Cell physiology at the Mount Desert Island Biological Laboratory: a brief look back and forward

Abstract

The Mount Desert Island Biological Laboratory (MDIBL) has played important roles in the development of modern physiological concepts and tools, particularly in the fields of kidney and epithelial cell physiology. Over the last decade, MDIBL has undergone remarkable growth and evolution. This article will briefly review MDIBL's past and outline its future directions. It is hoped that this overview will renew and stimulate interest in MDIBL and, in particular, will encourage an even wider community of physiologists to participate in its ongoing growth and development.

marine research stations have played central roles in the development of the biological sciences, and in particular, the field of physiology (8, 9, 13). A marine station that is well known for its contributions to physiology is the Marine Biological Laboratory (MBL) at Woods Hole, Massachusetts. While less well recognized than the MBL, the Mount Desert Island Biological Laboratory (MDIBL), located on Mount Desert Island in Maine, has also played important roles in the development of modern physiological concepts and tools.

A number of authors who publish in the American Journal of Physiology-Cell Physiology and other American Physiological Society journals have spent time working at MDIBL. This article will briefly review MDIBL's past and outline its future directions. It is my hope that this article will renew and stimulate interest in MDIBL and, in particular, will encourage an even wider community of physiologists to participate in its growth and development.

The Early Years

MDIBL had its beginnings in 1898 when John Kingsley, a biology professor at Tufts University, established an “unpretentious” teaching and research laboratory at South Harpswell, Maine. Scientific investigations in the early years focused primarily on natural history research, embryology, and comparative anatomy. Pioneering work on embryo cleavage was carried out at the Harpswell Lab in the early 1900s by Naohide Yatsu (e.g., 27). Warren Lewis and Margaret Reed Lewis were also early investigators at the lab. The Lewis' carried out extensive research on developmental processes and regeneration and played key roles in the development of cell and tissue culture methods and in the use of time-lapse photography to study cell division (6, 11).

The Harpswell Lab moved to Mount Desert Island in June 1921 at the suggestion of George Dorr, the father of Acadia National Park. Dorr worked tirelessly throughout much of his life to preserve Mount Desert Island it in its natural state. He helped raise the funds to purchase land that was deeded to the Harpswell Lab, which thereafter became known as the Mount Desert Island Biological Laboratory. Dorr was also instrumental in helping establish MDIBL's close neighbor, The Jackson Laboratory.

The First Transformation

MDIBL underwent its first major transformation in 1926. In the summer of that year, the physician-scientist E. K. Marshall visited the lab to work on a marine fish as a model to address an important question in kidney physiology. His visit began the establishment of MDIBL's reputation as a center for kidney and epithelial cell physiology research. It also launched a remarkably robust scientific culture of basic scientists working side-by-side in a highly collegial and productive manner with physician-scientists. This type of scientific culture, which is so critical for understanding and treating disease, is often little more than wishful thinking in large academic medical centers. However, it has existed at MDIBL for many decades and continues to be an important part of the lab's intellectual foundations.

Studies on kidney function led naturally to an MDIBL focus on epithelial cell physiology. Marine animals proved to be particularly valuable models for such efforts for a number of reasons: their epithelial tissues are relatively easy to isolate and robust enough to survive well in vitro, they exhibit high rates of solute transport making these processes relatively easy to study at the cellular and molecular levels, and they have large and hearty cells that permit all sorts of poking and prodding with microelectrodes. Some of MDIBL's key contributions that have furthered understanding of the kidney and epithelial cell physiology include characterization of renal hemodynamics and tubuloglomerular feedback; characterization of mechanisms of epithelial Cl⁻ transport, bile and cerebrospinal fluid formation, organic anion secretion, cell volume regulation, and urea excretion and secretion; biochemical characterization of the Na-K-ATPase; and characterization of carbonic anhydrase and its role in acid-base transport processes and homeostasis. Work carried out at MDIBL resulted in the cloning of the first NaCl and NaK2Cl cotransporters, which in turn launched an entire research field.

MDIBL also has a rich history in comparative physiology, much of it related to salt and water homeostasis and solute transport. For example, the discovery of nasal salt glands in sea birds was made by Knut Schmidt-Nielsen and colleagues at MDIBL. This work was the first to describe a mechanism for extrarenal salt excretion (23).

