Symbiosis: the view from 100,000 feet

January 30, 2014

By Mary Beth Saffo

It is a poor creature that doesn’t know its own inhabitants.

The Farandola

–      Madeleine L’Engle,  The Wind in the Door, 1973

Some things seem never to change (Exhibit A: the political headlines of the day, so often so depressingly similar to those of the day, week, month, year or decade  before; Exhibit B: the tragicomic constancy of human nature, its fundamentals evidently so impervious to the veneer of technology and other accoutrements of  “civilization”).  But in some spheres, things really do advance.

Symbiosis research in the last few years is one such tangible advance. In my own academic lifetime, symbiosis, especially mutualistic symbiosis, has been transformed from a marginal, esoteric, even vaguely disreputable topic into a mainstream field of research. Its practitioners have won wide recognition for their work.  Among American biologists alone (to cite merely a few recent examples, among many), Nancy Moran’s work on bacterial-insect symbiosis was recognized in 2010 by the prestigious Japan Prize.  Thanks to Margaret McFall-Ngai, Ned Ruby and their students, the bobtail squid Euprymna and its bacterial symbionts have graced the covers of high-impact journals worldwide. Symbiosis researcher and microbiologist Jo Handelsman now has the ear of the White House, as the newly chosen Associate Director  for Science at the White House Office of Science and Technology Policy. Finally, just a few weeks ago, the American popular science magazine Science News  cited the importance of animal microbiomes as the #1 science story for 2013 (https://www.sciencenews.org/article/year-review-your-body-mostly-microbes).

In the United States, federal funds for symbiosis research have (however inadequately) grown in concert with increasing recognition of the field. In recent years, there have been special funding initiatives at the National Institutes of Health to support research on host-associated microbial communities and the human microbiome,  support of microbial symbiosis research by the Dept. of Agriculture, and creation of a long-term funding program for basic research on pathogenic, parasitic and mutualistic symbiosis, “Symbiosis, Defense & Self-Recognition,” at the National Science Foundation.

As a particularly remarkable indicator of the growing influence of symbiosis research, progress in research on beneficial symbosis has begun to significantly influence everyday agricultural and medical practice.  Once firmly committed to the principle that “the only good microbe is a dead microbe”,  both enterprises have been enlivened by the belated understanding that beneficial (as well as  parasitic/pathogenic) microbial colonists have profoundly affected the ecology and evolution of both animals and plants and by the recognition that many of those fungal, protistan and bacterial microbes are not only a normal presence in their hosts, but even essential to plant and animal health. The widely reported examples of beneficial symbiosis have also penetrated popular understanding. (Do others besides me find it easier these days to explain to non-biologist friends what they do, now that everyone seems suddenly to know about “good bacteria”, and to understand the devastating biological consequences of coral bleaching?)

Finally, growing interest in symbiosis research is reflected in the growing complexity and sophistication of the field itself. With the extra boost of technical advances in genomics, microscopy, and related techniques (many of those advances created by symbiosis researchers themselves), symbiosis research has been stimulated and challenged by the explosive growth of data on all fronts. Recent research has created a deeper and more nuanced understanding, often revealing surprising new dimensions of long-known symbiotic interactions. New symbiotic associations are described, it seems, almost every week, confirming with ever-increasing detail the notion that symbiosis is – literally - everywhere.  So prevalent are symbiotic interactions now known to be among multicellular organisms that microbial symbiosis seems best viewed as not only an important factor in animal or plant biology, but as essentially a property of multicellular organisms.  Counting the symbiotic heritage of chloroplasts and mitochondria, one can argue (as Lynn Margulis so forcefully argued) that the symbiotic identity of eukaryotes is quite literally true.   But even considering only contemporary symbiotic interactions, the word “individual” seems an increasingly inadequate term with which to describe a given protist, plant or animal, or especially to characterize the ecological, evolutionary and physiological context of the multiple symbiotic interactions that shape fundamental aspects of their biology (for an account of bacterial symbiosis in animals, see  MJ McFall-Ngai, MG Hadfield et al., 2013: Animals in a bacterial world, an imperative for the life sciences. PNAS: 110: 3229-3236. www.pnas.org/cgi/doi/10.1073/pnas.1218525110).

Similarly, as biologists with more and more diverse backgrounds are drawn into the field, more and more symbiosis researchers are drawn into mutually beneficial, multidisciplinary conversations and collaborations as they seek novel approaches to address the complex interactions that have caught their attention.  Animal physiologists and plant ecologists find themselves learning microbiology and genomics. Medical researchers investigating the human microbiome have incorporated the principles of microbial ecology into their work. Molecular biologists have begun to appreciate the scientific importance of “non-model” organisms. Physiologists now take into account the importance of genetic variation of symbionts in assessing metabolic interactions, and consider the environmental and evolutionary context of the symbiotic interactions that they study. Evolutionary biologists discover the need to learn biochemistry; marine invertebrate zoologists with research interests in reef-building corals or siboglinid polychaetes become experts on photosynthesis and chemoautotrophy. Plant pathologists and mammalian immunologists find common molecular pathways to discuss. Each meeting of the International Symbiosis Society increases in the taxonomic diversity and disciplinary reach of its meeting agenda. Seeing the increasing cross-pollination of  disciplines in this field makes it, for me, a thrilling time to be a symbiosis researcher.

