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Salk’s Fred H. Gage on Neurogenesis in the Adult Brain

Despite the fact that the human brain is composed of some 100 billion neurons, it’s always been easy to imagine that this number is somehow fixed at birth—that we’re born with our full complement of neurons and then it goes downhill from there. Certainly these neuronal cells will not divide, as other cells do. Not with their enormously extended axons, and tree-like dendrites averaging a thousand synaptic connections each. So how would an adult brain ever add new neurons, and how would it possibly wire them successfully into such an unimaginably complex system?

Ever since the mid-1980s, with the discovery of new neurons in the brains of adult songbirds, this question of adult neurogenesis has been one of the most controversial areas in biology. Among the issues neuroscientists have struggled to understand is not just the how and why of this neuronal birth and development in the adult brain, but how this capacity might be enlisted and enhanced to repair trauma and age-related nerve damage in humans.



“The nervous system has the capacity for self-repair,” says Fred H. Gage of the Salk Institute for Biological Studies, La Jolla, California. “I hope to understand how this occurs normally and to learn about the molecular, cellular, and environmental factors that control it.”

Photo: Manuello Paganelli

In the past decade, no single researcher has had a hotter track record or more influence in the study of neurogenesis than neurobiologist Fred H. Gage of the Salk Institute for Biological Studies and the University of California, San Diego. Gage currently ranks second in the Essential Science Indicators (ESI) Web product listing of the hottest researchers in neuroscience & behavior, with more than 10,000 total citations. He also has the single highest citation average per paper of anyone in the field as tracked by ESI—averaging some 90 citations for each of over 100 articles since 1995. At this writing, Gage’s seminal paper, "Neurogenesis in the adult human hippocampus," published in Nature Medicine in November 1998, has alone racked up nearly 900 citations in just seven years (see the table below).

Gage, 54, did his undergraduate research at the University of Florida, and then earned his doctoral degree in neuroscience in 1976 from Johns Hopkins University. He spent the next four years at Texas Christian University before heading off to Sweden to work with Anders Björklund at the University of Lund in 1981. In 1985, Gage returned to the U.S. to become an associate and then a full professor at UC San Diego. Since 1995, he has also been a professor in the Laboratory of Genetics at the Salk Institute.

Gage spoke to Science Watch from his Salk office in La Jolla.

Why has it always been so hard for people to people to believe that the adult brain could give rise to new neurons?

First of all, neurons are very complex cells—long branches, receiving hundreds of thousands of connections. The idea that confused people is how something as complex as a neuron could undergo cell division. This idea was not well integrated with the emerging notion that maybe some primitive cells remained and that those were doing the dividing. That was part of the problem. The other roadblock was that there were several prominent statements in the literature contending that adult neurogenesis couldn’t happen, because the brain and structures like the hippocampus need to be stable for memory to be stable. If new brain cells were added, that would make it hard to store long-term memories. It was a loose statement, but it resonated with many people. The long-standing model for the brain was a computer, and this model required that the brain be hard-wired. This idea that there was re-wiring going on was not consistent with that computer model, and the data for structure changes in the adult brain weren’t that strong anyway. The methods were not definitive, so we spent a lot of time on methods trying to convince ourselves that it was true.

How did you, in fact, convince yourself that neurogenesis was going on in adult brains?

Among the important elements that helped convince us of this phenomenon were the application of the molecule BrdU—immunocytochemistry, combined with confocal microscopy and quantitative stereology to the measurement of neurogenesis led by Georg Kuhn when he was a post-doc in my lab. In addition, and equally important, was switching the environment of the mice we studied. We let these animals grow up in little mouse cages as they normally do, and then, when they were adults and were matched for sex, age, genetic background, etc, we took half of them out and put them in this big complex environment and let them stay there for 45 days. Then we just asked simply, are there any changes in the numbers of neurons in the hippocampus? We found this very big effect, and that was the paper we published in Nature in 1997 with Gerd Kempermann, who was then a post-doc in my lab. [See table, paper #3.]

We also knew that we had to find out whether or not this phenomenon was really occurring in primates. And I knew that some people were looking in monkeys and that the results were pretty controversial. So I got together with all the post-docs in the laboratory, some with a clinical background, and we noted that this experiment is being done in humans all the time. The data are there. I’ve mentioned this certain molecule, BrdU, which is sometimes used in cancer patients to mark tumors. Any cell undergoing cell division will incorporate it. Pathologists used to give a single dose of BrdU in various forms of cancer so they could then do biopsies and see how rapidly the tumors were developing. From deceased patients, you could get brain sections and see how the tumors had progressed. BrdU could be seen in the brain because it easily passes through the blood-brain barrier, but it wasn’t very convincing. What was needed was fresh tissue. So after we had this discussion, some of the physicians working in my laboratory went back to their own countries and linked up to clinical trials in order to obtain fresh tissue. This was done, for example, by Peter Eriksson, who went back to Gothenburg, Sweden, and worked with medical staff there to get fresh tissue from deceased patients. He and the others would send brain sections back to San Diego for us to work on, and this is how we showed that neurogenesis occurs in humans. That was an important finding for us, because it showed that this phenomenon could be generalized to other species. It happened in mice, in cats, in primates, and in people. All species so far examined. There was this proliferative event occurring in the hippocampus that gave rise to new neurons.

Did that put an end to the controversy?

Between that and the environmental-enrichment story, it got to be a very hot issue in neuroscience. By that point, several of the researchers who had been very critical of this phenomenon had taken to using this BrdU methodology and convinced themselves that neurogenesis actually did occur. A couple of the key papers were by skeptics, and when they came out in favor, that turned the tide. There was also a controversy about the cortex, and whether neurogenesis was going on there. By virtue of everyone looking at that very, very carefully to see whether or not it occurred in the cortex, it became clear that it certainly did occur in the hippocampus.

