Dedicated to Max Delbruck

Max Delbruck and his colleagues are famous as the founding fathers of the field of molecular genetics/biology. Max studied as a postdoctoral fellow in Nobelist Niels Bohr’s laboratory of quantum physics in Copenhagen. Bohr is often rated second only to Einstein in the world of physics. Bohr is best known for his application of reductionist philosophy to solve the first electronic structure of an atom. Following his research with Bohr Max changed fields from physics to biology, focusing on the nature of heredity. Max and his colleagues mimicked Bohr’s reductionist concept and laid the foundation for “cracking” the genetic code.

After Watson and Crick published the discovery of the structure of DNA in 1954, Max switched his interest once again to the molecular basis of neuroscience. Max and his colleagues championed a biological reductionist strategy for decoding memory. Nematodes became the favored research tool for studies of the molecular biology of neurons. Studies of neurons of nematodes remain the gold standard research tool in this field. Over several decades, there have been attempts to replace nematodes with E. coli as research tools.

During his long tenure at Caltech Max Delbruck was famous for inviting incoming students and new post docs to hike with him in the mountains behind Pasadena, CA. Ray C Valentine (RCV) became acquainted with Max as the result of these hikes and continued to hike with him for several years. The Southern California mountains that Max preferred to hike in were often hot at the height of the day. There were plenty of rest periods, especially after steep climbs; and when hiking alone with RCV Max would permit a little hard science to be discussed. During one of these breaks, RCV told Max about how he had used reductionist strategy to discover, name and transfer the nitrogen fixation nif genes. RCV intended this discussion to be a testament to Max’s wisdom in pioneering reductionism in biology. Max was polite and seemed to accept the importance of his reductionist views crossing the border into agricultural science (RCV’s interpretation). Max’s response was typically Max: “There are bigger fish to fry!” Max was not being mean-spirited. RCV believes he was saying, “Okay, you got your foot in the door so do something bigger.” This one is for you, Max! If Max were to rise from the grave for one last hike, I would tell him the following news regarding his quest to decipher principles of neurobiology:

1. Max, you are right. There are bigger fish to fry.

2. Indeed, BST believes that your reductionist strategy remains the best choice for cracking the human memory code.

3. BST has revisited microbiological data, obtained over two decades ago at Calgene, involving properties of a remarkable EPA recombinant of E. coli. These data turn out to be a Rosetta stone for decoding structure-function of memory molecules.

4. According to our current working model derived from the above EPA recombinant, CNS myelinated neurons store memory.

5. Specifically, we propose that memory is stored not IN, but rather ON axons.

6. We hypothesize that the memory of a person is stored in narrow, circular, myelin channels filled with cytosolic liquid. Importantly we speculate that the total end-to-end length of myelin channels might approach one hundred thousand miles. This number is estimated from data that the total length of myelinated axons of white matter are about 100,000 miles per person.

7. We believe that water, characteristic of a hydrogel, is the major component of memory polymers.

8. We suggest that other classes of biopolymers, including sugars, lipids and proteins along with macro-minerals and trace minerals, play essential roles in memory storage and retrieval.

9. We believe that viscosity three to five times that of the axoplasm is a characteristic and essential property of memory hydrogel.

10. We suggest that ionic, hydrogen-, van der Waal’s and covalent bonding are essential for stabilizing memory jelly.

11. We propose that the human brain has evolved a battery of specialized, powerful, protective mechanisms that are essential and required for maintaining homeostasis of memory.

12. We hypothesize that memory fluid stored in memory channels is relatively viscous (jelly-like) and uniform in bulk composition but is conformationally dynamic at the nano level.

We believe that the above points are only the tip of the iceberg. BST is eager to develop relationships with other scientists interested in decoding memory.

The final point of this section involves a selected list of milestones leading to development of the memory hydrogel hypothesis outlined above:

• 1993 RCV begins microbiological research at Calgene on decoding structure-function of DHA/EPA in excitatory and energy-transuding membranes.

• 1995 Metz and colleagues construct an EPA recombinant of E. coli in which all native fatty acid chains are replaced by EPA (See excitatory membrane references).

