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Just as Duman was beginning to see the biochemical connections between trophins, stress, and depression, Gould was starting to document neurogenesis in the hippocampus of the primate brain. Reading Altman’s and Kaplan’s papers, Gould had realized that her neuron-counting wasn’t erroneous: She was just witnessing an ignored fact. The anomaly had been suppressed. But the final piece of the puzzle came when Gould heard about the work of Fernando Nottebohm, who was, coincidentally, also at Rockefeller. Nottebohm, in a series of beautiful studies on birds, had showed that neurogenesis was essential to birdsong. To sing their complex melodies, male birds needed new brain cells. In fact, up to 1% of the neurons in the bird’s song center were created anew, every day.
Despite the elegance of Nottebohm’s data, his science was marginalized. Bird brains were seen as irrelevant to the mammalian brain. Avian neurogenesis was explained away as an exotic adaptation, a reflection of the fact that flight required a light cerebrum. In The Structure of Scientific Revolutions, the philosopher Thomas Kuhn wrote about how pre-paradigm-shift science excludes its contradictions: “Until the scientist has learned to see nature in a different way, the new fact is not quite a scientific fact at all.” Evidence of neurogenesis was excluded from the world of “normal science.”
But Gould, motivated by the strangeness of her own observations, connected the dots. She realized that Altman, Kaplan and Nottebohm all had strong evidence for mammalian neurogenesis. Faced with this mass of ignored data, Gould began pursuing cell birth in the adult brain of rats.
She would spend the next eight years quantifying endless numbers of radioactive rat hippocampi. But the tedious manual labor paid off. Gould’s data would shift the paradigm. More than thirty years had passed since Altman first traced the ascent of new neurons in the adult brain, but neurogenesis had finally become a real science.
After her wearisome post-doc, during which her data was continually criticized, Gould was offered a job at Princeton. The very next year, in a series of landmark papers, Gould began documenting neurogenesis in primates, thus confronting Rakic’s data directly. She demonstrated that adult marmosets created new neurons in their brains, especially in the olfactory cortex and the hippocampus. The mind, far from being stagnant, is actually in a constant state of cellular upheaval. By 1999, even Rakic had admitted that neurogenesis is real. He published a paper in Proceedings of the National Academy of Sciences that reported seeing new neurons in the hippocampus of macaques, an old world primate. The textbooks were rewritten. The brain, Elizabeth Gould had now firmly established, is always giving birth. The self is continually reinventing itself.
Gould’s finding has led, via work Duman has done that builds on it, to a rash of R&D to stimulate neurogenesis in the brain. Duman had an epiphany reading Gould’s papers. He realized that stress and depression didn’t simply kill cells, they might also prevent new cells from being born. “I was reading these papers by
McEwen and Gould,” Duman says, “and they were showing this relationship between stress and the adrenal hormones and neurogenesis. It just sort of all gradually came together.” Perhaps the time lag of antidepressants was simply the time it took for new cells to be created.
He immediately set to work to test this hypothesis. In December 2000, Duman’s lab published a paper in the Journal of Neuroscience demonstrating that antidepressants increased neurogenesis in the adult rat brain. In fact, the two most effective treatments they looked at—electroconvulsive therapy and fluoxetine, the chemical name for Prozac—increased neurogenesis in the hippocampus by 75% and 50%, respectively. Subsequent studies did this by increasing the exact same molecules, especially trophic factors, that are suppressed by stress.
Duman was surprised by his own data. Fluoxetine, after all, had been invented by accident. (It was originally studied as an antihistamine.) “The idea that Prozac triggers all these different trophic factors that ultimately lead to increased neurogenesis is just totally serendipitous,” Duman says. “Pure luck.”
But demonstrating a connection between antidepressants and increased neurogenesis was the easy part. It is much more difficult to prove that increased neurogenesis causes the relief provided by antidepressants, and is not just another of the drugs many side-effects. To answer this question, Duman partnered with the lab of René Hen at Columbia.
The research team, led by post-doc Luca Santarelli, effectively erased neurogenesis with low doses of radiation. All other cellular processes remained intact. If the relief from depression was due to changes in serotonin, then halting neurogenesis with radiation should have had no effect.
But it did. Hen and Duman’s data was unambiguous. If there is no increase in neurogenesis, then antidepressants don’t work in rodents. They stay “depressed.”
