A Better Pill to Swallow

A writer’s search for an alternative to antidepressants leads him to an unassuming office in Rockville and a potential miracle drug dubbed NSI-189



Photo illustration by Amanda Smallwood; thinkstock.com

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What if everything we thought we knew about treating depression was wrong?

What if the phalanx of antidepressants we’ve developed over the past four decades with optimistic names full of X’s and Z’s—Prozac, Zoloft, Paxil—was missing the mark?

What if there was a new treatment that could change our lives? That could enable those of us suffering from depression to stop swallowing that bitter pill every morning? That could undo the ravages not only of depression but of dementia, Alzheimer’s disease and the downhill slide of ordinary aging?

What if there was a drug that all of us might take someday?

I have personal reasons for asking. Seven years ago I shut down. Amid a crumbling marriage, I became emotionally paralyzed, unable to work, to write, to move. Emails and voice mails piled up unanswered. Slicing an avocado could leave me inexplicably sobbing. Then one day I stopped crying altogether. I went numb. Like so many other depression sufferers, I wondered if death might be easier. The thought scared me.

After five months of seeing a therapist with mixed results, I went to a doctor and walked away with a prescription for 10 milligrams of Lexapro, a cousin to Prozac. I had resisted turning to medication, but it helped.

Twenty milligrams helped even more. It didn’t make me feel good, but it made me feel less bad. It was a treatment, not a cure.

Yet a cure may be emerging at an unassuming office building in Rockville just 5 miles from my home.

Researchers at Neuralstem Inc. hope to eliminate depression by growing new neurons in the hippocampus, a part of the brain associated with memory and mood, a place deep inside the hemispheres where how we think and how we feel are neurologically entwined. Even the name of the process—neurogenesis—bridges science and the divine.

The company is in the midst of a three-round trial of a drug known as NSI-189. In development since 2000, the compound has shown success in mice, increasing the number of neurons in the hippocampus by as much as 20 percent. Now Neuralstem is conducting the first tests on humans.

“It’s quite revolutionary,” says Paul Currie, a neuroscientist at Reed College in Portland, Ore., who has followed recent scientific strides in understanding neurogenesis, the process by which neurons are generated.

Currie cautions, though, that researchers might be moving too fast, and that human trials could be premature. “It’s pretty exciting, but with excitement comes sometimes irresponsibility and overexaggeration, because we’re always looking for that magic bullet,” he says.

Until the ’60s, scientists believed neurogenesis was impossible. The brain was caged inside the skull with no room to grow. Then they discovered that new neurons were being generated inside the hippocampus, possibly to help us process new memories. It was a bright spot in an otherwise grim view of the brain. Cut your finger and it heals. Break your leg and it mends. Even blood refreshes itself. Except for the hippocampus and maybe a few other isolated areas, the brain has a set number of neurons, and they’re dying every day.

“That’s why brain damage and brain diseases are so horrible,” says Richard Garr, the 60-year-old Potomac resident who is Neuralstem’s president and CEO.

Neuralstem’s gambit is that it can treat not just the symptoms of depression but the very cause by developing a drug that intentionally grows new neurons in the hippocampus. Located deep within the temporal lobe of each hemisphere, the hippocampus takes its name from the scientific designation for the sea horse, which it resembles. Like Alzheimer’s patients, depression sufferers show damage there. A growing body of evidence suggests that antidepressants such as Prozac help repair the damage by creating new brain cells. They do it slowly, though; it’s not what they were designed to do. Neuralstem hopes to speed up the process with a specifically targeted drug.

“People use words like transformative a lot when they shouldn’t,” Garr says. “But if we’re right and it does work, this is completely transformative.”

At a world stem cell conference in London this past May, users of the biotech web platform Total BioPharma placed Garr at No. 15 among the 50 most influential people working on stem cells today.

With his short silver hair and narrow face, Garr looks disconcertingly like Roger Sterling, the disaffected ad executive on AMC’s Mad Men. He sits at a tidy desk decorated with models of dissected brains and spinal columns. Tiny, rectangular glasses nearly disappear on his face, and he speaks softly, interrupting his own thoughts by asking, “Right?” to make sure a listener follows along. He is the business side of Neuralstem. Karl Johe, the company’s chief scientific officer, heads up the research end.

