Evolutionary Anthropology 18:241–246 (2009)

Crotchets & Quiddities

Gray’s Anatomy

An Effort to Simplify Shows How Complex Life Really Is. How Does It Get That Way?

KENNETH M. WEISS

On July 1, 1858, papers by Charles lisher Parker & Son. That was Gray’s with Carter’s artistic help and the Darwin and Alfred Russell Wallace Anatomy, Descriptive and Surgical publisher’s encouragement, Gray were read before the Linnean Soci- (Fig. 1). Its story is also worth fol- aimed at something that could be ety. This was the first public presen- lowing from 1858 to the present. used effectively in class, a book with tation of their ideas about how natu- (The following history of Gray’s is simple descriptions and clear, utili- ral variation arose and proliferated largely from a recent book by Ruth tarian drawings to train future into new, diverse species. The meet- Richardson1). surgeons. After about two years of ing had been scheduled for June, but Like Darwin vis a` vis Wallace, the intense and patient work, with Carter had to be rescheduled because of the young anatomical star Dr. Henry often carving in less than the best of death of the Society’s vice-president Gray (1827–1861, Fig. 2a), Lecturer light to make its 363 woodcuts, (see Wikipedia, ‘‘Linnean Society’’). of Anatomy at St. George’s Hospital, Gray’s was published in 1858. The The evolution paper was shifted into also had a relatively unsung partner, initial edition of 2,000 copies sold the ad hoc summer meeting. Henry Vandyke Carter (1831–1897, out. Gray’s quickly went into subse- Famously, few people were there and Fig. 2b). While Gray wrote the crisp quent issues and became the new perhaps fewer paid any attention to descriptive text, it was Carter who standard. The result is history. the message (this may depend on drew the famously clear and estheti- The 1901 edition of Gray’s is still how many sherries had been con- cally beautiful illustrations that made available,4 though you’ll have to spot sumed). But the new ideas certainly their book a success. Carter’s wood for yourself which figures bear were noticed in the following year, engravings are still used by artists and Carter’s unique style, with its hand- 1859, when Darwin’s book on the many of us treasure our copies of engraved labeling embedded in the subject, On the Origin of Species, some edition of Gray’s just for its picture, because many new figures appeared. Darwin revised his book esthetics. Unlike Darwin, however, have been added. Also, Carter’s draw- through a sixth edition. Countless Henry Gray was not forthcoming in ings were altered when better pub- copies have been published. After giving due credit to his co-conspirator. lishing methods were developed. 150 years, it is still the book on evo- The young Dr. Gray undertook this It’s easy to refer to traits like the lution, still the original in Darwin’s project because he was dissatisfied ‘‘limb’’ or ‘‘head.’’ But these single word as well as name. with the existing anatomy books. words belie a boggling wealth of in- That story has been told many One was by John Bell (1763–1820)2. tricacy and detail. To ask the Dar- times. But other things were going Bell’s book was noted for its realistic winian question, ‘‘How did the head on in London in that remarkable but gruesome figures, which accu- evolve?’’ is but a metaphoric ques- year, 1858. Almost to the day of the rately depicted the socially degraded tion, and hardly a scientific one, as is Linnaean Society meeting, the edited people who were used in dissecting easy to see. Its anatomy alone, as proofs of another book, which theaters at the time (Fig. 3). Those seen in just a few of Gray’s figures became ‘‘the’’ book on its subject, whose parts were separated for med- depicting the head (Fig. 4) is daunt- were delivered to the London pub- ical students had first been separated ing. If it is even biologically mean- from their resting places by grave- ingful to speak of a head as one robbing. Bell’s illustrations often of structure, this one comprises a weav- Ken Weiss is Evan Pugh Professor of villains or paupers from the dregs of ing of arteries, veins, capillaries, lym- Anthropology and Genetics at Pennsyl- society further degraded them, and phatic vessels, blood, nerves, the vania State University. E-mail: kenweiss@ rather needlessly. many parts of the eyes, outer and psu.edu However, the standard text in inner ears, olfactory and taste sys- Gray’s day was Quain’s.3 It was au- tems, teeth, muscles, tendons, liga- thoritative, but too detailed for stu- ments, fascia, joints, marrow, pas- VC 2009 Wiley-Liss, Inc. dents, who needed training as physi- sages into and out of bones, and DOI 10.1002/evan.20240 Published online in Wiley InterScience cians and surgeons, not anatomists. muscles. Then there are the many (www.interscience.wiley.com). Anatomy books sold very well, so covering layers, the dura, pia, arach- 242 Weiss Crotchets & Quiddities

