a ‘triple-decker’ – in three volumes – of 1740 pages in all.
The two men were earnestly engaged for the following 18 months
in work for the new book. Gray wrote the text, and Carter created the
illustrations; all the dissections were undertaken jointly. Their working
days were long – all the hours of daylight, eight or nine hours at a
stretch – right through 1856, and well into 1857. We can infer from the
warmth of Gray’s appreciation of Carter in his published acknowledge-
ments that their collaboration was a happy one.
The Author gratefully acknowledges the great services he has derived in
the execution of this work, from the assistance of his friend, Dr. H. V.
Carter, late Demonstrator of Anatomy at St George’s Hospital. All the
drawings from which the engravings were made, were executed by him.
(Gray 1858)
With all the dissections done, and Carter’s inscribed wood-blocks at the
engravers, Gray took six months’ leave from his teaching at St George’s
to work as a personal doctor for a wealthy family. It was probably as
good a way as any to get a well-earned break from the dissecting room
and the dead-house (Nicol 2002).
Carter sat the examination for medical officers in the East India
Company, and sailed for India in the spring of 1858, when the book
Fig. 1 Henry Gray (1827–1861) is shown here in the foreground, seated
was still in its proof stages. Gray had left a trusted colleague, Timothy
by the feet of the cadaver. The photograph was taken by a medical
Holmes, to see it through the press. Holmes’s association with the first
student, Joseph Langhorn. The room is the dissecting room of St
edition would later prove vital to its survival. Gray looked over the final
George’s Hospital Medical School in Kinnerton Street, London. Gray is
shown surrounded by staff and students. When the photo was taken, on galley proofs, just before the book finally went to press.
27 March 1860, Carter had left St George’s, to become Professor of
Anatomy and Physiology at Grant Medical College, in Bombay (nowadays THE FIRST EDITION
Mumbai). The second edition of Gray’s Anatomy was in its proof stages,


to appear in December 1860. Gray died just over a year later, in June The book Gray and Carter had created together, Anatomy, Descriptive
1861, at the height of his powers. and Surgical, appeared at the very end of August 1858, to immediate e5


Historical introduction
acclaim. Reviews in The Lancet and the British Medical Journal were
highly complimentary, and students flocked to buy.
It is not difficult to understand why it was a runaway success. Gray’s
Anatomy knocked its competitors into a cocked hat. It was considerably
smaller and more slender than the doorstopper with which modern
readers are familiar. The book held well in the hand, it felt substantial,
and it contained everything required. To contemporaries, it was small
enough to be portable, but large enough for decent illustrations: ‘royal
octavo’ – 91 × 6 inches (24 × 15 cm) – about two-thirds of modern A4
2
size. Its medium-size, single-volume format was far removed from
Quain, yet double the size of Knox’s Manual.
Simply organized and well designed, the book explains itself confi-
dently and well; the clarity and authority of the prose are manifest. But
what made it unique for its day was the outstanding size and quality
of the illustrations. Gray thanked the wood engravers Butterworth and
Heath for the ‘great care and fidelity’ they had displayed in the engrav-
ings, but it was really to Carter that the book owed its extraordinary
success.
The beauty of Carter’s illustrations resides in their diagrammatic
clarity, quite atypical for their time. The images in contemporary
anatomy books were usually ‘proxy-labelled’: dotted with tiny numbers
or letters (often hard to find or read) or bristling with a sheaf of num-
bered arrows, referring to a key situated elsewhere, usually in a footnote,
which was sometimes so lengthy it wrapped round on to the following
page. Proxy labels require the reader’s eye to move to and fro: from the
structure to the proxy label to the legend and back again. There was
plenty of scope for slippage, annoyance and distraction. Carter’s illustra-
tions, by contrast, unify name and structure, enabling the eye to assimi-
late both at a glance. We are so familiar with Carter’s images that it is
hard to appreciate how incredibly modern they must have seemed in
1858. The volume made human anatomy look new, exciting, accessible
and do-able.
The first edition was covered in a brown bookbinder’s cloth embossed
all over in a dotted pattern, and with a double picture-frame border. Its


spine was lettered in gold blocking:
Fig. 2 Henry Vandyke Carter (1831–1897). Carter was appointed
GRAY’S
Honorary Surgeon to Queen Victoria in 1890.
ANATOMY
… with ‘DESCRIPTIVE AND SURGICAL’ in small capitals underneath. sense of calamity. The grand old medical man Sir Benjamin Brodie,
Gray’s Anatomy is how it has been referred to ever since. Carter was given Sergeant-Surgeon to the Queen, and the great supporter of Gray to
credit with Gray on the book’s title page for undertaking all the dissec- whom Anatomy had been dedicated, cried forlornly: ‘Who is there to
tions on which the book was based, and sole credit for all the illustra- take his place?’ (Anon 1908).
tions, though his name appeared in a significantly smaller type, and he But old JW Parker ensured the survival of Gray’s by inviting Timothy
was described as the ‘Late Demonstrator in Anatomy at St George’s Holmes, the doctor who had helped proof-read the first edition, and
Hospital’ rather than being given his full current title, which was Profes- who had filled Gray’s shoes at the medical school, to serve as Editor for
sor of Anatomy and Physiology at Grant Medical College, Bombay. Gray the next edition. Other long-running anatomy works, such as Quain,
was still only a Lecturer at St George’s and he may have been aware that remained in print in a similar way, co-edited by other hands (Quain
his words had been upstaged by the quality of Carter’s anatomical 1856).
images. He need not have worried: Gray is the famous name on the Holmes (1825–1907) was another gifted St George’s man, a scholar-
spine of the book. ship boy who had won an exhibition to Cambridge, where his brilliance
Gray was paid £150 for every thousand copies sold. Carter never was recognized. Holmes was a Fellow of the Royal College of Surgeons
received a royalty payment, just a one-off fee at publication, which may at 28. John Parker junior had commissioned him to edit A System of
have allowed him to purchase the long-wished-for microscope he took Surgery (1860–64), an important essay series by distinguished surgeons
with him to India (Fig. 2). on subjects of their own choosing. Many of Holmes’s authors remain


