Introduction
Whether we like to admit it or not, we all have an insatiable need to classify everything around us.1 It is our way of imposing a structure on the world we inhabit. We classify by drawing boundaries around groups of similar entities, and then we name them. Ideally, there is general agreement about the location of the cleavage lines. However, consensus is not always reached. For example, for more than 75 years after Pluto was discovered, it was regarded as our solar system’s ninth planet — a distant and frigid oddball, to be sure, but a member of Earth’s immediate family, nonetheless. Then, in 2006, the International Astronomical Union (IAU) reclassified Pluto as a ‘dwarf planet’, a newly created category that the organization explicitly stressed made Pluto distinct from the eight ‘true planets’. Many scientists and Plutophilic members of the public objected strongly to the IAU’s decision.2 The grounds for their objections are not important here. What is relevant is that even a bunch of very smart astrophysicists can disagree on matters of classification.
Few anatomists and histologists would argue with the idea that adipose tissue (fat) and connective tissue belong to the same group named “tissue” or that the heart and the brain, despite their vast differences in structure and function, are both “organs”. Even for those of us not well versed in formal definitions of these various classes, there is something almost intuitive in assigning most bodily structures to a specific group or level of organization.
What then do we make of the blood as an entity? How to we classify it according to our present-day organizational schemes? Is it a circulating tissue? A liquid organ? Or something altogether different? And do these considerations even matter?
Hierarchical levels of organization
All multicellular organisms are comprised of hierarchical levels of organization, from cells, to tissue, organs and organ systems.3
Cells
In the mid-19th century, the work of Theodore Schwann (1810–1882) and Mattias Jacob Schleiden (1804–1881) followed by Rudolf Virchow (1821–1902) laid the foundation for the cell theory, which states that:
- All organisms are made up of one or more cells
- All the life functions of an organism occur within cells
- All cells derive from preexisting cells
- The cell is the fundamental unit of life
The human body has over 200 unique types of cells, and all told they add up to some 20 trillion cells in a single individual. Virchow, also introduced the concept of cellular pathology, which put medicine on a new theoretical footing by explaining the origin of diseases as a malfunction of cells. For Virchow, the structure and function of whole organism were determined by the relationship between the cells. “Hence it becomes evident”, he wrote, “that the composition of a larger body, the so-called individual, always amounts to some kind of social institution”.4
Tissues
A tissue refers to groups of similar cells and their extracellular matrix that work together to perform a specialized function.5 Extracellular matrix is the non-cellular component present within all tissues that provide structural and biochemical support of surrounding cells. Think of it as the “stuffing” around cells. Tissues, then, are communities of cells that have functions beyond what any single cell type could accomplish.
The Ancient Greeks referred to tissues as homogeneous or homoeomerous parts, that is body parts that are simple, single, and continuous structures and cannot be further resolved by dissections.6, Galen, for example, identified several homoeomerous parts including membranes (e.g., peritoneum, pleura, pericardium, periosteum, pia mater, and heart valves), cartilage, bone, tendons, ligaments, nerves, veins, and parenchyma (or flesh).
Marie François Xavier Bichat (1771-1802), who is considered the father of descriptive anatomy, introduced the doctrine of tissues. He characterized and distinguished tissues by their changes upon boiling, soaking or baking, and even based on their reaction to acids and bases. Despite the availability of microscopes, he did not use them in his work because he found then untrustworthy. Bichat decomposed the human body into twenty-one distinguishable tissues (Bichat’s tissues essentially replaced Galen’s homoeomerous parts).7 He believed that a detailed analysis of these tissues was all that was necessary to understand the structure and function of organs.
The importance of the tissue doctrine was that it provided a new, more granular anatomical-clinical framework for understanding the seat of disease. At the time Bichat published his work, disease was thought to arise in organs. Bichat suggested that the tissue itself was the origin of disease. For example, instead of the whole heart suffering from an ailment, one of its two outer tissue layers, the pericardium or the myocardium, could be specifically affected by one or another disease.
