Update on the Neurogenesis Debate - Yes, There's a Neurogenesis Debate

            In 1999, Princeton investigators Elizabeth Gould and Charles Gross announced the discovery of newborn neurons in the brain’s neocortex, the area involved in complex thought.  Working with monkeys, they claimed that 4,000 new neurons were born each day in the primate neocortex, a finding that carried with it great promise as these cells could potentially be a cure for brain diseases if we can learn to control them.  This finding refutes a 1985 paper by Yale scientist Pasko Rakic, a giant in the field of neurogenesis, whose studies led him to conclude that what you’re born with is what you get, and that’s it.  At the time of the study, the thirty-six year old Gould was the youngest tenured professor at the Princeton psychology department while seventy-two-year old Rakic was (still is) chair of the neurobiology department and Yale and a former president of the 40,000-member Society for Neuroscience.  The study pitted Princeton against Yale and Gould against Rakic—the young, open-minded and female against the craggedy, oldschool, male-dominated scientific establishment.  It pitted the hope of new approaches to fighting brain disease against dark reality.

After Gould published her study in the top journal, Science, Rakic got right to work to see if he could replicate her findings.  In an interview later, Rakic said indeed he did identify newborn cells in the neocortex—but they weren’t neurons.  Instead he found that glial cells—cells that surround and support the function of neurons (their name derives from “glia,” the Greek word for glue) and observing the proliferation of which is nothing new—were the ones being born anew.  He said the mistake is understandable, that the glial cells sit flat like a pancake on top of the neurons and could easily be mistaken for neurons.  He suggested that Gould’s methods were flawed.

Ouch.

Gould responded by saying that she had replicated her initial study in a new group of primates: “These are neurons.”

Rakic took a trip to New Jersey and visited the Gould lab.  Gould handed over her slides so Rakic could take a look for himself.  After returning to Yale and analyzing the slides, Rakic once again concluded that he wasn’t seeing the newborn neurons that Gould was seeing.  The Rakic lab questioned the cell-labeling competency of the Gould lab and the Gould lab in turn questioned whether or not the man was adept enough in his old age to grasp the latest and most powerful techniques.  Who says scientists don’t have pizzazz?  (In earlier days of the neurogenesis field, one group at the University of New Mexico announced that they had seen newborn neurons in the neocortex to which Rakic replied, “Those [cells] may look like neurons in New Mexico, but they don’t in New Haven.”)

That’s how the debate stood in 1999.  Because of the promising implications for medicine a number of labs around the world picked up the torch and tried to see if they could spot Gould’s newborn neurons for themselves.  To this date no one has been able to replicate her results. 

The new data that settles the debate.

            Jonas Frisen’s group at the Karolinska Institute in Sweden are coming out with a paper in tomorrow’s issue of the Proceedings of the National Academy of Sciences that convincingly puts the controversy to rest.  Frisen’s group used an ingenious approach to answer the question of whether or newborn neurons are being formed in the adult human neocortex.  They exploited the fact that during the mid-twentieth century atmospheric levels of the carbon isotope, C-14, increased on a global scale as a result of above-ground nuclear testing.

Cells replicate by splitting in half.  You start with one, then you have two.  The original cell is called a parent cell and the two resultant cells are called daughter cells.  Before dividing, parent cells first replicate their DNA so that they have two copies.  The copies are then passed on to each of the daughter cells.  Any DNA synthesized in an environment enriched in C-14 would incorporate the isotopes into its structure.  The amount of C-14 present in the DNA can then be detected in laboratories.  Any cells—in the brain or elsewhere—born during this period of high atmospheric C-14 could be identified based on the presence of C-14 in their DNA; cells born before this period would have no C-14.  Frisen’s group did autopsies on individuals born in northern Europe before, during, and after the above-ground test period and checked for cells labeled with C-14 in the neocortex.  The verdict?  I’ll quote Rakic here: “Read my lips—no new neurons.”  The Frisen group didn’t find a single neuron in the neocortex labeled with C-14.  The only cells they found labeled with C-14 was, not surprisingly, glia cells.

That wasn’t the only experiment they conducted though.  Looking for C-14 in cells integrates the formation of new cells over fifty some years (making it extremely sensitive and goddamn so cool!) but it fails to address the question of whether or not some neurons are born and, after a short but electrifying stay, die off.  To answer this question, Frisen’s group again exercised imagination and took advantage of a technique commonly used in the treatment of cancer patients.  Cancer cells are cells in which the replication machinery screws up, causing the cells to proliferate out of control and form tumors.  To locate these tumors doctors will inject the patient with a chemical that, like C-14, incorporates itself into freshly-made DNA.  The power of this technique regarding the Frisen study lies in the short amount of time between injection of the chemical and the death of the patient.  In Frisen’s study, the shortest of these was four months.  That means if you don’t see any new neurons in that patient you can be sure that newborn neurons, if indeed they do exist in the brain but only transiently, they don’t live longer than four months.  This is an important point for Elizabeth Gould, as she’d always held the position that the newborn neurons were transient, saying “The brain is not being weighed down by mounds of new neurons.  They die off eventually.”

So what if Gould’s right?  What if new neurons are formed in the neocortex only to die off soon thereafter?  The Frisen group considered this possibility and based on the injection data calculated a theoretical upper limit of neuronal production.  The number they came up with was a mere 0.02% of the total neurons in the neocortex.  That translates to one new neuron every 50 years in what are called cortical columns, the basic functional units of information processing in the neocortex.  It’s hard to believe that that new neuron would mean anything at all.

I think we can agree with the reviewer of the Frisen paper, that the Frisen study “settles a hotly contested issue, unequivocally.  The data show that virtually all neurons (i.e., >99%) of the adult human neocortex  are generated before the time of birth of the individual, exactly as suggested by Rakic.”