structural and functional detail tional anatomy of, say, the face or within each of the aforementioned the ankle bones, and to suggest pos- structures. sible evolutionary scenarios for it, Similar complexities apply to every such as what kinds of natural selec- part of the body. Anyone who can tion might have been involved. This recall the dissecting room’s aura of was acceptable for most of the formalin knows that each of these twentieth century, which saw rapid features varies from person to per- growth in anatomical and histologi- son, within and between all primate cal knowledge. (Gray’s kept growing species. Yet for the most part these in size, too.) Some developmental complex structures, an arm, stom- experiments, such as manipulating ach, or head, are laid down in a very embryonic tissue in experimental similar way among individuals and organisms like the frog, chick, or among related species. They are, for mouse, showed the pattern of devel- example, similar on the left and right opment even at the cellular level, and sides, which to a great extent develop when and how that could be dis- independently. What differs are the rupted. But this was largely a black- relative sizes and timing of corre- box approach, because we had few sponding component parts. Despite ways to relate morphological phe- their variation, each newborn human nomena to the nature or evolution of or chimp is, after all, unambiguously their underlying genetic mechanisms Figure 1. Cover page of 1858 first edition of a human or chimp. that are presumed to be there. That’s Gray’s. Reconstituted from a photograph Anatomy develops through a genet- been changing dramatically as tech- in Richardson.1 ically choreographed embryological nologies in molecular development dance, with similar steps shared but and genetics have been opening up noid membranes, the bones, and syncopated among species. Carter’s the box. periostial layers, not to mention the figures from the nineteenth century The technological advances include layers, hairs, glands and other struc- show how very complex the mor- the availability of largely complete tures of the skin. And of course there phology of the human body is. And genome (DNA) sequences for is that minor item inside, known as Gray’s provided only a small subset humans and many other species; the brain. of the truth, as the growth in detail the ability to identify the genes In fact, these are just the gross in subsequent editions has shown. It expressed in any type of cell at any details that can be seen with the is hard to imagine how much com- time during embryonic development naked eye, and only of the adult, plexity is hidden just under the skin, by identifying the messenger RNAs not considering its embryological so to speak, even just anatomically, (mRNAs) that will be translated into stages, which include the timing, not to mention in our physiology, the proteins of each gene; and the location, size, formation, and miner- behavior, immunology, and our com- ability in a mouse or other labora- alization of each component of the plex sensory and other systems. tory vertebrate model to experimen- head. At the histological and cellular We’ve always been able to tally inactivate or modify the expres- level, there is a wealth of additional describe, and even test, the func- sion of any individual gene we might choose. After applying these tools for a couple of decades of intense and enormously successful research in developmental genetics, we have learned so much that the only remaining details we don’t yet under- stand are....most of the details. Nonetheless, we can see newer, bet- ter ways to approach an understand- ing of anatomy.

DISSECTING THE BLACK BOX

Modern genetic knowledge of ana- tomical development takes two gen- eral forms: breaking down and build- ing up. In the breaking-down depart- ment, for most traits genes are Figure 2. A brace of Henries: A. Gray, B. Carter. Public domain. known for which mutation has path- Crotchets & Quiddities Gray’s Anatomy 243