Today, the number of recognized tissue types has been dramatically shortened to include just 4 different types: connective tissue, muscular tissue, nervous tissue and epithelial tissue.
Organs
The word organ is derived from the Latin word for instrument, implement, or tool.8 The metaphor implies a structure operating mechanically to perform a specific function. Indeed, a typical definition of an organ today is a structure made up two or more tissues that function together for a common purpose, typically a vital or special function.9 This definition goes back as far as Galen, who wrote that an organ “is a part of an animal which carries out a complete function like the eye with respect to vision, the tongue to speech and the legs to walking”, and that it is made up of a combination of homoeomerous parts. Galen was not always consistent with his definitions. For example, in some of his works he describes the artery, vein and nerve as organs because of their complete function (like the eye or leg), and in other places he refers to veins as homoeomerous parts because they have only one coat (layer).
The Ancients liked to rank organs according to their importance in the animal economy. Aristotle viewed the heart as the most essential part of every animal. The heart is the origin of veins, the source of heat, and the embodiment of the sensitive and nutritive soul. “It is the heart that has supreme control”, he wrote.
Galen organized organs into three classes of decreasing importance: 1) those that maintain life itself (brain, heart and liver), 2) those that make life better (eyes, ears and nostrils), and 3) those that are important for preserving the race (genital organs). The heart is the principle organ in that loss of function of the heart can destroy function of the liver and brain, but loss of function of the liver and brain does not destroy that of the heart. The importance of the liver for Galen was its role in producing blood.
William Harvey compared the heart to the ruler of the state because it is the first organ to form during development and it does not depend on other organs for its functioning (it can be removed from the body and it still beats) while other organs depend on the heart. Virchow viewed the body as a cell state, patterned after a republic. In contrast to Harvey, he did not view a single cell type or special organ as representing the individual. Any such claims were figments of our imagination. Bichat viewed an organ as comprising several tissues, whereby disease might induce pathological change in one tissue only. In his book, Treatise on Membranes, Bichat wrote that organs “are themselves composed of several tissues of very different nature, which truly form the elements of these organs”.
Others viewed the whole organ as the seat of disease. For example, Battista Morgagni (1682–1771), who is considered the founder of pathologic anatomy, viewed the human body as a machine composed of several devices (organs), each entrusted with a specific function, and there was an interrelated composite relationship between individual organs which drives the machine (human body). A defect (lesion) in one of the devices would lead to a specific mechanical problem (disease) that would in turn affect the overall performance of the machine (human body). The lesion in the organ, revealed by autopsy, is considered by Morgagni as the fundamental cause of disease and of its origin, progress, and clinical symptoms. Organ pathology is still important in medicine today. Our clinical specialties revolve around organ systems, our history and physical exam are still organ-based and our diagnosis and treatment focus on alleviating organ dysfunction.
We can see most organs with the naked eye. And we can usually draw boundaries around them, at least with the mind’s eye. But there are additional ways to think about organs. For example, we might consider the developmental programs that guide their formation in the embryo. We now have detailed knowledge of the molecular pathways that underlie the growth and shape of distinct organs, including the pancreas, lung and heart, and we could just as easily define organs by these pathways. Instead of saying pancreas, I might speak of gene X or gene Y, or genetic network Z that forms the pancreas.
Another way to think about organs is through our capacity to recreate them in a petri dish. This involves using pluripotent stem cells (cells that are capable of giving rise to virtually any cell in the body) to form a three-dimensional construct composed of multiple cell types through self-organization. These so-called organoids can simulate the architecture and functionality of the native organ. To date, human pluripotent stem cells have been coaxed to generate intestinal, kidney, brain, and retinal organoids, as well as liver organoid-like tissues called liver buds. There is little question that the investigators spearheading these studies are viewing organs through a different prism than we are.
Finally, we can think about organs as being transplantable from one person to another. Examples include kidney, heart, lung and pancreas. This feeds into the concept of the organ as an anatomically defined structure.
