treatments a day on five consecutive days. While the same procedure cannot be performed on humans because of the invasiveness of fiber optics, Tonegawa says it is merely an "engineering problem." In the not-too-distant future, he foresees a fast-acting treatment, with fewer of the side effects of current medications.
"People are working on this," he said. "Others are using nanotechnology to try and activate the cells from outside the brain. It's difficult, but I think this will be overcome."
On the other side of the Charles River from Tonegawa, a 44-year-old physician-scientist named Paolo Cassano is also working on depression on the cellular level. His work, the first clinical trial of its kind, could similarly revolutionize patient treatment - not in a few years, but right now.
Like Tonegawa, Cassano came to psychiatric research in a roundabout fashion, through an infectious disease fellowship early in the AIDS epidemic. He became especially interested in patients' emotional suffering, a major reason why he turned to neuropsychopharmacology, ultimately focusing on treatment-resistant depression.
One theory of depression is that it is a metabolic disorder, an underfunctioning of the cellular process by which complex molecules are broken down to produce the energy needed to maintain life. Some research has found that a depressed brain's metabolism appears to be out of whack, storing energy instead of using it. How to unlock that became Cassano's mission. He knew that near-infrared light - closest on the spectrum to visible light - had been successfully tested on the brains of stroke patients and had helped to restore function. At low levels, working in a similar way, it had been approved by the Food and Drug Administration for certain kinds of pain relief.
From his lab at the Massachusetts General Hospital, Cassano wondered: Could an infrared "jolt" also restore normal function within the brain of someone suffering from depression?
His underlying hypothesis was that in depression, "deeper areas are overly firing," especially the emotion-driving amygdala, which overwhelm more superficial areas in the front of the brain that normally help control or inhibit that excessive activity.
Cassano's idea was to target those sluggish neurons close to the surface where mitochondria, the power sources of cells, could convert the near-infrared light into chemical energy. More chemical energy would mean more neuronal growth and repair, and more and better-functioning neurons in the prefrontal cortex would mean better control over the hyperactive amygdala.
If the hypothesis is correct, then Jerrie Spencer's prefrontal cortex has spent much of the past 52 years struggling to handle her amygdala's negativity.
Single and self-employed, Spencer has long suffered through bouts of crying, social isolation and an inability to be fully engaged in her work as a real estate agent. She has tried psychotherapy and group therapy, self-help books and long baths, fish oil and exercise. She took an antidepressant for a month but couldn't tolerate the side effects of fatigue and mental fuzziness. Depression wasn't just something psychological. It was physical.
"In my body, in my gut - like a heavy weight in my stomach, all the time," she said. "The feeling would come over me, and I felt helpless. It took away my life. . . . It brought me to my knees."
She also admits she felt ashamed because the depression was something she couldn't control. There were times when she might feel better for a few weeks or months, but they never lasted. Finally, in late spring, she sat down in front of her computer, went to Craigslist, and typed the word "depression" into the search engine for the Boston area where she lives. Up popped pictures of Depression-era glass and furniture for sale. But nestled between two of them was this simple question: "Are you feeling down, blue, in the dumps?"
It linked to information about Cassano's clinical trial at Massachusetts General, posted by one of his research assistants, who creatively also used the Boston transit system, Facebook and Twitter to try to spread the word.
From the people who responded, 22 were chosen, including Spencer. All were between the ages of 18 and 65 and had been diagnosed with major depression. A third were women.
Over a period of about 18 months, ending last August, they all took part in research structured so that half were randomly assigned by a computer to the light treatment and half to a placebo treatment. Neither they nor Cassano would know who was in which group - all critical elements of a gold-standard clinical trial. All but four participants finished the study, receiving twice-weekly treatments for eight weeks.
Spencer's sessions took place in a sparsely furnished room a few doors down from Cassano's office. She had done her own research online and discovered that near-infrared light therapy has been used both medically and cosmetically for various ailments and conditions, including mouth ulcers in cancer patients and age-related wrinkles. Its use on the brain is still relatively new, however. Animal studies and human trials for stroke, Parkinson's and traumatic brain injury have proved the procedure to be safe but of limited efficacy.
Before beginning, Spencer had questions: What could she expect? Would it hurt? She would experience no pain, Cassano replied, just a sensation of heat on her head. She might have a slight headache afterward, but even that was unlikely.
Each visit was much the same. As Spencer lay on her back on an examination table, Cassano used a tape measure to locate an area either on the front left or right side of her head where the near-infrared light device, about the size and shape of a TV remote, would be placed. He then marked the spot, using pewter-colored eyeliner, where he wanted to concentrate the light beams. They would penetrate her scalp, skull and about a half-inch of brain tissue.
Spencer donned what looked like swim goggles to protect her eyes. Cassano plugged in the device, set an egg timer for 20 minutes and left the room. The timer went with him. There would be no talking during the session, no music, just Spencer lying still.
After just the first 20-minute session in June, she was convinced she was getting the real thing.
"Afterward, everything was really vivid visually," she recounted recently. "I wasn't sure if I was imagining it. Then I went outside, and everything was bright and crisp. I stood there looking around, and I thought, this is great."
The biggest difference, though, was that heavy weight in her stomach. It was gone.
"I kept waiting for it that evening and the next day," Spencer said. "I was really surprised."
Of course, she still had no idea whether she was getting the real or the placebo treatment. "I said to Doctor Cassano, 'If I'm not being treated, someone should follow me around with a clipboard.' "
Cassano tracked the data throughout the trial. Three of the 21 subjects were excluded from his final analysis because they hadn't undergone the full series of treatments. Of the remaining 18, nine received the real therapy, nine the placebo.
Though near-infrared light for major depression had been tested only in a much smaller single-treatment trial, animal studies have shown it to have several beneficial biological effects. It increases connections in between neurons as well as stimulates the formation of new ones. It also decreases inflammation in the brain, which lessens cell damage.
Michael Hamblin, a principal investigator at Massachusetts General's Wellman Center for Photomedicine, says he is "totally convinced" by Cassano's approach. "Anything that is worn out, gotten old, you can stimulate tissue repair, improve function with light. The brain seems to respond well to near-infrared light. . . . It's like shining a flashlight on someone, so why not treat patients?"
Indeed, Cassano thinks light therapy could provide a groundbreaking new tool for depression treatment - one that is affordable, without side effects and more immediate than medication. He jokingly refers to it as a "tanning bed for the brain."
When the identities of the treatment groups were finally revealed at the conclusion of the trial in August, Cassano found his preliminary analysis had held up. Sadness, anxiety, lethargy, agitation - the results showed that all were dramatically reduced in the treatment group.
That group included Jerrie Spencer. And several months later, the weight in her stomach still hasn't returned.