The first edition print-run of 2000 copies sold out swiftly. A parallel important figures, even today: John Simon, James Paget, Henry Gray,
edition was published in the United States in 1859, and Gray must have Ernest Hart, Jonathan Hutchinson, Brown-Séquard and Joseph Lister.
been deeply gratified to have to revise an enlarged new English edition Holmes had lost an eye in an operative accident, and he had a gruff
in 1859–60, though he was surely saddened and worried by the death manner that terrified students, yet he published a lament for young
of his publisher, John Parker junior, at the young age of 40, while the Parker that reveals him capable of deep feeling (Holmes 1860).
book was going through the press. The second edition came out in the John Parker senior’s heart, however, was no longer in publishing.
December of 1860 and it too sold like hot cakes, as indeed has every His son’s death had closed down the future for him. The business, with
subsequent edition. all its stocks and copyrights, was sold to Messrs Longman. Parker retired
The following summer, in June 1861, at the height of his powers and to the village of Farnham, where he later died.
full of promise, Henry Gray died unexpectedly at the age of only 34. With Holmes as editor, and Longman as publisher, the immediate
Gray had contracted smallpox while nursing his nephew. A new strain future of Gray’s Anatomy was assured. The third edition appeared in
of the disease was more virulent than the one with which Gray had 1864 with relatively few changes, Gray’s estate receiving the balance of
been vaccinated as a child; the disease became confluent, and Gray died his royalty after Holmes was paid £100 for his work.
in a matter of days.
Within months, the whole country would be pitched into mourning THE MISSING OBITUARY
for the death of Prince Albert. The creative era over which he had pre-
sided – especially the decade that had flowered since the Great Exhibi- Why no obituary appeared for Henry Gray in Gray’s Anatomy is curious.
tion of 1851 – would be history. Gray had referred to Holmes as his ‘friend’ in the preface to the first
edition, yet it would also be true to say that they were rivals. Both had


THE BOOK SURVIVES just applied for a vacant post at St George’s, as Assistant Surgeon. Had
Gray lived, it is thought that Holmes may not have been appointed,
Anatomy Descriptive and Surgical could have died too. With Carter in despite his seniority in age (Anon 1908).
India, the death of Gray, so swiftly after that of the younger Parker, Later commentators have suggested, as though from inside knowl-
e6 might have spelled catastrophe. Certainly, at St George’s there was a edge, that Holmes’s ‘proof-reading’ included improving Gray’s writing


Historical introduction
style. This could be a reflection of Holmes’s own self-regard, but there were not as yet perfected, and in any case could not provide the bold
may be some truth in it. There can be no doubt that, as Editor of seven simplicity of line required for a book like Gray’s, which depended so
subsequent editions of Gray’s Anatomy (third to ninth editions, 1864– heavily on clear illustration and clear lettering. Recognizing the inferior-
1880), Holmes added new material, and had to correct and compress ity of half-tone illustrations by comparison with Carter’s wood-engraved
passages, but it is also possible that, back in 1857, Gray’s original originals, Pick and Howden courageously decided to jettison the
manuscript had been left in a poor state for Holmes to sort out. In other second-rate half-tones altogether. Most of the next edition’s illustrations
works, Gray’s writing style was lucid, but he always seems to have paid were either Carter’s, or old supplementary illustrations inspired by his
a copyist to transcribe his work prior to submission. The original manu- work, or newly commissioned wood engravings or line drawings,
script of Gray’s Anatomy, sadly, has not survived, so it is impossible to intended ‘to harmonize with Carter’s original figures’. They successfully
be sure how much of the finished version had actually been written by emulated Carter’s verve. Having fewer pages and lighter paper, the 1905
Holmes. (sixteenth edition) weighed less than its predecessor, at 4 lb 11 oz/2.1 kg.
It may be that Gray’s glittering career, or perhaps the patronage that Typographically, the new edition was superb.
unquestionably advanced it, created jealousies among his colleagues, Howden took over as sole editor in 1909 (seventeenth edition) and
or that there was something in Gray’s manner that precluded affection, immediately stamped his personality on Gray’s. He excised ‘Surgical’
or that created resentments among clever social inferiors like Carter and from the title, changing it to Anatomy Descriptive and Applied, and
Holmes, especially if they felt their contributions to his brilliant career removed Carter’s name altogether. He also instigated the beginnings of


were not given adequate credit. Whatever the explanation, no reference an editorial board of experts for Gray’s, by adding to the title page ‘Notes
to Gray’s life or death appeared in Gray’s Anatomy itself until the twen- on Applied Anatomy’ by AJ Jex-Blake and W Fedde Fedden, both St
tieth century (Howden et al 1918). George’s men. For the first time, the number of illustrations exceeded
one thousand. Howden was responsible for the significant innovation
A SUCCESSION OF EDITORS of a short historical note on Henry Gray himself, nearly 60 years after
his death, which included a portrait photograph (1918, twentieth
Holmes expanded areas of the book that Gray himself had developed edition).
in the second edition (1860), notably in ‘general’ anatomy (histology)
and ‘development’ (embryology). In Holmes’s time as Editor, the THE NOMENCLATURE CONTROVERSY
volume grew from 788 pages in 1864 to 960 in 1880 (ninth edition),
with the histological section paginated separately in roman numerals Howden’s era, and that of his successor TB Johnston (of Guy’s), was
at the front of the book. Extra illustrations were added, mainly from overshadowed by a cloud of international controversy concerning ana-
other published sources. tomical terminology. European anatomists were endeavouring to stand-
The connections with Gray and Carter, and with St George’s, were ardize anatomical terms, often using Latinate constructions, a move
maintained with the appointment of the next editor, T. Pickering Pick, resisted in Britain and the United States. Gray’s became mired in these
who had been a student at St George’s in Gray’s time. From 1883 (tenth debates for over 20 years. The attempt to be fair to all sides by using
edition) onwards, Pick kept up with current research, rewrote and inte- multiple terms doubtless generated much confusion amongst students,
grated the histology and embryology into the volume, dropped Holmes until a working compromise was at last arrived at in 1955 (thirty-second
from the title page, removed Gray’s preface to the first edition, and edition, 1958).
added bold subheadings, which certainly improved the appearance and Johnston oversaw the second retitling of the book (in 1938, twenty-


