Humans Vs. Aging; The Discovery of Adult Neurogenesis

Father Time plays a crucial role in determining the course of a human life. As we age, Time takes its toll on us. We shrink in stature, our hairs turn gray, and our minds lose their edge. Internally, our brains deteriorate in a process called neurodegeneration, which occurs as our brain cells die. As a result, our minds lose their ability to function and perform tasks. We become forgetful, slower, and less capable; we transition from a state of living to one of eternal rest. Long ago, we accepted this as an irreversible process. And, at the beginning of the 20th Century, the scientific community formally renounced hope of combating neurodegeneration.

In 1906, renowned neuroscientist Santiago Ramón y Cajal earned a Nobel Peace Prize for his revolutionary “Neuron Doctrine.” This Doctrine established the idea that the mammalian brain consists of a fixed number of independent brain cells, which he called neurons (before this, we thought our brains were one continuous body of tissue). Ramon y Cajal also postulated that once neural circuits were established, any changes or additions to the neural network would cause serious issues with circuitry and would interrupt the information communication systems in the brain. According to neuroanatomists of the time, it also seemed that brain architecture remained constant throughout life, which suggested that it was impossible for new neurons to be continuously added to the seemingly unchanging space. In a definitive statement, Ramón y Cajal famously declared that, “In adult centers, the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated”. This “immutable” nature of the human mind had multiple implications, a key one being that we were thought to have no natural protective mechanisms against the deterioration of our minds as we age. Top scientists in the field accepted our fate in the battle against Father Time, resigning to a model (the Neuron Doctrine) that gave us no hope against the relentless battery of aging.

That is, until Joseph Altman came along. In 1925, Joseph Altman was born in prewar Budapest, where he spent his childhood and teenage years in the local public library, soaking up information about brain anatomy, human behavior, psychology, and anything related to the human mind. As a young adult, Altman moved to New York and further fueled his passion for learning in his role as a librarian in the School of Education at New York University (NYU). Drawn to a life of scholarship, Altman ultimately left his position as a librarian and entered the PhD program for Psychology at NYU. This transition set the ball rolling on Altman’s esteemed and robust career of studying the human mind.

A few years before Altman began his PhD, in 1946, scientists Bélanger, Leblond and Pelc introduced the scientific community to a revolutionary method for studying cell proliferation (the creation of new cells). The method, called 3H-thymidine (3H-T) audiography, allowed scientists to easily identify new cells that had been created. The principle of 3H-T audiography is relatively simple; if you inject 3H-T (which is a molecular substance) into a tissue or cell, it becomes integrated into the DNA of those cells. Since DNA synthesis (the replication/production of cells) involves DNA making a copy of itself, when a 3H-T infused cell replicates its DNA, the resulting cell offshoots include the replicated 3H-T as well. Thus, since all cells created after the injection of 3H-T carry a 3H-T trace, it is relatively easy to track cell births by tracking the number of cells with 3H-T in a specific area over time. As a caveat, this audiography technology allowed scientists to observe the birth of any type of cell. Since many types of cells in the human body perform DNA synthesis, this technique did not provide any specific insight into the activity of brain cells (neurons). That is to say – 3H-T data did not contain any information regarding the type of cells that were replicating, it merely allowed for the observation of those cells’ replication. For now, don’t worry too much about this caveat – we’ll get back to it.

The discovery of 3H-T was revolutionary; at last, it provided scientists with a way to objectively mark the birthtime of cells and to measure cell proliferation. In hindsight, an obvious application of this new technology would be to look for definitive proof – or lack thereof! – of the birth of new brain cells in adult mammals. For the first time in history, we actually had a way to examine the question of adult neurogenesis. However, hindsight is 20/20 and the present moment is often less clear. In reality, Joseph Altman was the only person at the time who even bothered to look for adult neurogenesis with the new affordances of 3H-T technology. Nearly everyone else in the scientific community was satisfied with Ramón y Cajal’s Neuron Doctrine and considered the question of adult neurogensis to be a closed case.