SIGNS OF YOUTH

Despite the rapid, exciting growth in the field, there remains a symptom of the youth of this discipline, and a constant frustration: a continuing lack of clarity  about the definition of symbiosis.  Remarkably, 135 years after de Bary’s 1879 definition of symbiosis as “the living together” of two or more species (that is, an intimate inter-species interaction, regardless of the outcome of that interaction), there is still inconsistency in usage of “symbiosis”,  not only  in the popular press  but also even among the most distinguished researchers in the field. Is there any other example of a scientific discipline where even specialists in the field do not agree on what the field means? Perhaps most frustrating is the tendency for many researchers to pay lip service to deBary’s definition, while in practice, restricting  “symbiosis” implicitly to mean only “mutualistic symbiosis” in speaking and writing about their own research (see Saffo, M.B. 1993. Coming to terms with a field: words and concepts in symbiosis. Symbiosis 14: 17-31).

This chronic problem – the  usage of  “symbiosis” in a way that suggests “beneficial symbiosis” alone -- is not just a semantic one.  It matters because it affects the way we think. Such restricted usage restricts our thinking, with at least two unfortunate consequences:

a.     First, using “symbiosis” to imply only beneficial interactions deprives biologists of the most pragmatic use of the broader definition: as a vehicle to describe the many symbiotic interactions – arguably most of the symbiotic interactions thus far described -- where the outcome of the interaction is in fact unknown for one or more of the interacting partners or too complex or too variable to be neatly pigeonholed into a simple definition of “harmful” or “mutually beneficial”. It also blinds us to the complexities of mutualistic symbioses themselves, which can entail significant costs as well as benefits to both partners, and embed antagonistic elements within its overall benign veneer.

b.     Second, restrictive word usage inhibits fresh thinking about other aspects of symbiotic interactions, especially about the many biological challenges of interspecies intimacy shared by all symbioses (particularly endosymbioses) regardless of fitness outcome. With a broader perspective of symbiosis, we are likely to ask additional questions about the evolution of symbiotic interactions, beyond that of interaction outcome. We are better poised to discover, and to appreciate the significance of, intriguing similarities in infection mechanisms between mutualistic  and pathogenic bacteria, fungi, and protists; the provocative interactions between immune defenses and mutualistic endosymbionts; the close genomic relatedness between many pathogenic and mutualistic symbionts; the common features of pathogenic and beneficial intracellular symbiosis;  the mechanisms and long-term evolutionary persistence of parasitic and mutualistic horizontally-transmitted symbioses, despite once-a-generation opportunities to “divorce”; and the evidence for variability of interaction outcomes depending on the environmental context of the symbiosis in question.

THE  PARADOX OF SYMBIOTIC ASSOCIATIONS.

All parasitic, mutualistic and commensal symbioses, especially endosymbioses, share a basic underlying question: how and why do symbiotic interactions exist at all? We know that symbiosis is essentially everywhere, so pervasive that it is virtually a universal feature of life. Yet symbiosis exists in the face of another universal feature of life: the ability of every organism to distinguish self from non-self, an ability almost always linked to mechanisms which exclude, excise, encapsulate or destroy foreign cells and foreign DNA. How can symbiotic associations exist in the face of the universality of recognition of, and defenses against, non-self? An explanation along the lines of “immune defenses aren’t perfect” seems a little thin, even as an explanation for the success of physiologically clever pathogens and parasites, when even the just-barely-metazoan sponges display exquisitely tuned allorecognition systems (WEG Muller and IM Muller, 2003; Integrative Comparative Biology 43: 281-292), ctenophores show evidence of an induced immune response (S. Bolte et al., 2013. Biol. Lett. 9: 20130864), and plant immune defenses rival mammalian immunity in their head-spinning complexity and sophistication (JDG Jones and JL Dangl, 2006. Nature 444: 323-329; JL Dangl, DM Horvath, and BJ Staskawicz, 2013.  Science 341: 746-751). Similarly, explaining the presence of (allegedly) beneficial symbionts solely by noting the selective benefits of such symbiosis for their host is equally unsatisfactory, as such explanations dodge the crucial mechanistic question as to how such symbionts can evade or survive their host’s immune defenses to colonize their hosts in the first place. For me, a resolution of this paradox lies in the notion that symbiotic interactions are made possible precisely because of the universality of organismal mechanisms for preservation of integrity of self (M.B. Saffo. Complexity, variability and change in symbiotic associations. Family Systems. 2001.6: 3-19). With increasing attention to the role of immune systems in shaping gut microbiomes and other symbiotic communities, current research seems likely to generate richly informative and provocative answers to this fundamental question.

Mary Beth Saffo recently completed a three-year rotation as Program Director in the Symbiosis, Defense & Self-Recognition Program of the US National Science Foundation. Although part of this essay was written during her stint as Program Director, the views in this essay do not represent the official views of NSF. She is currently at work on a book for University of Chicago Press, “Lives of the Infectious and the Infected: perspectives on mutualistic and parasitic endosymbiosis”, and welcomes research updates and articles from her colleagues. Email: mbsaffo@gmail.com or mbsaffo@post.harvard.edu.