Figure 3. A gruesome representation of John Bell’s version. Source: public domain, from Bell.2 ological effects. Thus, mutational To account for this complexity in by testing for the expression of one of bashing of genes named Shh or Pax2 any simpler way is a challenge. The its genes, taken as an indicator, with- can lead to various forms of holopro- explosion of research findings in de- out needing to consider each of the sencephaly, facial midline defects velopmental genetics has occurred network’s participating members. such as cleft lip or palate, only a sin- long since Gray’s became too big to This helps reduce our lists. We might gle central upper incisor, or cyclopia, hold except on your lap (to the still be in some trouble if we could not the state of having only one central immense annoyance of your dis- generalize even further, but we can. eye. (Gene names may appear daunt- placed cat). Indeed, Gray’s has more Gene networks are, to a large ingly technical but they are just pages just to describe anatomy than I extent, involved in ‘‘signaling’’, by names, no more obscure than, say, have remaining words in which to which information is passed among Aloysius or Ethelberta). Mutations in try to explain how it works. But let’s cells, causing them to differentiate genes called Fgfr1, 2, and 3, or try to think in a more general way. by, for example, changing their gene- Twist1 can alter head shape or cause What we’ll see is that development expression patterns. Signaling, a premature fusion of the cranial produces things, like sphenoids, eyes, dynamic process in embryonic space sutures (craniosynostosis). and braincases, but is really about and time, is the most important Explanations of anatomic traits relational principles, or a kind of means by which cells build complex from the building-up perspective ‘‘logic’’ that is shared, along with organ structures like heads and feet requires a bit of background. The greatly overlapping lists of genetic and everything in between. hundreds of cell types in the body contributors, by all such structures. The use of signaling networks is change their behavior rapidly during Thinking in terms of genetic proc- both combinatorial and hierarchical. development. They do this by chang- esses provides a reduction in what Growing tissues are isolated from ing the genes they use at any given we might call the dimensionality of each other except when connected time. We have about 25,000 different causation, or the number of different by signaling, so that each can form genes, each capable of different things we have to keep track of. This its respective organs. Once a cell has expression depending on context. is because, unlike long lists of genes, changed, it ‘‘remembers’’ its gene- There also are many other kinds of there is a short list of basic princi- expression state and thus becomes functional units in our genomes that ples by which development is receptive to further change by being affect how genes are used, and may achieved. ready to detect and respond to subse- actually comprise the majority of Experiments have identified many quent signals. Signaling is spatial, genomic functions. Identifying these kinds of networks of interactions because it relates cells in different genetic elements yields very long lists among tens of genes that are used locations to each other; it is temporal that, like Victorian beetle collections, to build anatomical structures. For because one cascade of differentia- are the cynic’s archetype of mindless many purposes, we can determine tion leads subsets of those cells to data collection. when and where a network is active differentiate further. The result is 244 Weiss Crotchets & Quiddities

Figure 4. The complexity of the head a` la Gray’s Anatomy (1918 Edition): a sampler, Left to Right: Inner face, sphenoid, superficial head and neck. Additional images are on the cover.

locally nested, modular structures, cade of these signal-based processes. location of future types of teeth (inci- layers, repeated units, and branch- Like any drama, one act sets the stage sors, canines, or molars), then their ing, as Henry Carter’s drawings for the other, all of them sequestered numbers, and then their surface showed in the lobular structure of segments of the whole developmental cusps. During this process, many of lungs or salivary glands, the different play, but without intermissions. Each the same signal combinations are reit- numbers of bones from shoulder to cell maintains its inner environment eratively used (Fig. 5D), reducing the finger, different numbers and types and adjusts in response to its outer list of things we must consider to get a of teeth or vertebrae, and segmental environment. general sense of how teeth are made. variation within brains. This patterning occurs in soft tis- Even within a developing organ, NESTED, HIERARCHICAL, sue. The result is then put in stone, like an eye or stomach, different tis- REPETITIVE COMBINATIONS so to speak, as a cascade of minerali- sue layers respond to their local sig- OF GENES zation gene expression occurs, with naling environment, so that muscle, different members of the same fam- bone, nerve, vessels, and their own I can illustrate these principles with ily of genes used to form the enamel corresponding histological structures a description of one simple part of the and dentine, respectively.8 can develop. Cells expand into new head, the teeth. As shown in Figure 5, Teeth provide a good example of de- areas by division by clustering to- teeth form in the first branchial arch, velopmental processes because they gether, by recognizing the signal the mammalian descendant of the have been studied in great detail and receptor molecules on each other’s first gill arch in ancestral fish. When are visible and accessible. But the surfaces, or even migrating through the arch first appears, its covering same kinds of simple relational proc- a surrounding tissue by using their ectodermal layer broadly expresses a esses, and many of the same signaling signal receptors to detect the appro- signal gene named Fgf8, but this area combinations, are involved in the priate environment. These processes is narrowed through the inhibiting other structures of the head (and are used all over the developing action of another signal gene, Bmp4, elsewhere), keeping Carter and Gray embryo, employing different combi- resulting in separated spots along the burning the midnight oil to produce nations of signals and receptors. jaw where teeth will grow. The outer their book. While one cell may be actively pro- layer will form enamel in these areas, The scientific power of these gen- ducing the signal, entirely different while the underlying tissue, called eralizations can easily be seen by the cells may express a gene that codes mesenchyme, interactively responds way they guide research all across for a signal-receptor protein that with the ectoderm and will eventually the spectrum of life, from plants to enables them to react to the signal. produce the tooth’s pulp and dentine. animals.9 Even an enormously com- This is what keeps an embryo a Mesenchymal cells expressing a gene plex trait such as the skull makes coherent whole. called Pax9 respond to the ectoderm, genetic as well as developmental Starting with a single fertilized egg while neighboring areas are inhibited sense. It’s an exciting time, but it is cell, polarities, axes, and tissue layers, by Bmp2 expression. Subsequently, a only a beginning that, like Gray’s for as well as their respective branches, series of patches of expression of surgeons, represents a simplified segmented, modular, and repetitive specific combinations of signal and plan which developmental genetic structures, ensue in cascade after cas- responding genes specify first the research can be built. Crotchets & Quiddities Gray’s Anatomy 245