As the field of science now fondly remembers, Altman blew that case wide open with a series of studies in the 1960s that revealed preliminary evidence of neurogenesis in adult rat brains. Although rats are obviously different from humans in many ways, both species fall under the mammalian category, and this evidence directly contradicted the widely accepted claim that no adult mammals create new neurons. From 1962-1969 Altman published nine papers, which showed evidence for the production of new cells in the hippocampus, olfactory bulb and cerebral cortex of adult mice. Given the location of these cell birth sites (all within the depths of the brain), it appeared that the cells being created were indeed new neurons. This is where that caveat comes into play. Technically, Altman had no way to prove that the proliferating cells were neurons – they could have been glial cells (another type of cell in the brain that is functionally and structurally very distinct from a neuron). Unfortunately, this caveat was the hallmark of the harsh backlash that Altman faced for challenging scientific dogma. Although he published in very prestigious journals (including Nature and Science), his findings were ignored by the entirety of the scientific community. In fact, years after Altman published his findings, a new neuroscience textbook in 1970 blatantly claimed, “…there is no convincing evidence of neuron production in the brains of adult mammals”. Perhaps even more telling than this, Altman was not granted tenure at MIT due to the nature of his research, and he ended up having to move universities. Rejected by the scientific community and deterred from the topic, Altman laid his neurogenesis work to rest and spent his career as a leader in the field of neuroanatomy research instead.

Although Altman had to throw in the towel, an inkling of a redemption arc in his name began around a decade later in 1983 when Michael Kaplan reopened the case of adult neurogenesis. Once again, the development of new technology sparked innovation. Kaplan and his colleagues used 3H-T in combination with electron microscopy to examine the cell structure of cells as they proliferated in the hippocampus and olfactory bulb of adult rats (the same locations that Altman studied years earlier.) Electron microscopy is a technique that uses electron beams to magnify cell images, and it allows scientists to observe features of cells that are more than one million times smaller than optical microscopes (the primary microscopic tools used before this technology). This technique allowed Kaplan to identify specific characteristics (cell parts called dendrites and synapses) of the proliferating cells that are unique to neurons. Since glial cells do not contain dendrites or synapses, this evidence allowed Kaplan to explicitly rule out the major cause of skepticism regarding Altman’s work (that pesky caveat!). But wait – it is not yet time to sound the bells.

Following in Altman’s footsteps, Kaplan published his findings in very prestigious journals (including Science and the Journal of Neuroscience). And, in similar strides, his work was entirely disregarded. A key reason for the lack of interest expressed by the scientific community can be attributed to Dr. Pasko Rakic. At the time, Dr. Rakic was “the leading student of primate brain development,” which gave him an authoritative voice in the field. Less than a year after Kaplan published his findings of neurogenesis in adult rats, Dr. Rakic published a study that claimed to find no evidence of any developing neurons in the adult brain of rhesus monkeys. Since Rakic found no evidence of adult neurogenesis in this one study, the field readily accepted Rakic’s results as confirmatory evidence of the existing “no adult neurogenesis” dogma. The resulting backlash that Kaplan faced was so harsh it drove him entirely out of the research world, and he went on to become a doctor instead.

Then, throughout the late 1980s, the tide finally turned. The surfacing evidence became impossible to ignore, beginning with the work of Fernando Nottebohm. Nottebohm led a team of scientists in examining the ways that song birds learn new songs. While that work initially had nothing to do with neurogenesis, Nottebohm discovered that the volume of song-related nuclei fluctuated greatly throughout seasons and in stride with hormonal fluctuations. Intrigued, he decided to examine the possibility that the fluctuation of those nuclei was related to fluctuations in the number of neurons in the adult bird brains. From 1983-1996, Nottebohm published work that first identified the production of new cells in adult songbird brains (using 3H-T), then proved that the new cells were neurons (using ultrastructural evidence from electron microscopy), then demonstrated the functional applications of the new neurons by showing that the new neurons responded to sound. This research created an important link between neurogenesis and learning; the song birds appeared to generate new neurons that were responsible for handling the new information that they were learning. In short, they were adding brain cells to accommodate for the new knowledge that they were acquiring. With this evidence, the scientific community finally agreed to reopen the once closed case of adult neurogenesis.

While Nottebohm’s study may seem similar to the work of Altman and Kaplan, a few key distinctions helped him convince the wary scientific community. First, Nottebohm and his colleagues were separate from the scientific circle involved in the “adult neurogenesis” debate. As a team of researchers from outside the field, their findings were not driven by previous discourse or ulterior motives. Instead, while studying songbird learning patterns, Nottebohm happened upon evidence that confirmed adult neurogenesis. This contrasts with Altman, who sought to contradict key principles of the Neuron Doctrine, and Kaplan, who was in a direct head-to-head battle with Dr. Rakic. Beyond this “neutral outsider” backdrop, Nottebohm also found a key piece of the puzzle that had been missing – he answered the why of the equation. Altman and Kaplan were so focused on proving that neurogenesis was occurring that they did not address its functional significance. Nottebohm’s discovery – that neurogenesis enables adults to continue acquiring new knowledge and skills – gave the scientific community a compelling explanation for the phenomenon. Unlike his predecessors, Nottebohm was an external voice who not only discovered evidence of neurogenesis in adult mammals but also offered a start-to-finish explanation of his findings. In my personal opinion, it is this context that allowed Nottebohm to succeed in changing the minds of skeptics.