accessibility of the text. Pick said he had ‘tried to keep before himself seventh edition): it was now, officially, Gray’s Anatomy, finally ending
the fact that the work is intended for students of anatomy rather than the fiction that it had ever been known as anything else. Gray’s suffered
for the Scientific Anatomist’ (thirteenth edition, 1893). from paper shortages and printing difficulties in World War II, but suc-
Pick also introduced colour printing (in 1887, eleventh edition) and cessive editions nevertheless continued to grow in size and weight,
experimented with the addition of illustrations using the new printing while illustrations were replaced and added as the text was revised.
method of half-tone dots: for colour (which worked) and for new black- Between Howden’s first sole effort (1909, seventeenth edition) and
and-white illustrations (which did not). Half-tone shades of grey com- Johnston’s last edition (1958, thirty-second edition), Gray’s expanded
pared poorly with Carter’s wood engravings, still sharp and clear by by over 300 pages – from 1296 to 1604 pages, and almost 300 addi-
comparison. tional illustrations brought the total to over 1300. Johnston also intro-
What Henry Vandyke Carter made of these changes is a rich topic duced X-ray plates (1938) and, in 1958 (thirty-second edition), electron
for speculation. He returned to England in 1888, having retired from micrographs by AS Fitton-Jackson, one of the first occasions on which
the Indian Medical Service, full of honours – Deputy Surgeon General, a woman was credited with a contribution to Gray’s. Johnston felt com-
and in 1890, he was made Honorary Surgeon to Queen Victoria. Carter pelled to mention that she was ‘a blood relative of Henry Gray himself’,
had continued researching throughout his clinical medical career in perhaps by way of mitigation.
India, and became one of India’s foremost bacteriologists/tropical
disease specialists before there was really a name for either discipline. AFTER WORLD WAR II
Carter made some important discoveries, including the fungal cause of
mycetoma, which he described and named. He was also a key figure in The editions of Gray’s issued in the decades immediately following the
confirming scientifically in India some major international discoveries, Second World War give the impression of intellectual stagnation. Steady


such as Hansen’s discovery of the cause of leprosy, Koch’s discovery of expansion continued in an almost formulaic fashion, with the insertion
the organism causing tuberculosis, and Laveran’s discovery of the organ- of additional detail. The central historical importance of innovation in
ism that causes malaria. Carter married late in life, and his wife was left the success of Gray’s seems to have been lost sight of by its publishers
with two young children when he died in Scarborough in 1897, aged and editors – Johnston (1930–1958, twenty-fourth to thirty-second
65. Like Gray, he received no obituary in the book. editions), J Whillis (co-editor with Johnston, 1938–1954), DV Davies
When Pick was joined on the title page by Robert Howden (a profes- (1958–1967, thirty-second to thirty-fourth editions) and F Davies
sional anatomist from the University of Durham) in 1901 (fifteenth (co-editor with DV Davies 1958–1962, thirty-second to thirty-third
edition), the volume was still easily recognizable as the book Gray and editions). Gray’s had become so pre-eminent that perhaps complacency
Carter had created. Although many of Carter’s illustrations had been crept in, or editors were too daunted or too busy to confront the
revised or replaced, many others still remained. Sadly, though, an entire ‘massive undertaking’ of a root and branch revision (Tansey 1995). The
section (embryology) was again separately paginated, as its revision had unexpected deaths of three major figures associated with Gray’s in this
taken longer than anticipated. Gray’s had grown, seemingly inexorably, era, James Whillis, Francis Davies and David Vaughan Davies – each of
and was now quite thick and heavy: 1244 pages, weighing 5 lb whom had been ready to take the editorial reins – may have contributed
8 oz/2.5 kg. Both co-editors, and perhaps also its publisher, were dis- to retarding the process. The work became somewhat dull.
satisfied with it.
KEY EDITION: 1973
KEY EDITION: 1905
DV Davies had recognized the need for modernization, but his unex-
Serious decisions were taken well in advance of the next edition, which pected death left the work to other hands. Two Professors of Anatomy


turned out to be Pick’s last with Howden. Published 50 years after Gray at Guy’s, Roger Warwick and Peter Williams, the latter of whom had
had first suggested the idea to Carter, the 1905 (sixteenth) edition was been involved as an indexer for Gray’s for several years, regarded it as
a landmark one. an honour to fulfill Davies’s intentions.
The period 1880–1930 was a difficult time for anatomical illustra- Their thirty-fifth edition of 1973 was a significant departure from
tion, because the new techniques of photo-lithography and half-tone tradition. Over 780 pages (of 1471) were newly written, almost a third e7