Based on these considerations (together with a dose of intuition), it might seem straightforward to agree on what body part qualifies as an organ. Remarkably, however, that is not the case.10 There is no formal definition of an anatomical organ, and this gap leaves open the door for new discovery claims. Just in the past two years, we have witnessed two such pronouncements. The first was based on a microscopic study of the interstitium throughout the body. The interstitium is a fluid- and collagen-filled compartment that fills the space between cells in the body. The investigators noted that the interstitium contains less collagen and more fluid than previously recognized. They likened the interstitium to an “open, fluid-filled highway”, and raised the possibility that the fluid-filled spaces may act as shock absorbers to protect tissues during daily functions.
On the day they published their work, their home institution issued a press release heralding the study as “the first to define the interstitium as an organ … and as one of the largest. The findings and the publicity around them led to a chorus of dissent from the biomedical community. “The claim that it is a hitherto undiscovered organ and the largest one ever at that, seems a stretch”, bemoaned one critic, “… most biologists would be reticent to put the moniker of an ‘organ’ on microscopic uneven spaces between tissues that contain fluid. By this definition, the abdominal cavity and pleural spaces should be discrete organs”.11 One pathologist referred to the new organ designation as “marketing semantics”.12
In the second instance, a group from the University of Limerick demonstrated that the mesentery of the digestive system (the mesentery is a fold of membrane that attaches the intestine to the abdominal wall and holds it in place) is a contiguous structure that not only connects things together inside our body, but is also responsible for transporting blood and lymphatic fluid between the intestine and the rest of the body. Based on their observations, they reclassified the mesentery as an organ.13 Once again, there was significant pushback from the biomedical field. Without strict parameters, it was argued, anyone could declare their favorite body part an organ. These were not discoveries at all, but rather mere word play.14
Organ systems
Organs do not work in isolation. They interact with other organs, and in some cases these interacting parts form structurally and functionally related groups that are often termed organ systems. Examples include the nervous system (includes the brain, spinal cord and peripheral nerves), the cardiovascular system (the heart and blood vessels), the gastrointestinal system (the esophagus, stomach, liver, gall bladder, exocrine pancreas, and intestine) and the endocrine system (the pituitary, pineal, thyroid, parathyroids, endocrine pancreas, adrenals, testes, and ovaries). The function of an organ system is dependent on the integrated activity of its organs. These are diverse and complex systems, each with its own behavior pattern.
Ever since the Parisian school adopted an anatomico-pathological approach to disease, the medical world has viewed the human body through an organ-based prism. Medical school curricula and textbooks are organized around organs or organ systems, as are societies, journal and subspecialties. For example, cardiologists are concerned with the heart and large vessels, gastroenterologists with the entire length of the GI tract, and endocrinologists with the full gamut of endocrine glands. With increasing subspecialization we begin to see a shift in focus from organ system to single organ. A hepatologist is a type of gastroenterologist concerned primarily with the liver, while the endocrinologist with expertise in thyroid disease is dedicated to that one gland. A small minority of physicians, including the cornea specialist are tissue-centric in their approach to patient care.
Making sense of the human body
Once we have drawn boundaries around like-objects in the human body, how do we begin to make sense of the whole? We can remove a heart from the chest, place it on a table and watch it beat for a while. Eventually it will stop moving. Why? What critical connections are missing when the heart is removed from its native environment? How would we begin to study these connections? These are really difficult questions, and they speak to the challenges inherent in studying complex entities.
The reductionistic approach to scientific and biomedical discovery has dominated modern Western thought for centuries. Reductionism describes the idea that complex systems or phenomena can be understood by analyzing their simpler components, typically using a combination of molecular and cell biology tools. According to this view, the cell is the “unit” of the organism, and so, explanations of observations gathered at the tissue level of organization should necessarily be found at the cellular level.
