Scotophobin

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Kazimir Malevich's painting The Black Square . The molecular coding of memories and behavior was studied in the middle of the 20th century. Scotophobin seemed to code the fear of the dark in various animals.

Scotophobin (from ancient Greek σκότος skótos "darkness" and φόβος phóbos "fear") is the name of a hypothetical dark fear-producing compound that was discovered by neuroscientist Georges Ungar in 1968 and named in a press release on December 26, 1970. Scotophobin, the results of Ungar and his co-workers seemed to show, created fear of the dark in various mammals and fish . The scientifically controversial identification, isolation, and synthesis of this substance was for about a decade a key argument in support of the hypothesis that memories are stored in the brain on a molecular basis, and numerous conferences and books on the subject have followed.

As far as we know today, scotophobin could not have had the effect that was ascribed to it, because memory is not molecular, but stored in the structure and strength of the connections between nerve cells .

description

The molecular structure of Scotophobin having the sequence: Serine - Aspartic acid - asparagine -Asparagin- glutamine -Glutamin- glycine - lysine -Serin- alanine -glutamine-glutamine-glycine-glycine- tyrosine -NH 2 .

Scotophobin is a peptide of 15 amino acids , that is, a pentadecapeptide; the one -letter code is SDNNQQGKSAQQGGY. It was extracted for the first time from the brains of rats trained in fear of the dark, is commercially genetically engineered and can also be produced in total synthesis .

The exact function of scotophobin is still unclear today (as of 2016). The amino acid sequence similar to that of various neuropeptides , especially the enkephalins and substance P . So it was concluded that it could play a similar role in the nervous system. If scotophobin is actually relevant to the nervous system, it would probably be a peptide hormone or a neuromodulator .

prehistory

Nucleic acids store information, including for protein sequences, as Marshall Nirenberg and Heinrich Matthaei had shown with their poly-U experiment . Until the 1970s it was speculated that memories could be coded in this way or in a similar way.

The history of the theory of molecular substrates as the basis of memory goes back to work in the mid-20th century. After the discovery of the relationship between DNA and proteins , through the discovery that the immune system can produce antibodies against certain antigens for a lifetime , and since the genome encodes not only the external form of an organism but also its behavior , were biomolecules such as DNA or Proteins obvious candidates for how information could be stored in the brain . Joseph Katz and Ward Halstead formalized this idea in 1950.

Katz and Halstead suggested that an experience caused the production of a certain protein. They speculated that the protein could be a nucleoprotein that would do a similar job for the cell as a gene, and that the protein would be able to reproduce itself. Numerous copies of such proteins would be built into the cell membrane and, they speculated, could either influence the conduction of excitation or be passed on via synapses , whereby several cells would become part of a neural network . A group of nerve cells formed in this way could then be specifically activated by a certain stimulus in order to reproduce a learned behavior. Different memories would be distinguished by the different chemical composition and steric structure of the proteins.

Hypothesis: molecular code of memory storage

Dugesia subtentaculata : a representative of the Dugesia

A series of simple experiments in which members of the Dugesia , a genus in the class of the vortex worms , were classically conditioned and then fed to other Dugesia individuals, seemed to support that memories could be passed on in this way. The idea of ​​a “molecular memory” was subsumed under the term “biochemical engram”. From 1965 experiments on this type of memory transfer were also carried out in mammals. One of the first experiments by Georges Ungar, a scientist at Baylor University College of Medicine in Houston , appeared to show the transfer of resistance to the opiate morphine in rats . Further experiments then showed the transfer of habituation to loud noises even between species (from rats to mice ). Ungar called this hypothesis “a molecular code of memory”.

Discovery of scotophobin

In 1968, Ungar et al . Published another experiment in the journal Nature . In this experiment, rats were placed in a cage in which there was an illuminated part and a darkened part. As soon as an animal entered the darkened part, it was electrocuted, after which it fled again into the lighted part of the cage. The animals were conditioned in this way for several days. Their brains were then isolated, homogenized and, after various chemical treatments, injected intraperitoneally into mice . When Ungar carried out a similar experiment with the mice treated in this way, the mice spent significantly less time in the darkened part of a test cage than in the lighted one compared to the control group. Through various chemical treatments, the molecule that transferred the “fear of the dark” was narrowed to a peptide with a length of 6 to 10 amino acids . The study had a great impact in the professional world, and Ungar subsequently published a book on the molecular basis of memory in which numerous other contributions have been compiled. Finally, in 1972, the isolation, sequencing and total synthesis of scotophobin was reported.