Duman and Hen’s work was greeted, as expected, by a howl of criticism. Mice aren’t people. The experiment was flawed. The radiation wasn’t specific enough. Robert Sapolsky, whose work on stress paved the way for much of Duman’s own research, is one of the most incisive skeptics. He argues that neurogenesis researchers have no plausible model for how decreased neurogenesis might cause the symptoms of depression. Why would having a handful fewer new cells in the hippocampus have such an effect? “The more expertise someone has about the hippocampus,” Sapolsky wrote in a review in Biological Psychiatry, “the less plausible they find this novel role.”
Duman himself is reluctant to discuss the clinical implications of his data. He imagines that neurogenesis in humans is just a single part of the antidepressant effect. “It’s a long way from looking at mice in cages to talking about depression in humans. All of these connections are very exciting, but we still don’t understand what’s actually going on inside the brain. We don’t know what the function of all these new cells is, and we have no idea how they might relate, if they do, to the mechanism of action of antidepressants in humans.”
Nevertheless, Duman’s research is completely changing the way neuroscience imagines depression. Several major drug companies and a host of startups are now frantically trying to invent the next generation of antidepressants (a $12-billion-a-year business). Many expect these future drugs to selectively target the neurogenesis pathway. If these pills are successful, they will be definitive proof that antidepressants work by increasing neurogenesis. Depression is not simply the antagonist of happiness. Instead, despair might be caused by the loss of the brain’s essential plasticity. A person’s inability to change herself is what drags her down.
Scientists who pursue neurogenesis are audacious by definition—they have staked their career on a lark—and Dr. Jonas Frisén is no exception. He is probably the only person in Stockholm who wears a cowboy hat. “Super-exciting” is his favorite superlative. (He speaks English fluently, with a singsong Scandinavian accent.) Occasionally, Frisén gives his science papers titles lifted from Bob Dylan songs, as in his 2003 paper “Blood on the tracks: a simple twist of fate?” He thanks Dylan in the acknowledgments for “inspiration.”
Frisén has never known a brain that wasn’t filled with new cells. He became a neuroscientist after med school, just as neurogenesis was becoming a genuine fact. Although he is now a full professor in stem-cell research at the Karolinska Institute, the university in charge of administering the Nobel Prize for Medicine, Frisén began his career as a doctor. When he started medical school, he assumed he would become a brain surgeon, or perhaps a psychiatrist. That, after all, was how you healed the brain back then: either with a scalpel or with words. The few drugs that worked on the mind—like antidepressants—performed their job mysteriously.
Frisén has helped to change that. He has pursued the neurogenesis hypothesis into the realm of clinical medicine, and his rise has been astonishingly swift. In 1998, only three years after becoming a doctor, Frisén was a tenured professor, in charge of a 15-person lab. He has a long list of influential papers to his name, published in frequently-cited journals like Cell and Nature.
Frisén first leapt to the attention of the neuroscience community in 1999, when his lab announced that they had identified stem cells in the brain. Stem cells are the source of neurogenesis: It is their mitotic divisions that create new neurons.
Subsequent experiments in Frisén’s lab have explored exactly how these neural stem cells are regulated. His ambition is to decipher the complicated and convoluted cascade of proteins that connect the feeling of stress to a decrease in neurogenesis. Only then, Frisén says, “will we be able to create drugs that selectively target neurogenesis. And that is what everybody wants to do. Just think of all the things you can heal.”
To achieve this, Frisén has founded a biotech firm, NeuroNova, dedicated to pursuing drugs which stimulate neurogenesis. When it launched, neurogenesis remained a controversial concept; founding an entire company on its therapeutic promise seemed like an imprudent gamble. In Frisén’s case, the gamble is paying off.
The first disease NeuroNova targeted for treatment was Parkinson’s Disease. Parkinson’s is caused by the death of dopamine-producing neurons, and doctors have repeatedly tried to compensate for this selective cell death by surgically transplanting embryonic brain tissue into patients’ brains, often with disappointing results. Frisén realized that the Parkinson’s brain was capable, at least in theory, of healing itself. Driven by this radical hypothesis, NeuroNova began screening thousands of potential compounds for their effect on neurogenesis. Perhaps increased neurogenesis might compensate for the rapid death of dopamine neurons.