Figure 5. A few of the genes and processes involved in tooth development. A. Early embryo showing future jaws. B. Combinations of expressed genes specify future tooth initiation zones, as shown by the inset adult mouse jaw. C. Subsequently, combinations of different genes specify where each tooth type will form; redrawn after McCollum and Sharpe.5 D. Nested, repeated combinatorial expression of a few of the known signaling and responding genes in the upper (enamel) and lower (dentine) tooth layers, as teeth and their cusp structures form. Arrows show time passage; genes named at left of arrow induce expression of genes on the right. Communication between the two tissue layers is shown; modified after Jernvall and Thesleff.6 Final mineralization involves additional signaling, not shown. The specific gene names are unimportant here. For details see online dental development data base, http://bite-it.helsinki.fi/, as well as McCollum and Sharpe,5 Jernvall and Thesleff,6 and Kawasaki and Weiss.7

However, a ground plan of develop- sure to affect future editions of Gray’s. review in the Medical Times & Ga- mental processes does not tell us how But genetic knowledge will not zette12 blasted Gray for essentially tak- much of the genetic mechanism we change the what-structure-goes-over- ing from others without attribution actually need to understand. That what of anatomy, even if it helps and producing nothing new. In fact, as depends on the question one is ask- account for how it got that way when with many ambitious authors, Gray ing.9 To what extent a knowledge of it matters to know that. We should, at wanted credit and went out of his way the genetic mechanisms involved is least, understand and respect both at this time, as he had in an earlier col- relevant to understanding how the the complexities and the regularities laboration on a book about the spleen, morphology is used, how it affects of genetic mechanisms, because we’re to reduce recognition given to Carter.1 behavior, how it relates to past or no longer just dealing with a genomic He insisted, for example, on less than present ecologies, or the way selection or Darwinian black box. equally prominent billing for Carter on and drift molded the differences, is up the title page; his name had to be in a to each investigator. Genetics may be THE RECEPTION OF GRAY’S smaller font (Fig. 1). at the root of all of life, but we don’t Since then, in its many editions, all have to be geneticists. It may suf- Reviews of the first Gray’s were Gray’s, has ballooned. The latest fice to know that, sure enough, the mixed. The Lancet10:283 and British British edition is 1,576 pages (small genetic mechanisms we assume are Medical Journal11 were initially gush- print, 2,000 images), and ‘written’ by there can be worked out, and this is ing, but some months later a lengthy a large board of authors and editors. 246 Weiss Crotchets & Quiddities