Historical introduction
of the illustrations were newly commissioned, and the illustration cap- had developed a distinct character of its own in the interval), and sold
tions were freshly written throughout. With a complete re-typesetting extremely well there (Williams and Warwick 1973).
of the text in larger double-column pages, a new index and the innova- The influence of the Warwick and Williams edition was forceful and
tion of a bibliography, this edition of Gray’s looked and felt quite unlike long-lasting, and set a new pattern for the following quarter-century.
its 1967 (thirty-fourth edition) predecessor, and much more like its As has transpired several times before, wittingly or unwittingly, a new
modern incarnation. editor was being prepared for the future: Dr Susan Standring (of
This 1973 edition departed from earlier volumes in other significant Guy’s), who created the new bibliography for the 1973 edition of
ways. The editors made explicit their intention to try to counter the Gray’s, went on to serve on the editorial board, and has served as
impetus towards specialization and compartmentalization in twentieth- Editor-in-Chief for the last two editions before this one (2005–2008,
century medicine, by embracing and attempting to reintegrate the com- thirty-ninth and fortieth editions). Both editions are important for dif-
plexity of the available knowledge. Warwick and Williams openly ferent reasons.
renounced the pose of omniscience adopted by many textbooks, believ- For the thirty-ninth edition, the entire content of Gray’s was reorgan-
ing it important to accept and mention areas of ignorance or uncer- ized, from systematic to regional anatomy. This great sea-change was
tainty. They shared with the reader the difficulty of keeping abreast in not just organizational but historic, because, since its outset, Gray’s had
the sea of research, and accepted with a refreshing humility the impos- prioritized bodily systems, with subsidiary emphasis on how the
sibility of fulfilling their own ambitious programme. systems interweave in the regions of the body. Professor Standring
Warwick and Williams’s 1973 edition had much in common with explained that this regional change of emphasis had long been asked
Gray and Carter’s first edition. It was bold and innovative – respectful for by readers and users of Gray’s, and that new imaging techniques in


of its heritage, while also striking out into new territory. It was visually our era have raised the clinical importance of local anatomy (Standring
attractive and visually informative. It embodied a sense of a treasury of 2005). The change was facilitated by an enormous collective effort on
information laid out for the reader (Williams and Warwick 1973). It the part of the editorial team and the illustrators. The subsequent and
was published simultaneously in the United States (the American Gray’s current editions consolidate that momentous change. (See Table 1.)
Table 1 Gray’s Anatomy Editions
Edition Date Author/Editor(s) Publisher Title
1st 1858 Henry Gray JW Parker & Son Anatomy Descriptive and Surgical
The drawings by Henry Vandyke Carter. The dissections jointly by
the author and Dr Carter
2nd 1860 Henry Gray JW Parker & Son
3rd 1864 T Holmes Longman
4th 1866 T Holmes Longman
5th 1869 T Holmes Longman
6th 1872 T Holmes Longman
7th 1875 T Holmes Longman
8th 1877 T Holmes Longman
9th 1880 T Holmes Longman
10th 1883 TP Pick Longman
11th 1887 TP Pick Longman
12th 1890 TP Pick Longman
13th 1893 TP Pick Longman
Gray’s preface removed
14th 1897 TP Pick Longman
15th 1901 TP Pick & R Howden Longman
16th 1905 TP Pick & R Howden Longman
17th 1909 Robert Howden Longman Anatomy Descriptive and Applied
Notes on applied anatomy by AJ Jex-Blake & W Fedde Fedden
18th 1913 Robert Howden & Blake & Fedden Longman
19th 1916 Robert Howden & Blake & Fedden Longman
20th 1918 Robert Howden & Blake & Fedden Longman
First edition ever to feature a photograph and obituary of Henry Gray
21st 1920 Robert Howden Longman
Notes on applied anatomy by AJ Jex-Blake & John Clay
22nd 1923 Robert Howden Longman
Notes on applied anatomy by John Clay & John D Lickley
23rd 1926 Robert Howden Longman
24th 1930 TB Johnston Longman
25th 1932 TB Johnston Longman


26th 1935 TB Johnston Longman
27th 1938 TB Johnston & J Whillis Longman Gray’s Anatomy
28th 1942 TB Johnston & J Whillis Longman
29th 1946 TB Johnston & J Whillis Longman
30th 1949 TB Johnston & J Whillis Longman
31st 1954 TB Johnston & J Whillis Longman
32nd 1958 TB Johnston & DV Davies & F Davies Longman
33rd 1962 DV Davies & F Davies Longman
34th 1967 DV Davies & RE Coupland Longman
35th 1973 Peter L Williams & Roger Warwick Longman
With a separate volume: Functional Neuroanatomy of Man – being the
neurology section of Gray’s Anatomy. 35th edition, 1975
36th 1980 Roger Warwick & Peter L Williams Churchill Livingstone
37th 1989 Peter L Williams Churchill Livingstone
38th 1995 Peter L Williams & Editorial Board Churchill Livingstone
39th 2005 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice
40th 2008 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice
41st 2015 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice
e8


Historical introduction
THE DOCTORS’ BIBLE Howden R, Jex-Blake AJ, Fedde Fedden W (eds) 1918 Gray’s Anatomy, 20th
ed. London: Longman.
Neither Gray nor Carter, the young men who – by their committed hard
Lewis H Sinclair 1925 Arrowsmith. New York: Harcourt Brace; p. 4.
work between 1856 and 1858 – created the original Gray’s Anatomy,
Nicol KE 2002 Henry Gray of St George’s Hospital: a Chronology. London:
would have conceived that so many years after their deaths their book
published by the author.
would not only be a household name, but also be regarded as a work
of such pre-eminent importance that a novelist half a world away would Quain J 1856 Elements of Anatomy. Ed. by Sharpey W, Ellis GV. London:
rank it as cardinal – alongside the Bible and Shakespeare – to a doctor’s Walton & Maberly.
education (Sinclair Lewis 1925, Richardson 2008). From this forty-first Richardson R 2000 Death, Dissection and the Destitute. Chicago: Chicago
edition of Gray’s Anatomy, we can look back to appraise the long-term University Press; pp. 193–249, 287, 357.
value of their efforts. We can discern how the book they created tri-
Richardson R 2008 The Making of Mr Gray’s Anatomy. Oxford: Oxford
umphed over its competitors, and has survived pre-eminent. Gray’s is a University Press.
remarkable publishing phenomenon. Although the volume now looks
Standring S (ed.) 2005 Preface. In: Gray’s Anatomy, 39th ed. Elsevier:
quite different to the original, and contains so much more, its kinship
London.
with the Gray’s Anatomy of 1858 is easily demonstrable by direct descent,
every edition updated by Henry Gray’s successor. Works are rare indeed Tansey EM 1995 A brief history of Gray’s Anatomy. In: Gray’s Anatomy, 38th
that have had such a long history of continuous publication on both ed. London: Churchill Livingstone.
sides of the Atlantic, and such a useful one. Williams PL, Warwick R (eds.) 1973 Preface. In: Gray’s Anatomy, 35th ed.
London: Churchill Livingstone.