• 1993 to 2003, data obtained during this period were analyzed and published (See excitatory membrane references). Several novel properties attributed to EPA were reported but the mechanism responsible for the remarkable phenotypes described for this recombinant remained elusive.

• In early 2018 a hydrogel/semiconductor hypothesis to explain the multiple phenotypes of the EPA recombinant was developed.

• In late 2018, BST (Biological Semiconductor Technologies, Inc) was formed and registered as a company in Delaware.

• Matthias Kellermann and colleagues in Germany supplied pioneering data on structure-function of natural solid-state semiconductors, which jump-started BST efforts to decode biological hydrogels.

• Summer/early fall, 2020, RCV and BST volunteers—Matthias Kellermann, Marina Botana, David Paige, Sham Goyal, Linda and Gary Smith, Marcos Yoshinaga, Abhaya Dandekar, George Fareed, Renata Assis, David Valentine, and Cindy Anders—develop hydrogel model of memory storage. Thanks Glenn Prescott and John Palmer for your wisdom.

References—Myelin

1. Younjin Min 1, Kai Kristiansen, Joan M Boggs, Cynthia Husted, Joseph A Zasadzinski, Jacob Israelachvili. 2009. Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein. Proc Natl Acad Sci U S A. 106(9):3154-9. doi: 10.1073/pnas.0813110106.Epub 2009 Feb 13.

2. Yannick Poitelon 1, Ashley M Kopec 1, Sophie Belin. Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism. 2020. Cells. 9(4):812. doi: 10.3390/cells9040812.

3. Salla Ruskamo 1 2, Oda C Krokengen 3, Julia Kowal 4, Tuomo Nieminen 5, Mari Lehtimäki 1, Arne Raasakka 3, Venkata P Dandey 4, Ilpo Vattulainen 5 6, Henning Stahlberg 4, Petri Kursula. 2020. Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice. J Biol Chem. 295(26):8692-8705. doi: 10.1074/jbc.RA120.013087. Epub 2020 Apr 7.

4. Ruth M Stassart 1 2, Wiebke Möbius 1, Klaus-Armin Nave 1, Julia M Edgar. The Axon-Myelin Unit in Development and Degenerative Disease. 2018. Front Neurosci. 12:467.doi:10.3389/fnins.2018.00467. eCollection 2018.

5. Hideaki Tsuge. A myelin sheath protein forming its lattice. 2020. Biol Chem. 295(26):8706-8707. doi: 10.1074/jbc.H120.014273.

6. Larisa Yurlova 1, Nicoletta Kahya, Shweta Aggarwal, Hermann-Josef Kaiser, Salvatore Chiantia, Mostafa Bakhti, Yael Pewzner-Jung, Oshrit Ben-David, Anthony H Futerman, Britta Brügger, Mikael Simons. Self-segregation of myelin membrane lipids in model membranes. 2011. Biophys J. 101(11):2713-20. doi: 10.1016/j.bpj.2011.10.026.

References—Excitatory Membranes

7. Kellermann, M. Y., M. Y. Yoshinaga, R. C. Valentine et al. 2016. Important roles for membrane lipids in haloarchaeal bioenergetics. Biochim Biophys Acta (BBA) - Biomembranes 1858: 2940-56.

8. Metz, J. G., P. Roessler, D. Facciotti et al. 2001. Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes. Science 293:290-293.

9. Valentine, R. C. and D. L. Valentine. 2015. Human longevity: Omega-3 fatty acids, bioenergetics, molecular biology, and evolution. Boca Raton: Taylor and Francis Group.

10. Valentine, R. C. and D. L. Valentine. 2004. Omega-3 fatty acids in cellular membranes: a unified concept. Prog. Lipid Res. 43:383-402.

11. Valentine, R. C. and D. L. Valentine. 2013. Neurons and the DHA principle. Boca Raton: Taylor and Francis Group.

12. Valentine, R. C. and D. L. Valentine. 2009. Omega-3 fatty acids and the DHA principle. Boca Raton: Taylor and Francis Group.

13. Yoshinaga, M. Y., M. Y. Kellermann, D. L. Valentine et al. 2016. Phospholipids and glycolipids mediate proton containment and circulation along the surface of energy-transducing membranes. Progress in Lipid Research 64:1-15.