Boundary Conditions

I think every parent has the moment when speaking with their child, that they hear and begin to channel their parents. I know I have. My parents reside within my ‘self.’ In the past few weeks, I have thought more deeply about self and other, about how we identify the borders between us. What are the boundary conditions separating us? Why, does it feel so clear-cut at times and at other moments, so amorphous?

 

A classic approach to this question lies in philosophy – you know the usual Western suspects, Spinoza, Descartes, Hume. But rather than pursuing an intellectual approach, I followed a more biologic narrative. After all, self is such a visceral concept.

Did you know that cells make decisions? Or that plants signal to one another? Cells make ‘decisions’ to follow nutrient gradients and plants ‘turn’ toward light. Perhaps the word decision puts you off, thinking that decisions are conscious acts. Daniel Kahneman’s work, about thinking fast and slow tells us that not all decisions are conscious. Certainly our autonomic responses, our thinking fast, is much like the cell’s or plant’s travel toward nutrients and light? Maybe thinking slow obscures or prematurely frames the decision making of biological thought. 

Immunity, as with all life, is subject to evolution, present in all animals with varying sophistication for well over 200 million years. The long existence of the immune system makes me believe it is incredibly well-tuned for our environment. And understanding the boundary conditions defining self is, “immunity’s central motif.” Much of what I learned in medical school only approximates current thinking, it was a snapshot of the scientific ‘stepping-stones’ to a more expansive understanding. So I returned to reading an overview of immunity to understand the evolution of our thinking and understanding of immunity. (The Biological Notion of Self and Non-Self)

Initially the conceptualization of immunity built upon the work of Claude Bernard – the milieu intérieur, homeostasis.

“The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence …derives from the fact that in the living being, the tissues are in fact withdrawn from direct external influences and are protected by a veritable internal environment.”

The well-functioning interior is insulated from the outside by a boundary. Any internal instability results in reactive internal changes restoring the steady-state balance. Infection was lethal in Bernard’s time, and it’s disruptive effects provided an overarching narrative.

“Infectious disease afflicts the patient – a threatened self – and immunity is thus construed as protective of that agent.”

Boundary conditions in Bernard’s homeostatic view are well-demarcated, absolute, not porous at all.

Macfarlane Burnet raised on the large island of New Zealand, socially isolated in his teen years from his peers, forged a new, Nobel prize view of immunology in the late 1930’s and early days of World War II. Burnet’s model involved exposure of lymphocytes to self during fetal development and once defined they remained unchanged. Subsequently, exposure of these guardians of immunity to foreign antigens selects and amplifies a response to the non-self. 

“For Burnet, the hostile meeting between self and non-self – with its attendant imagery of combat, invasion, aggression, or counter-attack – is the archetypical description of immunity…”

Burnet’s boundary conditions are more porous; immunity is the defensive network countering the unavoidable porosity of boundary.

In both of these models, self is central either assumed by Bernard or learned as described by Burnet. Like the earth before Copernicus, self is central. And like earth after Copernicus and his cohorts, ‘self’ lost its central position.

Science in the later part of the 20th century witnessed the emergence of Mandelbrot, fractals, chaos theory, non-linear systems, the butterfly effect into mainstream thought and visualization. Culturally this was the time of “trust but verify”, of the Star War Defense, of our increasing use of National Technical Means of Verification (e.g. spy satellites). Why would immunity respond only to foreign attack? Why wait for the Pearl Harbor moment? Shouldn’t the immune system have a system of surveillance? After all, the immune system was responsible for repairing tissue damage, removing senescent cells, and eliminating malignancy. By definition, what was protected by surveillance was self. Self was not a single entity; neither static nor immutable. It was a property that emerged from the responses of the immune system; continuing to develop as long as the operations of surveillance continue.  Self changes as our provenance accrue. The boundary conditions are porous and the internal – the self – is a response to the external changes brought across the border into the homeland. Identity is diffuse, the boundary definition of self emerges through interaction with ‘other,’ the biologic equivalent of ‘trust but verify.’

There is another meme arising in the late 20th century ironically echoing immunity’s past narrative on infection. In 1854, John Snow created a map of cholera deaths in London leading to its source, the Broad Street pump. His cognitive heirs advanced the visualization of networks. Networks of people and ideas, patterns of weather or economies, the constant clamor and dialogue of life – a holistic ecology, a network of networks.