Ruth Richardson, MA, DPhil, FRHistS
Senior Visiting Research Fellow, Centre for Life-Writing Research, ACKNOWLEDGEMENTS
King’s College London;
Affiliated Scholar in the History and Philosophy of Science, For their assistance while I was undertaking the research for this essay,
University of Cambridge, UK I should like to thank the Librarians and Archivists and Staff at the
British Library, Society of Apothecaries, London School of Hygiene and
Tropical Medicine, Royal College of Surgeons, Royal Society of Medi-
REFERENCES
cine, St Bride Printing Library, St George’s Hospital Tooting, Scarbor-
Anon 1908 Henry Gray. St George’s Hospital Gazette 16:49–54. ough City Museum and Art Gallery, University of Reading, Wellcome
Institute Library, Westminster City Archives and Windsor Castle; and
Carter HV 1855 Diary. Wellcome Western Manuscript 5818; 25 Nov.
the following individuals: Anne Bayliss, Gordon Bell, David Buchanan,
Gray H 1858 Preface. In: Anatomy: Descriptive and Surgical. London: JW Dee Cook, Arthur Credland, Chris Hamlin, Victoria Killick, Louise King,
Parker & Son. Keith Nicol, Sarah Potts, Mark Smalley, and Nallini Thevakarrunai.
Holmes T (ed.) 1860 I: Preface. In: A System of Surgery. London: JW Parker Above all, my thanks to Brian Hurwitz, who has read and advised on
& Son. the evolving text.
e9


ANATOMICAL NOMENCLATURE
Anatomy is the study of the structure of the body. Conventionally, it is with the median plane; although often employed, ‘parasagittal’ is there-
divided into topographical (macroscopic or gross) anatomy (which fore redundant and should not be used. The coronal (frontal) plane is
may be further divided into regional anatomy, surface anatomy, neuro- orthogonal to the median plane and divides the body into anterior
anatomy, endoscopic and imaging anatomy); developmental anatomy (front) and posterior (back). The horizontal (transverse) plane is
(embryogenesis and subsequent organogenesis); and the anatomy of orthogonal to both median and sagittal planes. Radiologists refer to
microscopic and submicroscopic structure (histology). transverse planes as (trans)axial; convention dictates that axial anatomy
Anatomical language is one of the fundamental languages of medi- is viewed as though looking from the feet towards the head.
cine. The unambiguous description of thousands of structures is impos- Structures nearer the head are superior, cranial or (sometimes)
sible without an extensive and often highly specialized vocabulary. cephalic (cephalad), whereas structures closer to the feet are inferior;
Ideally, these terms, which are often derived from Latin or Greek, caudal is most often used in embryology to refer to the hind end of the
should be used to the exclusion of any other, and eponyms should be embryo. Medial and lateral indicate closeness to the median plane,
avoided. In reality, this does not always happen. Many terms are ver- medial being closer than lateral; in the anatomical position, the little
nacularized and, around the world, synonyms and eponyms still finger is medial to the thumb, and the great toe is medial to the little
abound in the literature, in medical undergraduate classrooms and in toe. Specialized terms may also be used to indicate medial and lateral.
clinics. The Terminologia Anatomica,1 drawn up by the Federative Com- Thus, in the upper limb, ulnar and radial are used to mean medial and
mittee on Anatomical Terminology (FCAT) in 1998, continues to serve lateral, respectively; in the lower limb, tibial and fibular (peroneal) are


as our reference source for the terminology for macroscopic anatomy, used to mean medial and lateral, respectively. Terms may be based on
and the text of the forty-first edition of Gray’s Anatomy is almost entirely embryological relationships; the border of the upper limb that includes
TA-compliant. However, where terminology is at variance with, or, more the thumb, and the border of the lower limb that includes the great toe
likely, is not included in, the TA, the alternative term used either is cited are the pre-axial borders, whilst the opposite borders are the post-axial
in the relevant consensus document or position paper, or enjoys wide- borders. Various degrees of obliquity are acknowledged using com-
spread clinical usage. Synonyms and eponyms are given in parentheses pound terms, e.g. posterolateral.
on first usage of a preferred term and not shown thereafter in the text; When referring to structures in the trunk and upper limb, we have
an updated list of eponyms and short biographical details of the clini- freely used the synonyms anterior, ventral, flexor, palmar and volar, and
cians and anatomists whose names are used in this way is available in posterior, dorsal and extensor. We recognize that these synonyms are
the e-book for reference purposes (see Preface, p. ix, for further discus- not always satisfactory, e.g. the extensor aspect of the leg is anterior with
sion of the use of eponyms). respect to the knee and ankle joints, and superior in the foot and digits;
the plantar (flexor) aspect of the foot is inferior. Dorsal (dorsum) and
PLANES, DIRECTIONS AND ventral are terms used particularly by embryologists and neuroanato-
RELATIONSHIPS mists; they therefore feature most often in Sections 2 and 3.
Distal and proximal are used particularly to describe structures in
To avoid ambiguity, all anatomical descriptions assume that the body the limbs, taking the datum point as the attachment of the limb to the
is in the conventional ‘anatomical position’, i.e. standing erect and trunk (sometimes referred to as the root), such that a proximal structure
facing forwards, upper limbs by the side with the palms facing forwards, is closer to the attachment of the limb than a distal structure. However,


and lower limbs together with the toes facing forwards (Fig. 1). Descrip- proximal and distal are also used in describing branching structures,
tions are based on four imaginary planes – median, sagittal, coronal e.g. bronchi, vessels and nerves. External (outer) and internal (inner)
and horizontal – applied to a body in the anatomical position. The refer to the distance from the centre of an organ or cavity, e.g. the layers
median plane passes longitudinally through the body and divides it of the body wall, or the cortex and medulla of the kidney. Superficial
into right and left halves. The sagittal plane is any vertical plane parallel and deep are used to describe the relationships between adjacent struc-
tures. Ipsilateral refers to the same side (of the body, organ or structure),
bilateral to both sides, and contralateral to the opposite side.
Teeth are described using specific terms that indicate their relation-
1Terminologia Anatomica (1998) is the joint creation of the Federative Committee on
Anatomical Terminology (FCAT) and the Member Associations of the Interna- ship to their neighbours and to their position within the dental arch;
tional Federation of Associations of Anatomists (IFAA). these terms are described on page 517.
xvi