The results so far have exceeded everyone’s expectations. In November 2005, NeuroNova announced that one of their leading drug candidates—clandestinely called sNN0031—restored normal bodily movement in rodent models of Parkinson’s. Rats that were barely able to walk had their symptoms erased after only five weeks of treatment. Furthermore, initial results suggest that the drug worked by rapidly increasing neurogenesis, thus restoring normal dopamine signaling in the rat brain. “The results really are spectacular,” Frisén says.
The next step is to begin testing in primate models of Parkinson’s, beginnig early this year. If the drug doesn’t produce toxic side effects—and that’s unlikely, since it is already approved as a human treatment for an unrelated condition—human clinical trials are expected to begin shortly thereafter.
Neurogenesis is an optimistic idea. Though Gould’s lab has thoroughly demonstrated the long-term consequences of deprivation and stress, the brain, like skin, can heal itself, as Gould is now beginning to document, finding hopeful antidotes to neurogenesis-inhibiting injuries. “My hunch is that a lot of these abnormalities [caused by stress] can be fixed in adulthood,” she says. “I think that there’s a lot of evidence for the resiliency of the brain.”
On a cellular level, the scars of stress can literally be healed by learning new things. Genia Kozorovitskiy, an effusive graduate student who began working with Gould as a Princeton undergrad, has studied the effects of various environments on their colony of marmosets. As predicted, putting marmosets in a plain cage—the kind typically used in science labs—led to plain-looking brains. The primates suffered from reduced neurogenesis and their neurons had fewer interconnections.
However, if these same marmosets were transferred to an enriched enclosure—complete with branches, hidden food, and a rotation of toys—their adult brains began to recover rapidly. In under four weeks, the brains of the deprived marmosets underwent radical renovations at the cellular level. Their neurons demonstrated significant increases in the density of their connections and amount of proteins in their synapses.
The realization that typical laboratory conditions are debilitating for animals has been one of the accidental discoveries of the neurogenesis field. Nottebohm, for example, only witnessed neurogenesis in birds because he studied them in their actual habitat. Had he kept his finches and canaries in metal cages, depriving them of their natural social context, he would never have observed such an abundance of new cells. The birds would have been too stressed to sing. As Nottebohm has said, “Take nature away and all your insight is in a biological vacuum.”
Gould has also become concerned about the details of experimental design. She now stresses the importance, for both rodents and primates, of living in a naturalistic setting. An artificial cage creates artificial data.
(Precisely how artificial prior data from studies on brains of animals kept in un-naturalistic settings remains to be determined. Gould said that studying neurogenesis had led her to “reflect much more on the question of experimental design. This really should be a concern for all neuroscientists.”)
The mind is like a muscle: it swells with exercise. Gould’s and Kozorovitskiy’s work reminds us not only how easy it is to hurt a brain, but how little it takes for that brain to heal. Give a primate just a few extra playthings, and its neurons are capable of escaping the downward cycle of stress.
When Gould first presented at the Society of Neuroscience’s annual meeting, there was no such thing as the field whose birth she was there to announce; she was filed away in the “spinal cord rejuvenation” section. Today, she is almost frightened that her field has grown so big: “I do get worried sometimes that neurogenesis has gotten overblown. The science of it still isn’t clear. But at the same time I understand why there is so much enthusiasm for the idea. It’s a new way of looking at a lot of old problems.”
Neurogenesis is a field that doubts itself. Because it has been scorned from the start, its proponents talk most emphatically about what they don’t know, about all the essential questions that remain unanswered. Their modesty is accurate: The purpose of all of our new cells remains obscure. No one knows how experiments done in rodents will relate to humans, or whether neurogenesis is just a small part of our mind’s essential plasticity.
Nevertheless, it is startling how much has been accomplished since Liz Gould, confused by her counting, went to the library in search of an answer. In 1989, no one would have dared to imagine that the environment we live in can profoundly influence the actual structure of our brain, or that childhood stress might have permanent neurological effects. No scientist could have guessed that Prozac modulates cellular division, or that a Swedish start-up would one day get a rodent brain to repair itself. If neurogenesis has taught us anything, it is that these extraordinary new facts aren’t simply answers to an old set of questions. The paradigm has shifted: what Gould and others are working on now is a whole new list of mysteries. And like the newborn neurons in our brain, these scientists are only beginning.
Originally published February 22, 2006
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