Bombs and Brains

Great minds met to conceive the first atomic bomb. Now the atomic bomb has helped researchers confirm some long-held suspicions about the human brain.

Up until the 1960s, it was a widely accepted belief that we are born with a finite number of neurons that last our entire life. In 1965, researchers presented the first contrary evidence to this popular theory by showing neurogenesis, the production of new neurons, occurs in the rat brain. Fast-forward to 1998. Ericksson et al. demonstrated for the first time in adult human brain the birth of new neurons by labeling dividing cells in patients and analyzing their brains for new cells after death. As groundbreaking as this new study was, the results left a number of questions surrounding the quantity of cells produced and whether or not this number was great enough to actually impact brain function. Were these new neurons just duds?

Human post-mortem tissue studies are descriptive by nature. The brains have been preserved either through freezing or fixation, a chemical process used to preserve tissue from decay, and researchers are unable to look at dynamic functions of the brain, such as the creation of new cells, in the same capacity as in experimental animal models and culture systems. Brilliantly, Spalding et al. circumvented these issues with a novel strategy using radiocarbon (¹⁴C) dating and knowledge of the atomic bomb tests to evaluate neurogenesis in the adult human brain.

Kirsty L. Spalding et al. (2013). Dynamics of Hippocampal Neurogenesis in Adult Humans. Cell 153(6): 1219-1227. Click HERE to go to this article.

What is ¹⁴C? ¹⁴C is a radioactive carbon isotope, meaning that it has an unstable nucleus due to an increased number of neutrons – normally carbon has 6, radiocarbon has 8. ¹⁴C is found to naturally exist on Earth but only in trace amounts that can be formed through the interaction of nitrogen and cosmic rays in the atmosphere. Radiocarbon in the atmosphere is integrated into carbon dioxide molecules. Plants absorb carbon dioxide from the environment and incorporate the carbon into their fibers. Our food chain begins with plants. People eat plants. People also eat animals that consume plants. And the result of all this eating? The more ¹⁴C that is in the atmosphere, the more it is integrated into our own body’s DNA when new cells are created.

Radiocarbon dating using ¹⁴C measurements was first pioneered in the fields of geology and archeology and were used to look at the age of really old rocks and ancient artifacts. Spalding and colleagues put a spin on this and developed a retrospective dating system to identify the birth date of neurons.

Changes in radiocarbon over time in New Zealand and Switzerland. Graph (source) U.S. Department of Commerce, NOAA

How was retrospective dating neurons possible? In the mid-1950s the country was in the heart of the Cold War. Atmospheric detonation of atomic bombs from 1955-1963 shot worldwide ¹⁴C levels through the roof. In 1963, the United States, Soviet Union, and United Kingdom governments signed the Partial Nuclear Test Ban Treaty prohibiting all nuclear detonations unless they were performed underground. Upon establishment of this treaty, atmospheric levels of ¹⁴C began to decline and it is through this documented radiocarbon timetable that researchers were able to determine when each new neuron clocked-in at birth by looking at the ¹⁴C DNA concentration signature in each cell.

Great! Now we know that each neuron’s DNA should have a particular amount of ¹⁴C because it  correlates with atmospheric ¹⁴C at the time it was born and there was a huge spike in it during atomic bomb testing, so  birth date can be determined. But how the heck can we measure ¹⁴C in neuronal DNA? Enter accelerator mass spectrometry (AMS). This technique allows scientists to scan infinitesimal DNA samples and accurately report concentrations of ¹⁴C.

Spalding et al. isolated cells nuclei from human post-mortem hippocampus, the brain region that plays an important role in memory and has been shown to undergo neurogenesis in animal models. Then using AMS they measured the amount of ¹⁴C in the neurons and developed a sophisticated biological transport equation to look at cell turnover dynamics.

Ah yes, this equation takes me back to my undergraduate days of biological transport class with Dr. Patzer. The man made learning the transport dynamics of cooking a Thanksgiving turkey fun. Basically the equation contains elements that track with the age of the person and the age of each cell and makes sure to account for cell death processes as well. When you apply particular settings and solve the equation you can obtain neuron density and importantly evaluate how many new neurons are born in the hippocampus throughout life.

Having the model down pat, researchers then looked at the data and reconfirmed that neurogenesis occurs after birth by observing four phenomena:

Hippocampal neurogenesis in the adult human brain.

1. ¹⁴C concentrations in hippocampal neurons correspond to atmospheric concentrations with dates after subject birth. New neurons are being made!
2. Some of the oldest subjects in the study had higher amounts of ¹⁴C integrated into their DNA than were present preceding bomb testing, when atmospheric ¹⁴C levels were low. Thus ¹⁴C must have been incorporated into hippocampal neuronal DNA later in life.
3. There doesn’t appear to be any dramatic decline in hippocampal neurogenesis with aging because individuals born prior to 1955 have incorporated high levels of ¹⁴C into their DNA even if they were born several years earlier.
4. Subjects born before 1955 have lower levels of ¹⁴C in their DNA than anyone born after 1955, suggesting that although the hippocampus does create new neurons, a large number of neurons are not new.

Combined these facts once again help dispel the myth that we are born with all the neurons we will ever have in our lifetime.

Knowing that new neurons are generated in the hippocampus, the next questions became how many neurons are born and how quickly does this renewal happen? By modeling the cells with the biological transport equation described above, data suggests that a subpopulation of hippocampal neurons renew constantly whereas other neurons are non-renewing. Spalding and colleagues estimate the renewing population could be as many as one-third of all hippocampal neurons, around 700 new neurons a day! A great deal more than originally suspected. Additionally, neurons that are non-renewing do not seem to be replaced following death.

Critically, Spalding et al. addressed whether or not these adult born neurons could impact brain function. While this is based in conjecture, they suggest that the large number of neurons being born in the hippocampus is sufficient to contribute to cognitive function because young hippocampal neurons have enhanced synaptic plasticity, which impacts learning and memory.

History recorded the dark side of atomic bomb testing and the looming danger of nuclear war. Today research is showing us a bright side… Many many new neuron birthdays throughout your life!

Spalding K., Bergmann O., Alkass K., Bernard S., Salehpour M., Huttner H., Boström E., Westerlund I., Vial C. & Buchholz B. & (2013). Dynamics of Hippocampal Neurogenesis in Adult Humans, Cell, 153 (6) 1219-1227. DOI: 10.1016/j.cell.2013.05.002