In reductionist biology, technological developments (for example microscopy, and other methods with fancy names like proteomics, transcriptomics or deep sequencing) are leveraged to zoom in and study increasingly hidden levels of organization (molecules and signaling pathways) within a cell, with the hope of learning about higher-level phenomena. However, as helpful as these approaches are, they yield diminishing returns. Biology itself cannot be subdivided into ever smaller, and thus more understandable, units without losing crucial information about the whole. Stated another way, the behavior of the system is greater than the sum of its parts and cannot be predicted from the properties of these parts. To return to our example of the beating heart on a table, can you imagine a scenario where even the where even the most detailed study of heart muscle cells in a petri dish could answer the question of why the beating eventually stops? I can’t.
Another approach to making sense of the human body is to apply systems theory.15 Systems theory focuses less on the parts themselves, and more on the arrangement of and relations between the parts and how they work together as a whole.16 The jargon gets complicated but bear with me, it should become clear. Systems are composed of inter-related subsystems. The human body, for example, is an amalgam of nested subsystems, including organ systems, organs, tissues and cells. Humans are also embedded into a hierarchy of “supersystems” (now we are zooming out) for example, species, genera, classes (in the biological hierarchy), or family, tribe, and nation (in the social hierarchy).17
In this scheme, the whole (tissues and organs) are the product of the parts (tissue or cells, respectively), but the parts in turn depend upon the whole for their own functioning and existence. Each system level has level-specific rules that influence and regulate the components, which they contain and need for their proper functions. The whole and its parts reciprocally determine functioning of each other. Specific networks exist within and between levels of the hierarchy. In one sense then, a tissue, organ or organ system may be defined by an assembly of cells, interconnected in a specific way. Viewed from that perspective, it is likely that there are tissues and organs (defined by critical connections and networks) that we have not yet identified.
The human organism is an integrated network, where multi-component organ systems continuously interact through various feedback mechanisms and across different spatio-temporal scales to optimize and coordinate their function. Coordinated interactions of organ systems are essential to maintain health and to generate distinct physiologic states. Altering or disrupting organ communications can lead to dysfunction of individual systems or to collapse of the entire organism, e.g., fever, hypertension, pneumonia, coma, multiple organ failure. Yet, despite the importance to understanding basic physiologic functions and the broad clinical relevance, we know little about the nature of the dynamical interactions between diverse organ systems and their collective role as an integrated network in maintaining health.
Understanding integrated physiologic function as emergent phenomena from complex interactions among diverse organ systems is the main focus of an evolving field called network medicine. Network medicine combines two areas that have followed independent trajectories over past years: systems biology and network science. Systems biology describes the use of experimental, high-level computational and mathematical approaches to obtain, analyze and model large datasets from complex biological systems. The idea is to analyze not just one molecule (for example a single gene or protein) but rather thousands or even tens of thousands of genes or proteins and to use the information – often in time series – to infer emergent behavior at the cell, tissue or organ level. Network science simply specifies the type of modeling that is used to analyze these big data sets. Network science approaches complex systems as interacting components. The field uses terms such as nodes and links (connections between nodes). Network science has been applied to physics, computer science, engineering, economics and the social sciences. Its application to the medical sciences has given rise to the field of network medicine.
Where does blood fit?
With this background in hand, let’s now turn our attention to blood and consider its place in the structural hierarchy of the human body. Is blood simply a collective of cells? Or is blood a tissue? Can we be bold enough to call it an organ or an organ system? Or is it something else altogether?
If we start at the fundamental unit of the cell, we already face certain challenges. No one will argue that leukocytes are cells in every sense of the word. They have a cell membrane, a nucleus and a healthy repertoire of cell organelles including endoplasmic reticulum and mitochondria. However, mammalian red blood cells and platelets are highly unusual in that they lack a nucleus. How to we reconcile this finding with the fact that a defining feature of a eukaryotic cell, as opposed to the prokaryote (like a bacteria), is the presence of the genome-containing nucleus that directs the whole organization of the cell?