There have even been efforts to try book had quickly become the increasing number in anthropology. to cut it back, though the future ver- standard. Somehow, each individual cell, grop- sions probably will be mainly online, Henry Carter had moved to a ing only in the light of its immediate in which case contributors may not major position in the Indian health neighborhood, plays a part in the be able to resist the unlimited cyber- service in Bombay before their book intricate dance that generates the space they might use up. The name’s was published. He did not see the beautifully complex material that the the same, but the original purpose proofs or the title page through their unsung Henry Carter so lovingly and is gone, perhaps replaced by market final editing; transportation at that patiently drew for us to see. rather than instructional considera- time was slow and so was the mail. tions. Perhaps also there is the feel- Although Carter was pleased with ing of authorial pride that this leg- the final product, his new mission NOTES endary book must remain the defini- was to help the Indian medical serv- I welcome comments on this col- tive source on anatomy, rather than ices as a physician and eventually as umn: [email protected]. My fre- the basic tutorial for mere students Deputy Surgeon-General, not as an quent co-author Ann and I maintain that Gray’s was intended to be. artist. He served successfully in India a blog on relevant topics at EcoDe- In attempting to envelope the for 30 years before returning to the vo.blogspot.com. I thank Anne Bu- human body in all its glorious com- UK, where he died in 1897 at age 65. chanan, Nina Jablonski, and John plexity, the authors and publishers He was not a celebrated figure. Fleagle for critically reading this have lost sight of the bigger—or per- Even for those who have no direct manuscript. This column is written haps I should say littler—picture. interest, or are impatient, a browse with financial assistance from funds Yet, for many purposes, perhaps for through Gray’s, perhaps especially an provided to Pennsylvania State Evan most purposes, it is the simpler earlier and simpler edition, can be a Pugh professors, and NSF grants cogent facts that are most useful and sobering experience. It shows how BCS 0343442 and Hominid Project even the most informative. The best very much we have yet to explain in BCS 0725227. ideas of the future, about the devel- genetic and developmental terms, opment, functioning, and evolution just about the parts of the body we of the body will probably arise from can see with the naked eye. But syntheses based on simpler princi- think of anatomy from the cell’s-eye REFERENCES ples rather than the plethora of more view. Each cell only knows its own 1 Richardson R. 2008. The making of Mr. complex facts. immediate environment and is blind Gray’s anatomy. Oxford: Oxford University Things have turned out differently to the bigger picture; yet the embryo Press. 2 Bell J. 1810. Anatomy of the bones, muscles with Darwin. There has, of course, organizes itself without an outside and joints. London: Longman. been a similar inundation of relevant coordinator. In every organ in every 3 Quain J. 1837. Elements of anatomy. London: facts in genetics and evolution since part of the body, it does so by cas- Taylor and Walton. Origin of Species. But instead of serial cades of hierarchical signaling, each 4 Gray H, NetLibrary Inc. 1974. Anatomy, de- scriptive and surgical. Philadelphia Running editions of ‘‘Darwin’s Origin of Spe- local stage partially sequestered from Press Book Publishers. cies’’ edited by large teams of contrib- its antecedents and neighbors so that 5 McCollum M, Sharpe PT. 2001. Evolution utors, it has remained literally the it can differentiate in new ways, and development of teeth. J Anat 199(Pt 1–2): same book with the same single modifying the scenery on the stage 153–159. 6 Jernvall J, Thesleff I. 2000. Reiterative signal- author, providing the same source to that was set for it. ing and patterning during mammalian tooth go to to for an understanding of Dar- Generalizations like those I’ve out- morphogenesis. Mech Dev 92:19–29. win’s own thinking. Of course, newer lined account for each cell’s experi- 7 Kawasaki K, Weiss KM. 2006. Evolutionary texts in genetics seem as driven as the ence as it sends, detects, and genetics of vertebrate tissue mineralization: the origin and evolution of the secretory calcium- publishers of Gray’s to present every responds to genetic signals. You and binding phosphoprotein family. J Exp Zool B fact, detail, technological method, I are the result of countless cells act- Mol Dev Evol 306:295–316. and promise that one can dream up. ing together in space and time, each 8 Kawasaki K, Buchanan AV, Weiss KM. 2007. Gene duplication and the evolution of verte- As with Gray’s, the deeper truth of the only knowing and responding to its brate skeletal mineralization. Cells Tissues bigger picture, sometimes seems to be immediate external conditions. A few Organs 186:7–24. becoming lost in the detail. simple principles applied again and 9 Weiss KM, Buchanan AV. 2009. The mer- maid’s tale: four billion years of cooperation in In 1861, at the age of only 34, again from the molecular to the the making of living things. Cambridge MA: Henry Gray died of smallpox. He organismal level provide the kind of Harvard University Press. apparently believed that he would be general explanation we need. In a 10 The Lancet. 1858. Issue II. 9:282–283. protected by a vaccine he received sense, the rest is just (a lot of) specific 11 The British Medical Journal. 1858. Issue in childhood and volunteered to details. For any given structure, like 13.II:949. 12 Medical Times and Gazette. 1859. Issue tend his nephew who had fallen ill to the limb, dentition, or head, we will 5.3:241–244. the disease. Gray’s death was noted have to work out those details specifi- at the time because he was promi- cally. That is being done in laborato- nent in his own right and his ries around the world, including an VC 2009 Wiley-Liss, Inc.