It shows the relative time it takes mice to get out of one of two labyrinths. Some of the mice were injected with brain lysate from animals that each knew one of the labyrinths. The curves labeled xy show experiments in which mice were tested in labyrinth x and received the lysate from animals from labyrinth y. These data seem to show that the 1-1 and 2-2 animals find their way significantly faster than the other groups.

Contemporary criticism

The experiments with Dugesia were already heavily discussed because of the surprising results, and in fact even Georges Ungar was surprised by the strength of the effect he had observed. Early on, this led to an article in the journal Science , signed by 23 scientists, who presented 18 experiments, all of which could not reproduce the transfer of memories.

In 1971, after an application for research funding from the National Institute of Mental Health, Georges Ungar's work was peer-reviewed in his laboratory. The review panel suggested ensuring that the results were not due to non-specific transmission of stress or arousal. He was also recommended to make samples of synthetic scotophobin available to other laboratories. In the review by B. Setlow it is speculated that Ungar realized after this assessment that the behavior of the animals could only have faked an effect due to the lack of controls.

The response of Ungar and his co-workers was to both specify their results and publish a complete theory of chemically encoded memories. This led to a number of critical comments on the isolation and synthesis of scotophobin. Particularly noteworthy is the study by Walter W. Stewart, a biochemist with the National Institutes of Health , who showed in detail "that the researchers [Ungar et al.] Had no idea what they had really found." Stewart went so far as to propose a hypothetical substance, pseudo-scotophobin , whose properties matched the data presented by Ungar better than scotophobin itself.

However, Ungar continued his work and published several reviews on the theory of the molecular substrate of memory until his death in 1978. The results of the review under Roger W. Russel were published in 1972.

Reception in public

The supposed results with scotophobin had a clear impact in public. In the late 1960s and 1970s there were a number of articles in numerous newspapers, and the idea of ​​the principle of “molecular memory” survives to this day, for example in the 1996 film Unforgettable , the TV series iZombie, and popular science works.

Today's assessment

Despite the once intensive study of the peptide, this line of research came to an end around 15 years after the first specialist articles. Neurobiologist James L. McGaugh believes that this chapter in brain research is still viewed with some embarrassment. So many scientific careers have been destroyed by these experiments that there is still a kind of shame within the field about the entire era:

"The memory transfer experiments drew in so many researchers initially and subsequently destroyed enough careers that, even today, there seems to be a sense of collective embarrassment in the field about the whole era."

"The memory transfer experiments originally cast a spell over so many researchers and subsequently destroyed enough careers that there is a certain collective embarrassment about the entire era in the research field even today."