A real estate attorney by training, Garr has come to know a lot about how the brain works. Twenty-two years ago, his only son, Matthew, developed a brain tumor. Matthew was just 4 years old, and Garr found himself navigating the complex geography of the human brain and the complications that can result both from a tumor and from the imperfect process of removing it.

Matthew survived, thrived even, but the experience affected him. Now 26, he has trouble remembering, and although he has a driver’s license, he doesn’t feel comfortable behind the wheel. A few years ago he nearly died when fluids that doctors left behind from the removed tumor created complications. They weren’t worried about removing all the fluids, Garr says, because “he wasn’t expected to live this long.”

After a difficult recovery from surgery, Matthew started kindergarten a year late at the McLean School in Potomac. There he became best friends with a new classmate named Arthur Johe. Meanwhile, Garr became friends with Arthur’s father, Karl, a scientist at the National Institutes of Health in Bethesda.

Karl Johe was pursuing a question tangentially related to Garr’s recent struggles with Matthew’s tumor: He wanted to know how something as simple as a fertilized egg can create something as complicated as the brain.

“I was trying to capture a way to study that moment of switch from being simple to becoming complex,” Johe says. “If we could understand that process, or glimpse into it, then maybe we could learn about how the brain functions.”

Johe’s question led him to discover neural stem cells. It also unlocked what he hoped could become a treatment for an array of brain disorders. Unlike fetal stem cells, which hold medical promise because scientists can transform them into any cell in the body, neural stem cells only become brain or spinal cord cells. That specialization is their strength, but because they’re also derived from fetuses, they are no less controversial.

“At the time, there was a ban on fetal tissue,” says Johe, now 52 and living in Miami. “At NIH, being the federal government, there was an imminent danger that I could not continue the research.”

Johe was also frustrated by academia and the various agendas of organizations offering research grants. If he wanted to use neural stem cells to find cures, he decided, he needed to form a company.

“Yes, there is a capitalistic motivation,” Johe says, “but the efficiency of achieving the goal is much higher in the private sector. In the private sector, the goal is crystal clear. In an academic setting, that’s not so clear.”

In 1997, the two men partnered to create Neuralstem in a Montgomery County business incubator. Cutting-edge research at NIH and Johns Hopkins University had made the county one of the nation’s top biotech centers. Neuralstem remains there, sharing the building on Great Seneca Highway with GeneImmune, Bethesda Pharma and similar companies.

“Like all parents who are faced with a child’s serious illness, you think about things like research and wonder how you can help, even if it will not help your child,” Garr says. “I felt that this was an opportunity to get involved in a very real way with a technology that could someday be very important for lots of people.”

Sixteen years later, Neuralstem is a “near-virtual” company, with just 16 employees split between Rockville and a San Diego lab. Seven years ago, the company went public with the ambitious stock ticker symbol “CUR.” It’s also leading human trials to treat stroke patients in China, with more planned in countries as far-flung as Mexico and Malaysia.

“We have patients all over the world, and we envision what we call a ‘near simultaneous’ worldwide rollout,” Garr says. The company has secured patents on its compounds worldwide. In many countries, Garr says, trials move faster and cost less than in the United States without sacrificing world-class science.

“How can you not be doing work all over the world?” he asks.

Before its work with the brain, Neuralstem established itself as a leader in repairing spinal column damage. It’s best known for its work in treating Lou Gehrig’s disease. Formally called amyotrophic lateral sclerosis, or ALS, the disease weakens muscle function in the lungs until it suffocates its sufferers.  Neuralstem set out to attack ALS by injecting spinal cord stem cells into the spine.

About half of the company’s money and time is still devoted to the creation of its ALS treatment. In 2011, Ted Harada, a former FedEx manager from Atlanta, became a minor celebrity when he made the rounds at CNN and CBS, proclaiming that his disease had receded after he took Neuralstem treatment NSI-566 in Phase I trials.

This past May, the company announced that its drug had virtually halted ALS over the course of two years in six test subjects, including Harada, who has stopped using a walking cane. Last year, Harada was strong enough to take part in a 2½-mile ALS walkathon, a remarkable victory against a disease that can kill in two years. The FDA has approved Phase II trials for the drug at centers in Atlanta and Ann Arbor, Mich., where patients will be given as many as 40 injections of up to 400,000 cells each directly into the spinal column.

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