AnAtomicAl nomenclAture
SUPERIOR ASPECT
Coronal plane
Anterior or ventral
Posterior or dorsal
Median or sagittal plane
Inferior or caudal
Superior or cranial
Transverse or horizontal plane Lateral
Medial
POSTERIOR ASPECT
RIGHT LATERAL ASPECT
Lateral (external) rotation
Medial (internal) rotation
Proximally
Distally
Proximally
LEFT LATERAL ASPECT
ANTERIOR ASPECT Supination
Pronation
Distally
Lateral (external) rotation
Medial (internal) rotation
Eversion
Inversion
INFERIOR ASPECT
Fig. 1 The terminology widely used in descriptive anatomy. Abbreviations shown on arrows: AD, adduction; AB, abduction; FLEX, flexion (of the thigh at
the hip joint); EXT, extension (of the leg at the knee joint).
xvii


BIBLIOGRAPHY OF SELECTED TITLES
The following references contain information relevant to numerous Haaga JR, Dogra VS, Forsting M, Gilkeson RC, Ha KH, Sundaram M
chapters in this edition. They are therefore cited here rather than at the 2009 CT and MR Imaging of the Whole Body, 5th ed. St Louis:
end of individual chapters. For an extended historical bibliography, all Elsevier, Mosby.
references from the thirtyeighth edition (which includes all references Lasjaunias P, Berenstein A, ter Brugge K 2001 Surgical Neuroangio
cited in earlier editions, up to and including the thirtyeighth edition) graphy, vol 1. Clinical Vascular Anatomy and Variations, 2nd ed. Berlin,
are available in the ebook that accompanies Gray’s Anatomy. New York: Springer.
Meyers MA 2000 Dynamic Radiology of the Abdomen: Normal and
TERMINOLOGY
Pathologic Anatomy, 5th ed. New York: Springer.
Federative Committee on Anatomical Terminology 1998 Terminologia Pomeranz SJ 1992 MRI Total Body Atlas. Cincinnati: MRIEFI.
Anatomica: International Anatomical Nomenclature. Stuttgart: Thieme. Spratt JD, Salkowski LR, Weir J, Abrahams PH 2010 Imaging Atlas of
Dorland WAN 2011 Dorland’s Illustrated Medical Dictionary, 32nd ed. Human Anatomy, 4th ed. London: Elsevier, Mosby.
Philadelphia: Elsevier, WB Saunders. Sutton D, Reznek R, Murfitt J 2002 Textbook of Radiology and Imaging,
7th ed. Edinburgh: Elsevier, Churchill Livingstone.
BASIC SCIENCES
Whaites E, Drage N 2013 Essentials of Dental Radiography and Radiol
ogy, 5th ed. Edinburgh: Elsevier, Churchill Livingstone.
Abrahams P, Spratt JD, Loukas M, van Schoor AN 2013 McMinn and
Abrahams’ Clinical Atlas of Human Anatomy: with STUDENT CONSULT Wicke L 2004 Atlas of Radiologic Anatomy, 7th ed. Philadelphia:
Online Access, 7th ed. London: Elsevier, Mosby. Elsevier, WB Saunders.


Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P 2007 Molecu
CLINICAL
lar Biology of the Cell, 5th ed. New York: Garland Science.
Berkovitz BKB, Kirsch C, Moxham BJ, Alusi G, Cheeseman T 2002 Birch R 2010 Surgical Disorders of the Peripheral Nerves, 2nd ed. Edin
Interactive Head and Neck. London: Primal Pictures. burgh: Elsevier, Churchill Livingstone.
Boron WF, Boulpaep E 2012 Medical Physiology: with STUDENT Bogduk N 2012 Clinical and Radiological Anatomy of the Lumbar
CONSULT Online Access, 2nd ed. Philadelphia: Elsevier, WB Spine, 5th ed. Edinburgh: Elsevier, Churchill Livingstone.
Saunders.
Borges AF 1984 Relaxed skin tension lines (RSTL) versus other skin
Crossman AR 2014 Neuroanatomy: An Illustrated Colour Text, 5th ed. lines. Plast Reconstr Surg 73:144–50.
Edinburgh: Elsevier, Churchill Livingstone.
Burnand KG, Young AE, Lucas JD, Rowlands B, Scholefield J 2005 The
Fitzgerald MD 2011 Clinical Neuroanatomy and Neuroscience: with New Aird’s Companion in Surgical Studies, 3rd ed. Edinburgh: Elsevier,
STUDENT CONSULT Online Access, 6th ed. Edinburgh: Elsevier, Churchill Livingstone.
Saunders.
Canale ST, Beaty JH 2012 Campbell’s Operative Orthopaedics, 12th ed.
Hall JE 2010 Guyton and Hall Textbook of Medical Physiology: with Philadelphia: Elsevier, Mosby.
STUDENT CONSULT Online Access, 12th ed. Philadelphia: Elsevier,
Cormack GC, Lamberty BGH 1994 The Arterial Anatomy of Skin Flaps,
Saunders.
2nd ed. Edinburgh: Elsevier, Churchill Livingstone.
Kerr JB 2010 Functional Histology, 2nd ed. London: Elsevier, Mosby.
Cramer GD, Darby SA 2013 Clinical Anatomy of the Spine, Spinal Cord,
Kierszenbaum AL 2014 Histology and Cell Biology: An Introduction to and ANS, 3rd ed. MO: Elsevier, Mosby.


