Carlos Chavez Ramirez

Memory in a Molecule?

Memory in a Molecule? The Rise and Fall of Scotophobin

How does the brain store experience? An important problem in neuroscience is determining the biological substrates of memory. In the 1960s and 1970s, a small group of researchers led by Dr. Georges Ungar argued that memory could be stored in molecules. A chemical nature of memory implies that it could be transferred between animals. This work gained a large amount of attention at the time but was quickly disregarded and forgotten after a couple of decades.

A brief 2-page paper described the initial experiment that sparked this idea. The researchers hit a steel hammer against a metal plate, scaring their rats. After delivering this loud sound every 5 seconds for 2 hours, the rats were habituated to the sound and they no longer responded to it.1

These sound-habituated rats were euthanized, and their brains were pooled and homogenized. Brain homogenates were also created from non-habituated rats. Then, brain homogenates from habituated or control rats were injected into mice. Strikingly, mice that were injected with brain homogenate from rats exposed to the sound habituated to the loud sound much faster than control mice.1

The researchers were interested in determining exactly which part of the brain mixture caused the behavioral transfer. They found that treating the homogenate with chymotrypsin (which degrades proteins) caused a disappearance of memory transfer. This indicated that a protein was responsible for the reduction in habituation time after injection.1

Similar experiments showed that a fear of the dark could also be transferred between species, and more detailed biochemistry even identified the exact peptide involved in this process.2 It was named scotophobin, and its Greek roots mean “fear of the darkness.” Some reports even claimed that the peptide’s source did not need to be from the brain of a trained rat. Injection of synthetic scotophobin was able to induce fear of the dark in mice and even goldfish!3

In an interview with Time Magazine in January of 1971, Dr. Ungar enthusiastically described his experiments and then speculated about the significance of his work. He claimed that “simple injections of the chemicals of memory” would someday be able to enhance knowledge and treat senility and mental disorders.4 While the idea captured the public imagination (this was not the only time these experiments would appear in the popular media), it was met with deep skepticism from the neuroscience community.

In the years that followed, this work was immediately met with strong resistance from the scientific community. In one case, Dr. Ungar’s paper was followed by critical comments on the very next page of Nature describing failure to reproduce the results described in the previous page.5 Another critic, Dr. Goldstein, even went as far as visiting Dr. Ungar in his laboratory to learn the methodology and prevent any misunderstandings in methods.6 Many of the papers on memory transfer were followed by responses from researchers who had failed to reproduce results or had found inconsistencies between the different publications.

In response to his critics, Dr. Ungar argued that those calling his experiments “fanciful, implausible, superfluous, and worse” had a fundamental misunderstanding of his molecular coding theory.7 He assured that his discovery aligned with neuronal circuit theory and could mean that his memory molecules were themselves establishing new connections between neurons. Ultimately, despite Dr. Ungar’s best efforts, the scientific consensus was that either the biochemical techniques or the behavioral assay were poorly designed and not robust enough, leaving the claims unsupported.

By the 1980s, Dr. Ungar’s work was already being omitted from review articles and mentions of scotophobin at conferences drew chuckles from the audience.8 One researcher even described the aftermath of the affair as causing “collective embarrassment in the field about the whole era.”8 It is difficult to find any research article with scotophobin in the title since then.

The possibility of memory molecules has not completely disappeared from the scientific community yet. A similar debate about transfer of memory through a molecule is ongoing today in the C. elegans community. There have been reports of single small RNA molecules causing worms to avoid specific bacteria, even when they never learned to avoid it in the past.9 Dr. Coleen Murphy’s publications have been met with claims about irreproducibility that are reminiscent of the scotophobin story.10 Similar to Dr. Ungar, the research group has responded to critics in a preprint with the provocative title: Absence of Evidence is Not Evidence of Absence: The many flaws in the case against transgenerational epigenetic inheritance of pathogen avoidance in C. elegans.11

It remains to be seen whether memories can really be stored in molecules and transferred between animals. Throuhghout the history of science, there have been examples of ideas that were initially doubted but ended up being widely accepted later. This story highlights how important repetition and reproduction is in research. It is critical to confirm results, especially the most exciting ones!

References

  1. Ungar, G., & Oceguera-Navarro, C. (1965). Transfer of Habituation by Material extracted from Brain. Nature, 207(4994), 301–302. https://doi.org/10.1038/207301a0↩

  2. Ungar, G., Desiderio, D. M., & Parr, W. (1972). Isolation, Identification and Synthesis of a specific-behaviour-inducing Brain Peptide. Nature, 238(5361), 198–202. https://doi.org/10.1038/238198a0↩

  3. Bryant, R. C., Santos, N. N., & Byrne, W. L. (1972). Synthetic Scotophobin in Goldfish: Specificity and Effect on Learning. Science, 177(4049), 635–636. https://doi.org/10.1126/science.177.4049.635↩

  4. TIME. (1971, January 11). Science: Of Mice and Memory. TIME. https://time.com/archive/6814561/science-of-mice-and-memory/↩

  5. Stewart, W. W. (1972). Comments on the Chemistry of Scotophobin. Nature, 238(5361), 202–209. https://doi.org/10.1038/238202a0↩

  6. Goldstein, A. (1973). Comments on the “isolation, identification and synthesis of a specific-behaviour-inducing brain peptide.” Nature, 242(5392), 60–62. Scopus. https://doi.org/10.1038/242060a0↩

  7. Ungar, G. (1974). Peptides and memory. Biochemical Pharmacology, 23(11), 1553–1558. https://doi.org/10.1016/0006-2952(74)90366-9↩

  8. Setlow, B. (1997). Georges Ungar and memory transfer*. Journal of the History of the Neurosciences. https://doi.org/10.1080/09647049709525701↩

  9. Moore, R. S., Kaletsky, R., & Murphy, C. T. (2019). Piwi/PRG-1 Argonaute and TGF-β Mediate Transgenerational Learned Pathogenic Avoidance. Cell, 177(7), 1827-1841.e12. https://doi.org/10.1016/j.cell.2019.05.024↩

  10. Gainey, D. P., Shubin, A. V., & Hunter, C. P. (2024). Irreproducibility of transgenerational learned pathogen-aversion response in C. elegans. eLife, 13. https://doi.org/10.7554/eLife.100254.1↩

  11. Kaletsky, R., Moore, R., Sengupta, T., Seto, R., Ceballos-Llera, B., & Murphy, C. T. (2024). Absence of Evidence is Not Evidence of Absence: The many flaws in the case against transgenerational epigenetic inheritance of pathogen avoidance in C. elegans (p. 2024.06.07.597568). bioRxiv. https://doi.org/10.1101/2024.06.07.597568↩

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