Other important work done at MDIBL during the same era included Ray Rappaport's studies on cleavage in sand dollar eggs, which are widely recognized as having provided fundamental contributions to our understanding of cytokinesis (19). Bill Kinter and colleagues carried out some of the earliest work on DDT and oil toxicity at MDIBL (12, 15, 18, 19). Kinter's studies helped launch a research focus at the lab on cellular toxicology and stress biology, which in turn initiated a rapidly growing and evolving bioinformatics program (7).

The Second Transformation

Until 2000, MDIBL was largely a seasonal facility with the majority of its activity occurring in May through September when weather permitted use of its largely unheated and uninsulated laboratory buildings. An effort to begin year-round operation was made in 1971 when Bill Kinter and Bodil Schmidt-Nielsen took up full-time residence at the Lab. The effort was short-lived, however. Kinter died tragically in 1978 and Schmidt-Nielsen retired eight years later.

By the mid-1990s, senior leadership recognized that MDIBL could no longer survive solely as a seasonal research facility. MDIBL began moving toward year-round operation in the late 1990s. Pollard noted that “the Mt. Desert Island Biological Laboratory is a rustic collection of wooden buildings, a world apart from the pretentious palaces designed by signature architects that house many biological research labs today” (19). “Rustic” is certainly an appropriate adjective. As a summer investigator in 1994, I remember having no running water in my lab, being able to see daylight through its plywood walls, and lining up to use the single public restroom on campus. Clearly, the physical plant had to change dramatically if MDIBL was going to transform itself into a credible full-time institution.

All laboratory buildings on campus have been renovated and brought to modern standards in the last decade. Nearly 10,000 square feet of space were winterized for year-round use. In 2008, a state-of-the-art, 15,000 square foot “green” research building that houses four resident research groups, core facilities, and a teaching lab was opened. A National Institutes of Health-funded 10,000 square foot addition to this building is under construction and scheduled to open in late 2011.

There were four full-time employees at MDIBL when I was a seasonal investigator in 1994. Today, the lab is the professional home for nearly 50 employees including 10 faculty members. Faculty recruitment is ongoing with the goal of developing a critical mass of 12–15 independent resident research groups. MDIBL's annual budget has grown over 17-fold in the last decade and was $10.3 million in 2010.

For 111 years, MDIBL directors have conducted their duties on a part-time basis while maintaining a full-time academic position at another institution. As initial efforts to recruit permanent faculty began to succeed, it became clear that developing MDIBL into a credible full-time institution would require a full-time director. Recruitment of a new Director began in 2007. I moved to Maine and began my tenure as the lab's first resident Director in January 2010.

Core Values

In the midst of changes as dramatic as those occurring at MDIBL over the last decade, core values can get lost in the inevitable attempts to preserve traditions and long-remembered ways of doing things. In the context of this article then, it is important to define the core values that make MDIBL unique and that will continue to serve as its foundation as the Institution grows and evolves.

MDIBL's core values can be divided into those that define the lab's community and its overall approach to biological research. The MDIBL community is defined by its relatively small size, informality, multidisciplinary makeup, collegiality and collaborative spirit, and its connection to nature. Why are these values important and what impact do they have on how science is done? In answering these questions, it is interesting to note that these same values served as cornerstones for the establishment of the Howard Hughes Medical Institute's (HHMI) Janelia Farm research campus, which opened in 2006 (e.g., 1, 16, 21).

While MDIBL needs to grow further to sustain itself, maintaining a small campus is a central component of its growth plan. MDIBL's size and lack of academic boundaries fosters interaction and cooperation. The beauty of the Maine coastline, Mount Desert Island and nearby Acadia National Park, and the campus setting has a strong impact on everyone who works at and visits MDIBL. All campus buildings overlook Frenchman Bay and Schoodic Mountain (Fig. 1). Not only is this natural setting inspiring, but it breaks down barriers to communication and interaction that can be part of conventional academic culture.

Fig. 1.

Aerial view of Mount Desert Island Biological Laboratory (MDIBL) lower campus and view of Frenchman Bay at sunset from the campus dock.

From its inception MDIBL has operated as a research facility for visiting scientists. The visiting scientist program has always made research at MDIBL a multidisciplinary effort. In a typical summer, 50–60 basic scientists, including physician-scientists, from large and small academic institutions congregate with their students and postdocs to share diverse knowledge, ideas, and expertise. Nowhere is this more evident than during summer Monday morning seminars, which are held on Laboratory Point about 15 feet above the high tide line (Fig. 2).