Pathology, 4th ed. St Louis: Elsevier, Mosby.
Dyck PJ, Thomas PK 2005 Peripheral Neuropathy: 2Volume Set with
Lowe JS, Anderson PG 2014 Stevens & Lowe’s Human Histology, Expert Consult Basic, 4th ed. Philadelphia: Elsevier, WB Saunders.
4th ed. London: Elsevier, Mosby.
Ellis H, Mahadevan V 2013 Clinical Anatomy: Applied Anatomy for
Male D, Brostoff J, Roth D, Roitt I 2012 Immunology: with STUDENT Students and Junior Doctors, 13th ed. WileyBlackwell.
CONSULT Online Access, 8th ed. London: Elsevier, Mosby.
Ellis H Feldman S, HarropGriffiths W 2004 Anatomy for Anaesthetists,
Moore KL, Persaud TVN, Torchia MG 2015 Before We Are Born: Essen 8th ed. Oxford: Blackwell Science.
tials of Embryology and Birth Defects, 9th ed. St Louis: Elsevier.
Morris SF, Taylor GI 2013 Vascular territories. In: Neligan PC (ed.)
Pollard TD, Earnshaw WC 2007 Cell Biology: with STUDENT CONSULT Plastic Surgery, vol. I. Principles, 3rd ed. London: Elsevier, Saunders.
Access, 2nd ed. Philadelphia: Elsevier, WB Saunders.
Rosai J 2011 Rosai and Ackerman’s Surgical Pathology, 10th ed. London:
Salmon M 1994 Anatomic Studies: Book 1 Arteries of the Muscles of Elsevier, Mosby.
the Extremities and the Trunk, Book 2 Arterial Anastomotic Pathways
Shah J 2012 Jatin Shah’s Head and Neck Surgery and Oncology: Expert
of the Extremities. Ed. by Taylor GI, Razaboni RM. St Louis: Quality
Consult Online and Print, 4th ed. London: Elsevier, Mosby.
Medical.
Zancolli EA, Cozzi EP 1991 Atlas of Surgical Anatomy of the Hand.
Young B, O’Dowd G, Woodford P 2013 Wheater’s Functional Histology:
Edinburgh: Elsevier, Churchill Livingstone.
A Text and Colour Atlas, 6th ed. Edinburgh: Elsevier, Churchill


Livingstone.
CLINICAL EXAMINATION
IMAGING AND RADIOLOGY/RADIOLOGICAL
O’Brien M 2010 Aids to the Examination of the Peripheral Nervous
ANATOMY System, 5th ed. London: Elsevier, WB Saunders.
Lumley JSP 2008 Surface Anatomy: The Anatomical Basis of Clinical
Butler P, Mitchell AWM, Healy JC 2011 Applied Radiological Anatomy,
Examination, 4th ed. Edinburgh: Elsevier, Churchill Livingstone.
2nd ed. New York: Cambridge University Press.
Ellis H, Logan BM, Dixon AK 2007 Human Sectional Anatomy: Pocket
xviii Atlas of Body Sections, CT and MRI Images, 3rd ed. CRC Press.


4
1
NOITCES
CHAPTER
1
Basic structure and function of cells
Epithelial cells rarely operate independently of each other and com-
CELL STRUCTURE
monly form aggregates by adhesion, often assisted by specialized inter-
cellular junctions. They may also communicate with each other either
GENERAL CHARACTERISTICS OF CELLS by generating and detecting molecular signals that diffuse across inter-
cellular spaces, or more rapidly by generating interactions between
The shapes of mammalian cells vary widely depending on their interac- membrane-bound signalling molecules. Cohesive groups of cells con-
tions with each other, their extracellular environment and internal stitute tissues, and more complex assemblies of tissues form functional
structures. Their surfaces are often highly folded when absorptive or systems or organs.
transport functions take place across their boundaries. Cell size is Most cells are between 5 and 50 µm in diameter: e.g. resting lym-
limited by rates of diffusion, either that of material entering or leaving phocytes are 6 µm across, red blood cells 7.5 µm and columnar epithe-
cells, or that of diffusion within them. Movement of macromolecules lial cells 20 µm tall and 10 µm wide (all measurements are approximate).
can be much accelerated and also directed by processes of active trans- Some cells are much larger than this: e.g. megakaryocytes of the bone
port across the plasma membrane and by transport mechanisms within marrow and osteoclasts of the remodelling bone are more than 200 µm
the cell. According to the location of absorptive or transport functions, in diameter. Neurones and skeletal muscle cells have relatively extended
apical microvilli (Fig. 1.1) or basolateral infoldings create a large shapes, some of the former being over 1 m in length.
surface area for transport or diffusion.
Motility is a characteristic of most cells, in the form of movements
of cytoplasm or specific organelles from one part of the cell to another. CELLULAR ORGANIZATION
It also includes: the extension of parts of the cell surface such as pseu-
dopodia, lamellipodia, filopodia and microvilli; locomotion of entire Each cell is contained within its limiting plasma membrane, which


cells, as in the amoeboid migration of tissue macrophages; the beating encloses the cytoplasm. All cells, except mature red blood cells, also
of flagella or cilia to move the cell (e.g. in spermatozoa) or fluids overly- contain a nucleus that is surrounded by a nuclear membrane or enve-
ing it (e.g. in respiratory epithelium); cell division; and muscle contrac- lope (see Fig. 1.1; Fig. 1.2). The nucleus includes: the genome of the
tion. Cell movements are also involved in the uptake of materials from cell contained within the chromosomes; the nucleolus; and other sub-
their environment (endocytosis, phagocytosis) and the passage of large nuclear structures. The cytoplasm contains cytomembranes and several
molecular complexes out of cells (exocytosis, secretion). membrane-bound structures, called organelles, which form separate
Surface projections
(cilia, microvilli)
Surface invagination
Actin filaments
Vesicle Mitochondrion
Cell junctions
Plasma membrane
Desmosome Peroxisomes
Cytosol
Nuclear pore
Intermediate
filaments Nuclear envelope
Smooth endoplasmic Nucleus
reticulum
Nucleolus
Ribosome
Rough endoplasmic
reticulum
Microtubules
Golgi apparatus Centriole pair
Lysosomes
Cell surface folds
Fig . 1 .1 The main structural components and internal organization of a generalized cell .