Red blood cells form from erythroblasts, which extrude their nuclei at the final stage of differentiation in the bone marrow. Platelets by contrast are released from large bone marrow progenitor cells called megakaryocytes through a process of cytoplasmic fragmentation. Whereas each erythroblast gives rise to a single red blood cell, one megakaryocyte generates thousands of platelets.18
Yet despite their anucleate state, red cells and platelets have fully formed cell membranes and are capable of receiving signals (environmental cues) from the outside and responding in ways that are adaptive to the host. They seem to carry out their critical functions without any need for new RNA synthesis or cell division.
That red cells lack nuclei does not “break” any rule or law of nature. Virchow, who championed and expanded on the cell theory wrote: “nearly all the histologists at the present time are agreed that the colored corpuscles of the blood of man and the higher mammalia contain no nuclei… [one might doubt their cellular nature] if we did not happen to know that, at certain periods of development of the embryo, they do contain nuclei”. Virchow and his contemporaries did not know that red cells in the adult were derived from nucleated precursor cells in the bone marrow, but he used embryonic studies to show the same phenomenon. Virchow was writing before the discovery of platelets.19
Does blood resemble any of the four recognized tissue types in the body, namely connective tissue, muscular tissue, nervous tissue and epithelial tissue? It is clearly distinct from muscular and nervous tissue. Epithelial tissues are essentially large sheets of cells covering the external surface of the body as well as hollow organs and body cavities, including blood vessels that are lined by a special type of epithelium, the endothelium. Epithelial cells have basal and apical sides, the latter facing towards the outside world or body cavity. The distribution of organelles and membrane-bound proteins differs between their basal and apical surfaces. This property is called cell polarity. Moreover, epithelial cells are adjoined to one another by specialized intercellular connections called cell junctions. Blood cells do not demonstrate cell polarity and while they may briefly communicate with one another as they wrestle their way through small capillaries, they do not form lasting cell-cell bonds. Blood is not an epithelial tissue.
So that leaves connective tissue, whose major function is to support and connect other tissues. Unlike epithelium, which is composed of cells closely packed with little or no extracellular space in between, connective tissue cells are dispersed in a sea of extracellular matrix. Connective tissue may be loose, as in the case of adipose tissue, or dense, for example in ligaments and tendons. Some classification schemes include blood as a specialized fluid connective tissue that transports fluid, nutrient, waste and chemical messengers.20 According to this view, blood consists of dispersed cells surrounded by a fluid matrix (the plasma), which collectively connect all the organ systems of the body. And what’s more, blood elements share the same embryonic origin (mesodermal) as other connective tissue types.21
Should we accept that blood is simply a collective of connective tissue cells surrounded by a fluid extracellular matrix – an entity on the same level as other connective tissues like adipose tissue, cartilage, and bone?22 Maybe. Or does blood have transcendent properties that warrant a different type of categorization, say as an organ?23
As we saw, there is no formal definition of an anatomical organ.24 According to Paul Neumann, professor at the Department of Anatomy and Neurobiology at Dalhousie University, an organ should consist of more than one kind of tissue, exist as a discrete unit and perform a specific function. The blood can certainly be viewed as an independent unit, and it does perform specific functions, not least of which is delivery of oxygen to all cells of the body. However, unless we accept its designation as a fluid connective tissue, blood does not contain even a single tissue type. So, things are not so clear cut.
If blood is neither tissue nor organ, what is it? Do all parts of the body have to be assigned to one or another tissue type or organ? One approach to classify (remember, we are all classifiers) the plethora of body parts, proposed by Neumann, is to consider the body as being composed of organs and entities that connect organs including connective tissue, blood and lymphatic vessels, ducts and nerves. “Functions such as occupying space between organs, physically linking body parts, or mediating transport or communication to and/or from an organ, do not appear to be sufficient to merit the designation as an organ… On the other hand, it appears to be an anatomical entity on the same hierarchical level as an organ”. 25 So now we have cells, tissues, organs and connecting entities. Perhaps “connecting entity” applies to a blood vessel; it just doesn’t do justice to the blood inside the vessel.