So does it occur in the cortex also?

So far we haven’t seen it under normal conditions. It’s been claimed in other areas as well, and we’re not saying that it doesn’t happen at very, very low frequency or under damaged conditions, but we haven’t seen it. I’m still open to the idea, however, since we’ve shown that even cells from the spinal cord can be induced to become neurons after being cultured and transplanted to the hippocampus, and there’s no neurogenesis going on naturally in the spinal cord. So our conclusion is that there are neural stem cells all over the brain and in the spinal cord, but they don’t give to rise to neurons under normal conditions because the local environment doesn’t provide them with the appropriate cues.

Can other adult stem cells give rise to neurons, or just these neural stem cells?

This is the plasticity issue that gets a lot of attention, and it’s one that’s been claimed but not proven—that stem cells, particularly from the blood, can give rise to brain or other kinds of tissues. That was a very popular idea, and it would be wonderful if it’s true. But it’s confused by the phenomenon, which has been observed, of fusion. That means that a stem cell can fuse with a somatic cell. Its nucleus would be in the same cell. If that happens, then proteins could be made from the stem cell in the somatic cell, and you would get this confusing picture in which a neural stem cell or blood stem cell appears to give rise to a neuron, when in fact it’s just fused to it and expressing the same proteins. In the last couple of years people have had to take that into consideration any time they evoke the concept of pluripotentiality of somatic cells. Thank goodness, it put this whole idea of stem-cell plasticity into a much more cautious light. It’s more difficult for someone to make claims now without demonstrating thoroughly that the cell has actually transitioned from one lineage to another. And that’s a very tough experiment to do.

So what role does neurogenesis play in the brain, and why in the hippocampus in particular?

That’s an open question. Why has this part of the brain reserved the capacity to generate neurons? It’s not a ubiquitous phenomenon. So why does it happen in this brain structure? We don’t know yet, although I think it will be resolved in the next couple of years. In order to know what role neurogenesis plays in hippocampal function or system-wide function, we have to know what role the hippocampus is playing. We’re not able to understand neurogenesis itself, without understanding this structure in which it occurs. So this is a very exciting time for developing model systems—knockout technologies, for instance. Every day in the literature, there’s another neurogenesis article published. There are some really smart people getting into this field, and they’re discovering some wonderful things.

How would you describe the overall theme or evolution of your research?

We’re working to understand the system-wide role that neurogenesis plays in normal, healthy brain function. Others are looking from the perspective of disease, asking the question that if neurons are being born, can we then recruit them in some way to repair the brain—for depression, stroke, or epilepsy? Others are looking into the role these cells play and how knowledge of their function and variability could be used to enhance, modify, or assist in any kind of functional recovery. Since we’ve had an in vitro and an in vivo system, we’ve spent a lot of time looking at the molecular mechanisms underlying how cells make choices. That’s been a major area of research in our lab for the last five or six years. And we’re making good progress on this, in terms of separating phenomena into a couple of different categories. The cells divide, for instance, so what are the mechanisms that control cell division? The cell differentiates. It makes the choice to become either a neuron or an astrocyte or an oligodendrocyte, the three lineages. How does the cell make that choice to stop dividing and become one of these cells? And once it makes that choice, how then does it mature? What conditions induce it to migrate, to move, to fully differentiate into a fully working cell? By dividing the process up that way, we can get in vitro models for each part and try to get at the underlying mechanisms.

On your website, it says that one focus of your laboratory is to induce recovery of function following damage to the central nervous system (CNS). How do see yourself getting from this basic research to that clinical application?

We are convinced that in the mammalian nervous system there are many residual, immature, uncommitted progenitor cells—stem cells—that exist. And so one of the goals of this kind of discovery work we do is to understand enough about these endogenous cells that we can activate them and get them to participate in the repair process. Everything I have done so far in the CNS leads me to believe that the nervous system tries to repair itself after an injury. It does this at one level or another, and usually it accomplishes some moderate level of recovery. I’m less interested now in engineering from the outside and transplanting cells, but rather in activating and amplifying the existing cell-repair process that’s already there in the CNS. I think this harks back to the original reasons I was interested in the brain. It has this capacity for self-repair, and by discovering and working within this field of neurogenesis, I hope to understand how this occurs normally and to learn about the molecular, cellular, and environmental factors that control it. And once we do that, maybe we can then control the environment and molecular and cellular events locally to effect repair in an injured state or an aging state.

Highly Cited Papers by Fred H. Gage et al.,
Published Since 1995
(Ranked by total citations)
Rank Paper Citations
1 L. Naldini, et al., "In vivo delivery and stable transduction of nondividing cells by a lentiviral vector," Science, 272(5259): 263-7, 1996. 1383
2 P.S. Eriksson, et al., "Neurogenesis in the adult human hippocampus," Nature Medicine, 4(11): 1313-7, 1998. 887
3 F.H. Gage, "Mammalian neural stem cells," Science, 287(5457): 1433-8, 2000. 772
4 G. Kempermann, H.G. Kuhn, F.H. Gage, "More hippocampal neurons in adult mice living in an enriched environment," Nature, 386(6624): 493-5, 1997. 682
5 H.G. Kuhn, H. Dickinson-Anson, F.H. Gage, "Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronoal progenitor proliferation," J. Neuroscience, 16(6): 2027-33, 1996. 559
SOURCE: Thomson Scientific Web of Science