Tufts researchers propose new paradigm for cellular pathways

With broad implications for drug development and the treatment of disease, a team of researchers at Tufts University in Massachusetts is developing a new paradigm for understanding biochemical and bioelectrical action at the sub-cellular level.

Their innovation centers on a new definition of the concept of pathway, a common term used in medicine and biology to indicate a linkage of consecutive sub-cellular activities. The widely used approach in modern medicine and pharmacology is to intervene on some stage of the pathway which is not functioning correctly.

The Tufts researchers believe this common interpretation of the pathway is overly limited and mechanistic. They compare the current approach of pharmaceutical intervention and gene therapy to the early stages of computer technology where innovation was accomplished by changes in the hardware. In this analogy, biochemical pathways are the molecular analogs of computer hardware, and the focus of modern drug design is to “rewire” the molecular hardware. 

Instead, the researchers note that the cellular pathways actually share properties like memory and learning, similar to the artificial neural works used in information processing. Thus changes to the “software” could be needed to restore proper functioning of an organism. 

Their paper, “Cellular Signaling Pathways as Plastic, Proto-cognitive Systems: Implications for Biomedicine,” appears Dec. 1, 2022 on OSF Preprints, the website of the Center for Open Science. The four person team is led by Dr. Michael Levin, director of the Allen Discovery Center at Tufts and an associate at the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Tolerance and sensitization

A key point examined in the paper is the process of tolerance and sensitization experienced by biological systems. 

They view the habituation-sensitization process as the simplest kind of memory, which is exhibited even in unicellular systems, where memory is defined as the “ability to alter future behavior in light of past experience.”

In the case of drug resistance, memory of this kind is seen as an important limitation on the use of pharmaceuticals. By analogy with Pavlovian psychology, the authors regard not just the known pathway of pharmacokinetic effect, but also the “associations” that might be produced when the drug is administered, which could affect the resistance. 

Just as behavioral science views acquired resistance to repeated stimuli as a kind of memory, the authors believe that a similar approach could be effective in analyzing and overcoming drug resistance. For example resistance to pathogens can be overcome by use of combination therapies, as is done with resistant Staphylococcus aureus infections. 

In cancer treatment, combination chemotherapies (non-targeted) often with toxic side effects, are more often used than combination targeted therapies, which may have fewer side effects. The authors looked at recent studies of targeted therapies and found that of the many tested, only two, both of them combination targeted therapies, were approved for first line use, which they believe “shows the power of this approach to cancer treatment.” 

Environmental context and tolerance

Continuing the analogy to Pavlovian conditioning, the authors looked at alcohol- and drug-induced effects. They cite as an example earlier studies by Shepard Siegel and colleagues that show that a large majority of heroin overdose deaths are not due to the quantity of drug administered, but rather to a change in environmental context normally present at time of drug administration, which resulted in a loss of conditioned tolerance. 

Examining numerous more recent studies of acquired resistance and drug combination therapies the researchers conclude, “It is becoming increasingly clear that environmental cues have a strong impact on conditioning for drugs.”

The significance of this “place conditioning,” they say, is that “to understand and predict the action of a particular pharmacological agent, it is not sufficient to know the details of the pathway of its actions.”

“Our understanding of what functionally defines ‘a pathway’ cannot only be a high-resolution focus on the local chemical interactions.” the researchers note. “It must broaden to include events distant in time [past experiences of the patient] and in space [effects in the brain and nervous system even if the drug-relevant tissue is elsewhere in the body].”

Bioelectric signaling

In a more speculative discussion section of their paper, the authors examine hypotheses reminiscent of the yet-unresolved debates prevalent in early 20th Century studies of embryogenesis and morphology.

“It has long been known,” they note, “that networks of neural cells [i.e., brains] exhibit learning, plasticity and other information-processing capabilities that enable a very powerful form of functional control [such as] behavior-shaping [training], not requiring the micromanagement of molecular events. 

"In other words bioelectric signaling in the brain binds a large number of individual cells into a larger-scale emergent agent with specific cognitive properties that do not belong to any of the cells,” they added.

“The exciting emerging field of developmental bioelectricity,” they continue, “emphasizes that these capacities are not unique to the CNS [central nervous system] but are evolutionary modifications of an ancient bioelectric communication system that was using the same strategies to navigate a different problem space before they were used to navigate 3D space via muscle motion: navigation in morphospace.”

Then, invoking recent breakthroughs in the study of morphogenesis, the authors wrote, “Much of the necessary information-processing that enables distributed groups of cells to ascertain current anatomy and execute changes to bring it closer to the species-specific target morphology is carried out by bioelectrical communication across tissues . . . using the same [highly conserved, ancient] molecular components: ion channels and electrical synapses known as gap junctions.”

Thus ion channels, in addition to their accepted electrochemical function, form a part of a communications and control system, a sort of biological “software,” necessary for healthy functioning of an organism.

Citing parenthetically numerous current studies, the authors said, “Endogenous bioelectric dynamics [via slowly changing patterns of resting potential] have now been shown to be required for the formation of organs such as the wing, face, eye, brain, and heart, as well as functioning in the control of single-cell parameters such as stem cell differentiation, cancer suppression, and organ-level size control."

Summarizing the future potential of this approach, the authors concluded, “All in all, we believe the future of biomedicine will look a lot more like behavior-shaping than molecular engineering, with all the benefits of high-level communication and control that the intelligence of the body enables.”

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Juanita Mathews et al. Cellular Signaling Pathways as Plastic, Proto-cognitive Systems: Implications for Biomedicine, OSF Preprints (Dec 01, 2022).

DOI: https://doi.org/10.31219/osf.io/c6n9r">https://doi.org/10.31219/osf.io/c6n9r