In the years following, countless studies irrefutably demonstrated adult neurogenesis in both animal and human populations. At last, Altman and Kaplan were vindicated. Years later – merely five years before he passed away – Joseph Altman was awarded with the “Prince of Asturias Award” from the Crown Prince of Spain as well as the “International Prize for Biology” from the Japan Society for the Promotion of Science. And, in an act of great redemption, in 2001, Michael Kaplan published a critical and opinionated article to capture the problems within the scientific community that delayed (and blatantly interfered with) the discovery of neurogenesis for so long.

In his article, Kaplan explains how a deeply ingrained faith in dogma prevented the scientific community from considering the new evidence that he and Altman presented. He also addresses how Dr. Rakic’s position as a “prominent figure in the Neuroscience community” turned the tide in Rakic’s favor and caused the “political death” of Kaplan’s “controversial” findings. In a final critique of the scientific community, Kaplan somewhat sarcastically recalls attending a Neuroscience conference after the widespread acceptance of neurogenesis. He explains, “it was like entering a new world. Everywhere, people were talking about… neurogenesis as if it had always been that way. At one seminar I saw movies of dividing neurons with ‘neuronal-like processes’: twenty years ago… I thought wryly… [those] neuronal-like processes would be ignored without ultra-structural identification.” With those words, Kaplan (not so slyly) called out scientists for looking at evidence through the lens of scientific consensus rather than objectivity. It was a belief in dogma, Kaplan believes, that prevented Rakic and other leaders in the field from observing neurogenesis with open and receptive eyes.

Unfortunately, the consequences of scientific bias are not constrained to conferences and academic circles. Everyone pays the price. So, what did the stubbornness of the scientific community prevent us from learning? It turns out that adult neurogenesis may play a vital role in protecting against the deterioration of our minds as we age. The ability for adults to create new neurons could be our secret weapon in the battle against Father Time; adult neurogenesis challenges the “irreversibility” of cognitive aging. Which leaves us with a critical question – is scientific dogma preventing us from any other groundbreaking insights?

References:

1. Abdissa, D., Hamba, N., & Gerbi, A. (2020). Review Article on adult neurogenesis in humans. Translational Research in Anatomy, 20, 100074. https://doi.org/10.1016/j.tria.2020.100074

2. Bayer, S. A. (2016). Joseph Altman (1925-2016): A life in neurodevelopment. The Journal of Comparative Neurology, 524(15), 2933-2943. https://doi.org/10.1002/cne.24058

3. Gey, W. (1974). Autoradiography of Human Chromosomes with 3H-Thymidine. In: Schwarzacher, H.G., Wolf, U., Passarge, E. (eds) Methods in Human Cytogenetics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-65787-0_7

4. Gross, C. G. (2009). Three before their time: Neuroscientists whose ideas were ignored by their contemporaries. Experimental Brain Research, 192(3), 321–334. https://doi.org/10.1007/s00221-008-1481-y

5. Kaplan, M. S. (2001) Environment complexity simulates visual cortex neurogenesis: death of a dogma and a research career. Trends in Neurosciences, 24(10), 617-620. https://doi.org/10.1016/S0166-2236(00)01967-6

6. National Institute of Neurological Disorders and Stroke. (2025, February 25). Brain Basics: The Life and Death of a Neuron. https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-life-and-death-neuron

7. Otero, J. J. (2018). Neural Regeneration a Century after Ramón y Cajal’s Decree. The American Journal of Pathology, 188(1), 4–5. https://doi.org/10.1016/j.ajpath.2017.09.003

8. Sidman, R.L. (1970). Autoradiographic Methods and Principles for Study of the Nervous System with Thymidine-H3. In: Nauta, W.J.H., Ebbesson, S.O.E. (eds) Contemporary Research Methods in Neuroanatomy. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-85986-1_12

9. U.S. Department of Veteran Affairs. (2017, August 1). What Is an Electron Microscope (EM) and How Does It Work? https://www.va.gov/DIAGNOSTICEM/What_Is_Electron_Microscopy_and_How_Does_It_Work.asp