Fig. 2.

MDIBL visiting scientist, Dr. Billy Hudson from Vanderbilt University, delivering a Monday morning seminar on Laboratory Point. Hudson is describing the formation of a new type of chemical bond he and his colleagues discovered, the sulfilimine bond, which joins the two halves of a type IV collagen dimer.

MDIBL's scientific values also contribute to its uniqueness. Whether they are PhD or physician-scientists, MDIBL investigators approach biological problems from the perspective of comparative biology. They exploit the diversity of life to understand basic biological processes. For example, Marshall first came to MDIBL to work on the goosefish because its kidneys lacked glomeruli, thus allowing him to test definitively the hypothesis that urine could be formed by renal tubule secretion (14). Eggs of marine organisms are well suited for studies of early developmental events because of their large size, hardiness, and the ease with which they can be isolated and manipulated. The urinary bladder of the winter flounder has a number of characteristics that make it well-suited for transepithelial transport studies. Stokes exploited these traits and demonstrated that the robust Cl⁻ transport across the bladder was mediated primarily by thiazide-sensitive electroneutral NaCl cotransport similar to that of the mammalian distal tubule (25). Building on this knowledge, Hebert and coworkers (10) utilized the flounder bladder as a rich source of cotransporter mRNA, allowing them to clone the first NaCl cotransporter. Forbush and coworkers (26) utilized a similar strategy to clone the first NaK2Cl cotransporter from the rectal gland of the dogfish shark. A new generation of MDIBL investigators is exploiting organismal diversity to understand how animals regenerate damaged and lost body parts, and why humans and other mammals have largely lost this ability.

It goes without saying that biology cannot be understood without understanding the proximate mechanisms that underlie biological processes. Understanding the evolution of biological processes is also essential. How and why did a particular process or structure evolve? How has it been modified through evolutionary time to allow organisms to adapt to their unique environmental constraints? Answers to questions like these invariably provide deeper mechanistic insight. An evolutionary perspective can also provide important and unique insights into diseases and their treatment (17, 24). Evolutionary thinking is central to the research carried out at MDIBL.

Kidney and epithelial cell physiology research dominated much of MDIBL's past. Physiology is an inherently integrative discipline, focusing not on reductionism alone, but also on defining how the sum of the parts gives rise to the functions of the whole. The twenty-first century postgenome sequencing era is widely viewed as the era of integrative biology. The John W. and Jean C. Boylan Center for Cellular and Molecular Physiology was founded in 2009 with the express purpose of ensuring that integrative biology and integrative thinking remain inherent in the way science is done at MDIBL.

Looking Forward

Over the coming decade, there will be greatly increased focus at MDIBL on the use of genetically tractable models such as Caenorhabditis elegans and the zebrafish Danio rerio. These types of organisms provide powerful tools for defining the genetic and molecular bases of fundamental biological processes and human disease. This new focus on genetic models has been partly responsible for greatly stimulating collaborative interactions with MDIBL's neighbor, The Jackson Laboratory, a premier institution for mouse and human genetics research. Several interinstitutional research efforts are developing to facilitate investigations between mice and genetic model species such as zebrafish, which offer the advantages of speed and economy for defining gene function and genetic pathways.

Despite this new focus on genetically tractable models, research on marine organisms will continue at MDIBL, both because they provide models to uniquely address important biological and biomedical questions, and because they are important to study in their own right so as to better understand our oceans and the life within them. Nowhere is the value and power of this type of comparative approach better illustrated than by the rapidly growing field of regenerative biology and medicine (2, 5, 22). Humans and other mammals have very limited abilities to regenerate damaged and lost body parts. However, numerous invertebrate and nonmammalian vertebrate animals are experts at doing so. For example, small pieces cut from almost any location in an adult planarian can regenerate into entire new animals (20). The zebrafish is capable of regenerating its heart, retina, fins, and spinal cord (3). Urodele amphibians regenerate numerous body parts including intestine, retina, spinal cord, jaw, and limbs (4).

If we are going to understand the molecular bases of regeneration and why humans have largely lost this ability, and if we are going to develop regenerative therapies to treat a host of human ills, then I believe strongly that it is essential to understand cell and tissue regeneration from a comparative and evolutionary perspective. Only by doing this can we answer important questions such as: Are there common molecular and cellular pathways that underlie regenerative processes, or do different animals do this in different ways? We have almost certainly not lost the genes required for regeneration. Why then do evolutionarily more ancient animals fully regenerate lost body parts while we only form scar tissue when we lose a limb or our heart is damaged? Can genetic circuits in humans be manipulated to improve wound healing and stimulate regeneration?