What if immunity was a web of interlocking modules of activity that respond when disturbed? What if we removed self entirely? By building upon homeostasis, defense, and surveillance, immunity came to be thought of as involving pattern recognition and context; where pattern recognition, the component identifying ‘self,' is subservient to context. Immunogenicity, our immune self, arises from “temporal and ‘spatial’ patterns of antigens.” As the pattern of incoming antigens differs from homeostasis, there is increasing disturbance and immune activation. Boundary conditions are wholly different; there is no longer a clear-cut inner and outer, self and non-self. There are only responses to our surroundings, an ecological understanding where self, networks with 'other selves.' In this model, the immune response is not due merely to the presence of other; it requires additional signals, perturbation of our steady-state, cell injury.

We know that the mere presence of other is insufficient, that other signals must be present because of the protection of chimerism – the presence of two different genetic cell lines, two separate genetic selves, in one individual. Pregnancy is a natural form of chimerism suggesting why the networked immunologic self may be a better approximation. Consider the multitude of differing genetic cells lines within all of us. Mitochondria and the microflora of the gut biome are both ‘other’ and our constant companions, our symbionts. Immune self is many necessary and different genetic threads; we are holobionts – ‘multicellular eukaryotes plus its colonies of persistent symbionts.’

“Animals cannot be considered individuals by anatomical, or physiological criteria because a diversity of symbionts is both present and functional in completing metabolic pathways and serving other physiological functions. … animal development is incomplete without symbionts, …. Most pertinent to our discussion, the immune system also develops, in part, in dialogue with symbionts, and thereby functions as a mechanism for integrating microbes into the animal-cell community… Indeed, the extraordinary diversity and richness of symbiotic functions has led to a growing understanding of how the host’s internal ecology confers an ever-evolving identity. So while the defensive role of immunity is clearly prominent in the medical and agricultural contexts, that point of view must be balanced with how the internal milieu of the individual organism integrates ‘foreign’ elements.”  

 

These four conceptualizations of immunity and self, Bernard’s, Burnet’s, surveillance and ecologic network are increasingly more sophisticated and better approximations of reality. Each model provides insight and builds upon one another. With each model I tried to provide a cultural framework for the time because there is be no better example of the interplay of culture, language, and science than immunology, which provides “a political metaphor for American culture marked by atomistic individuality.” Our scientific tools and language define our vision, in turn redefining science and language in a continuous conversation with an inevitable lag and asynchrony as they leap over one another, promoting, facilitating the dialogue., The nuanced metaphor of language reshapes the vision and the new vision reshapes cultural expression.

Let me reverse the conversation, use science to explain culture, to make a point regarding our impassioned national debate about national self and boundary conditions. 

Bernard’s vision of boundary characterizes, historically suggests the United States through the mid 19th century, isolated and looking inward. The Barbary Coast Wars, the War of 1812, assert our sovereignty. The Louisiana Purchase, Manifest Destiny, and the Civil War – the ultimate homeostatic processes. Burnet’s model of the boundary, it’s inevitable porosity and needs for defense echoes America through the cold war era. Beginning with the ‘Yellow’ Peril and influx of unwashed from Eastern and Southern Europe with their foreign clothes and food and ideas; the turning back of the MS St. Louis, the quota system. There were also chimeric moments, Emma Lazarus, the Melting Pot, the 13th Amendment; and autoimmune responses, the war on Native Americans, the internment of the Japanese, Jim Crow.

Self as surveillance characterizes current times, where there is an alphabet soup of visa options to become part of our self. Did you know that there is a visa if you invest $1 million in a “new commercial enterprise that employs at least ten full-time U.S. workers?” or if you are “persons of extraordinary ability in the sciences, arts, education, business, or athletics …”. The increasing role of the NSA, the TSA and Edward Snowden – haven’t they all been responses to external threats to a homeland?

Understanding immunity, a 200 million-year-old evolutionary solution to self and borders, offers, perhaps, a better way forward, a more ecological view of our American self. Is it time to proclaim the true source of American exceptionalism, our society’s holobiont nature?

To rewrite an earlier quote:

The United States cannot be considered individuals by geographic, or cultural criteria because a diversity of others is both present and functional in completing pathways and serving our country. …our development is incomplete without others, …. the United States also develops, in part, in dialogue with others, and thereby functions as a mechanism for integrating others into the community… Indeed, the extraordinary diversity and richness of others’ functions have led to a growing understanding of how our internal ecology confers an ever-evolving identity.

Perhaps we need to heed the lesson evolution, and our immune system provides.