- James L. McGaugh, quoted in B. Setlow: Georges Ungar and memory transfer. 1997

Individual evidence

  1. ^ Stanley Finger, Francois Boller, Kenneth L. Tyler: History of Neurology: Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab) . Elsevier, 8 December 2009, ISBN 978-0-7020-3541-8 , p. 610.
  2. ^ A b G. Ungar, L. Galvan, RH Clark: Chemical transfer of learned fear. In: Nature. Volume 217, Number 5135, March 1968, pp. 1259-1261, PMID 5643106 .
  3. ^ P. Mosley: Memory Created in Test Tube, Scientists at Baylor U. Claim , The Washington Post, Times Herald (1959–1973) - Washington, DC, Dec. 27, 1970.
  4. ↑ a b c G. Ungar, DM Desiderio and W. Parr: Isolation, identification and synthesis of a specific-behavior-inducing brain peptide. In: Nature. Volume 238, Number 5361, July 1972, pp. 198-202, PMID 4558348 .
  5. ^ For example, through the Max Planck Society in Göttingen , at the MPI f. biophysical chemistry, Symposium on Memory and Transfer of Information , Göttingen, 24. – 26. May 1972.
  6. ^ Howard Eichenbaum:  Memory . In: Scholarpedia . (English, including references)
  7. ↑ a b c Synthesis and History in Jared T. Hammill: Syntheses of Peptidic, Natural Product-inspired, and Heterocyclic Molecules as Biological Probes , University of Pittsburgh 2012
  8. ^ Database entry for scotophobin isolated from rats . Retrieved April 27, 2016.
  9. ↑ For example at mybiosource , accessed on April 22, 2016.
  10. ↑ D. Wilson: Scotophobin resurrected as a neuropeptide. In: Nature. Volume 320, Number 6060, 1986 Mar 27-Apr 2, pp. 313-314, doi: 10.1038 / 320313c0 , PMID 3960116 .
  11. ↑ a b c d B. Setlow: Georges Ungar and memory transfer. In: Journal of the history of the neurosciences. Volume 6, Number 2, August 1997, pp. 181-192, doi: 10.1080 / 09647049709525701 , PMID 11619520 .
  12. ^ JJ Katz and WC Halstead: Protein organization and mental function. in Comparative Psychology Monographs . Williams & Wilkins, 1950. Volume 20, pp. 1-38.
  13. ^ JV McConnell and JM Shelby: Memory transfer experiments in invertebrates . In Georges Ungar, David Allenby Booth: Molecular mechanisms in memory and learning . Plenum Press, 1970. pp. 71-101.
  14. ^ M. Rilling: The mystery of the vanished citations: James McConnell's forgotten 1960s quest for planarian learning, a biochemical engram, and celebrity. In: American Psychologist . Volume 51, 1969, pp. 589-598, doi: 10.1037 / 0003-066X.51.6.589 .
  15. ^ A b G. Ungar: Chemical transfer of learning: Its stimulus specificity. In: Federation Proceedings. Volume 25, Number 207, 1966
  16. ↑ G. Ungar, C. Oceguera-Navarro: Transfer of habituation by material Extracted from brain. In: Nature. Volume 207, Number 994, July 1965, pp. 301-302, PMID 5886227 .
  17. ^ G. Ungar and M. Cohen: Induction of morphine tolerance by material extracted from brain of tolerant animals. In: International journal of neuropharmacology. Volume 5, Number 2, March 1966, pp. 183-192, PMID 5959957 .
  18. ^ Sudhir Kumar: Biochemistry of Brain . Elsevier Science, October 22, 2013, ISBN 978-1-4831-5359-9 , p. 383 ff .: Georges Ungar: Molecular Neurobiology of Memory , hypothesis of “a molecular code of memory”.
  19. ^ Georges Ungar, David Allenby Booth: Molecular mechanisms in memory and learning . Plenum Press, 1970.
  20. ↑ The figure is a reprint of Figure 2 in G. Ungar: Evidence for molecular coding of neural information from 1973; a chapter in the book Memory and Transfer of Information .
  21. ^ WL Byrne, D. Samuel, EL Bennett, MR Rosenzweig and E. Wasserman: Memory transfer. In: Science. Volume 153, Number 3736, August 1966, pp. 658-659, PMID 5939939 .
  22. ^ A. Goldstein: Comments on the "isolation, identification and synthesis of a specific-behavior-inducing brain peptide". In: Nature. Volume 242, Number 5392, March 1973, pp. 60-62, PMID 4735102 .
  23. ^ WW Stewart: Comments on the chemistry of scotophobin. In: Nature. Volume 238, Number 5361, July 1972, pp. 202-210, PMID 4558349 .
  24. ↑ Philip M. Boffey: Two Critics of Science Revel in the role ; New York Times, April 19, 1988; accessed on May 1, 2016.
  25. ^ Reed Business Information: New Scientist . Reed Business Information, Aug. 3, 1972, pp. 240-241, ISSN  0262-4079 .
  26. ^ G. Ungar: Molecular coding of memory. In: Life sciences. Volume 14, Number 4, February 1974, pp. 595-604, PMID 4595997 (review).
  27. ^ G. Ungar: Peptides and behavior. In: International review of neurobiology. Volume 17, 1975, pp. 37-60, PMID 166956 (review).
  28. ↑ RW Russel, G. Ungar, E. Usdin: Seminar on the requirements for testing of hypotheses about molecular coding of experience: Transfer studies. In: Psychopharmacology Bulletin. Volume 8, Number 2, April 1972, pp. 5-13.
  29. ↑ Louis N. Irwin: Scotophobin: Darkness at the Dawn of the Search for Memory Molecules . Hamilton Books, 2007, ISBN 978-0-7618-3580-6 .