Building on MDIBL's history and core scientific strengths, research on regenerative biology will become a major focus for the lab. The Kathryn W. Davis Center for Regenerative Biology and Medicine was founded at MDIBL in 2010 with philanthropic support and funding from the Department of Defense. Faculty are being recruited with the goal of developing a highly collaborative and multidisciplinary group of scientists working on this important problem.

By virtue of its location and scientific core values, MDIBL is and will remain committed to understanding our oceans and improving ocean health. In 2009, the Martha and Wistar Morris Center for Environmental Health Sciences was formed to focus research activity on environmental problems and related human health issues. Research in this center focuses on defining the cellular and molecular mechanisms that allow organisms to cope with natural and human-induced environmental stressors and on defining how environmental chemicals contribute to human disease via changes in gene activity and function.

Activities in the Morris Center also include efforts to preserve and conserve local marine environments. MDIBL's marine preservation and conservation efforts have served as an important platform on which to build a collaborative network of organizations with similar interests, including The Nature Conservancy, College of the Atlantic and the Maine Department of Marine Resources. Much like a multidisciplinary and collaborative faculty is better able to address scientific problems in innovative ways, a diverse group of collaborative organizations can tackle complex environmental problems in ways not possible for a single organization.

Formal educational activities are expected to expand at MDIBL in the coming years. Over the last decade, several courses developed and run by faculty at traditional academic institutions have been launched. These courses, which include Quantitative Fluorescence Microscopy and Environmental Genomics, are intensive hands-on laboratory experiences that are geared toward upper level trainees and faculty.

Among similar types of research institutions, MDIBL is unique in hosting intensive hands-on laboratory courses for medical students and practicing physicians. Medical education includes courses such as Origins of Renal Physiology and Molecular Mechanisms of Human Disease. These courses contribute to MDIBL's multidisciplinary environment, in creating an intellectual atmosphere that bridges basic science and medicine, and in improving understanding of physiological principles essential to patient care.

In addition to hosting a growing number of formal courses, MDIBL has become an increasingly attractive location for small, Gordon-style scientific conferences. Courses and conferences at MDIBL are facilitated by a modern conference center, a state-of-the-art teaching lab opened in 2008 (Fig. 3), extensive on- and off-campus housing and an on-campus cooperative style dining hall. MDIBL is easily accessed and is located approximately 10 and 50 min by car from the Bar Harbor Airport and Bangor International Airport, respectively. Mount Desert Island receives over 2 million visitors annually and is a major destination for tourists from all over the world who are attracted to Acadia National Park, numerous outdoor recreational activities, and the island's cultural attributes, which include many diverse museums, art galleries, and excellent restaurants.

Fig. 3.

Participants in the MDIBL Quantitative Fluorescence Microscopy (QFM) course. QFM is run by faculty from the University of Pittsburgh and Vanderbilt University.

With the evolution of MDIBL into a full-time institution, the disposition of its seasonal research activities naturally comes into question. HHMI's Janelia Farm established a visiting scientist program at its inception to stimulate multidisciplinary research and to ensure that the Institution's relatively small size and location away from traditional academic and urban centers did not create a sense of isolation. For the same reasons, MDIBL not only needs to preserve and grow its seasonal research program but to expand it to year-round operation. Indeed, this is already occurring with students and collaborators from other institutions working with MDIBL resident faculty throughout the year.

The visiting scientist program is supported by extensive on-campus housing, which includes cottages, efficiency apartments, and student dormitories. Research facilities for visiting scientists include rented seasonal laboratory space and extensive on-campus scientific equipment cores. Additional core scientific resources are available at The Jackson Laboratory, which is a 15-min drive from MDIBL. Competitive fellowship funding is available on an annual basis to support the research activities of visiting scientists.

Working at MDIBL, whether full-time or as a visiting scientist, provides freedom from traditional academic boundaries and bureaucracy and administrative and teaching responsibilities. The lab's small size, informality, and inspiring location not only foster but demand a culture of collegiality and cooperation, which in turn, creates a multidisciplinary research environment that spurs innovation and discovery. MDIBL's second century will be an exciting one as the Institution grows and as its core values serve as an important driving force for the evolution of its research efforts.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).