And this brings us back to systems theory and network medicine. All biological systems are formed by subsystems of various orders and are part of suprasystems of a higher order.26 According to this definition, the identification of system components at any given level depends on identifying boundaries and establishing structural and functional links between elements, rather than relying on arbitrary designations of tissue or organ. If we accept blood as a biological system, then the endothelial lining of the blood vessel wall may be thought of as the boundary, separating blood from other systems.27 Blood may be considered a nested system consisting of various subsystems, including red blood cells, white blood cells, platelets, endothelial cells and plasma. Blood itself is embedded in a supersystem, the hematological system that includes bone marrow, blood, and perhaps the lymphatic system.
In addition to these obvious groupings, there may be additional supersystems involving blood that we don’t even think about, or that we are unaware of. A simple example is an established connection between red blood cells and hepatocytes (the main cell type in the liver). Red cells take up glucose as their main food. They convert glucose to lactate, and use the energy generated to fuel their basic needs. Lactate is a toxic byproduct that is released from the red cell into the blood. Lactate is then taken up by hepatocytes, which are professional detoxifiers, and converted back to glucose. The glucose is then released into the blood to feed erythrocytes and other cells. In liver disease, failure of the hepatocytes to process red cell-derived lactate may result in elevated lactate levels in the blood, which in turn causes metabolic acidosis, a harmful turn of events. Here we have a closed loop that functionally links blood with liver, or a supersystem comprised of two systems. Maybe red cell-hepatocyte interactions are more complex than we ever envisioned. Perhaps there is a link between the two that is particularly critical to human health, and which represents a breakthrough novel therapeutic target. In a future era of super specialized medicine, what would stop a physician from hanging out their shingles advertising expertise in the new blood-liver organ?
The point is that there are no secrets between body parts. Everyone talks to everyone else, and the unearthing of important links, many of which we are completely ignorant of today, may lay a foundation for new systems that have their own diagnostic rules, therapy and prognosis. And of all the systems in the body, it is the blood that has the most intimate contact – just one degree of separation (the blood vessel wall) – with all other systems.
Do names even matter?
Why consider blood’s place among tissues, organs and systems? What purpose does this exercise fill? Is it just a semantic problem of interest to philosophers of science? It is true that categorization of structures into tissues, organs, and systems is arbitrary. However, it has considerable utility as it provides a structural hierarchy within which one can more easily navigate the human body. It helps to identify levels of organization so that we may properly adjust our lens when we study blood, and when we diagnose and treat patients with blood disorders. At the most granular level, we can appreciate subcellular processes, and as we zoom out, we are able to capture the form and function of individual cells as well as collectives of cells, whether they be white blood cells, red blood cells or platelets. This view of the blood – as mere (largely independent) groupings of cells – has provided an invaluable plane of focus for investigators and clinicians alike. At academic centers, it is not unusual for hematologists to carve out an area of expertise in red cell disorders or platelet disorders. The resulting cell-type-inspired fragmentation of the field, while allowing for increasingly detailed understanding of individual elements, ignores important levels of organization.
It would be helpful to arrive at an organizational designation that refocuses our gaze. Different types of blood cells interact with one another and with the surrounding plasma matrix. Blood, in turn, has intimate connections with the vascular endothelium, and the dance that takes place between blood and endothelium – together with instructions from the underlying organs of the body – determines when and where cells and material get across the blood vessel wall. Blood is not a mere collection of cells that happen to be passively moving. It is a highly complex living system that forms reciprocal relationships with virtually every other part of the body.28
By categorizing blood as a biological system, we avoid the inevitable musings about who qualifies for access to the tissue or organ club. In addition, the system designation provides practical and novel perspectives from which to view human biology in health and disease. If we want to understand blood, we need to study it as a whole.29 More importantly, we must establish the importance of connections and links between elements within the system (the various blood cells and the plasma) and between blood and other systems.