Cell structure
5
1
RETPaHC
CC MMVV AAPPMM
AAJJCC
Receptor
Transmembrane protein
pore complex
of proteins
Carbohydrate
residues
External
(extracellular)
surface
MM
MM
CCyy
LLPPMM
Internal
(intracellular)
surface
NN Lipid bilayer
appearance
in electron
microscope
Intrinsic
membrane
protein Extrinsic Transmembrane
protein
protein Transport Non-polar tail
or diffusion of phospholipid
channel Cytoskeletal
Polar end of
element
EENN phospholipid
Fig . 1 .3 The molecular organization of the plasma membrane, according
to the fluid mosaic model of membrane structure . Intrinsic or integral
membrane proteins include diffusion or transport channel complexes,
receptor proteins and adhesion molecules . These may span the thickness
of the membrane (transmembrane proteins) and can have both
extracellular and cytoplasmic domains . Transmembrane proteins have
hydrophobic zones, which cross the phospholipid bilayer and allow the
Fig . 1 .2 The structural organization and some principal organelles of a
protein to ‘float’ in the plane of the membrane . Some proteins are
typical cell . This example is a ciliated columnar epithelial cell from human
restricted in their freedom of movement where their cytoplasmic domains
nasal mucosa . The central cell, which occupies most of the field of
are tethered to the cytoskeleton .
view, is closely apposed to its neighbours along their lateral plasma
membranes . Within the apical junctional complex, these membranes form
a tightly sealed zone (tight junction) that isolates underlying tissues from,
charides and polysaccharides are bound either to proteins (glycopro-
in this instance, the nasal cavity . Abbreviations: AJC, apical junctional
teins) or to lipids (glycolipids), and project mainly into the extracellular
complex; APM, apical plasma membrane; C, cilia; Cy, cytoplasm; EN,
domain (Fig. 1.3).
euchromatic nucleus; LPM, lateral plasma membrane; M, mitochondria;
In the electron microscope, membranes fixed and contrasted by
MV, microvilli; N, nucleolus . (Courtesy of Dr Bart Wagner, Histopathology


heavy metals such as osmium tetroxide appear in section as two densely
Department, Sheffield Teaching Hospitals, UK .)
stained layers separated by an electron-translucent zone – the classic
unit membrane. The total thickness of each layer is about 7.5 nm. The
and distinct compartments within the cytoplasm. Cytomembranes
overall thickness of the plasma membrane is typically 15 nm. Freeze-
include the rough and smooth endoplasmic reticulum and Golgi appa-
fracture cleavage planes usually pass along the hydrophobic portion of
ratus, as well as vesicles derived from them. Organelles include lyso-
the bilayer, where the hydrophobic tails of phospholipids meet, and
somes, peroxisomes and mitochondria. The nucleus and mitochondria
split the bilayer into two leaflets. Each cleaved leaflet has a surface and
are enclosed by a double-membrane system; lysosomes and peroxi-
a face. The surface of each leaflet faces either the extracellular surface
somes have a single bounding membrane. There are also non-
(ES) or the intracellular or protoplasmic (cytoplasmic) surface (PS). The
membranous structures, called inclusions, which lie free in the cytosolic
extracellular face (EF) and protoplasmic face (PF) of each leaflet are
compartment. They include lipid droplets, glycogen aggregates and pig-
artificially produced during membrane splitting. This technique has
ments (e.g. lipofuscin). In addition, ribosomes and several filamentous
also demonstrated intramembranous particles embedded in the lipid
protein networks, known collectively as the cytoskeleton, are found in
bilayer; in most cases, these represent large transmembrane protein
the cytosol. The cytoskeleton determines general cell shape and sup-
molecules or complexes of proteins. Intramembranous particles are
ports specialized extensions of the cell surface (microvilli, cilia, flag-
distributed asymmetrically between the two half-layers, usually adher-
ella). It is involved in the assembly of specific structures (e.g. centrioles)
ing more to one half of the bilayer than to the other. In plasma mem-
and controls cargo transport in the cytoplasm. The cytosol contains
branes, the intracellular leaflet carries most particles, seen on its face


many soluble proteins, ions and metabolites.
(the PF). Where they have been identified, clusters of particles usually
represent channels for the transmembrane passage of ions or molecules
Plasma membrane
between adjacent cells (gap junctions).
Biophysical measurements show the lipid bilayer to be highly fluid,
Cells are enclosed by a distinct plasma membrane, which shares fea- allowing diffusion in the plane of the membrane. Thus proteins are able
tures with the cytomembrane system that compartmentalizes the cyto- to move freely in such planes unless anchored from within the cell.
plasm and surrounds the nucleus. All membranes are composed of Membranes in general, and the plasma membrane in particular, form
lipids (mainly phospholipids, cholesterol and glycolipids) and pro- boundaries selectively limiting diffusion and creating physiologically
teins, in approximately equal ratios. Plasma membrane lipids form a distinct compartments. Lipid bilayers are impermeable to hydrophilic
lipid bilayer, a layer two molecules thick. The hydrophobic ends of each solutes and ions, and so membranes actively control the passage of ions
lipid molecule face the interior of the membrane and the hydrophilic and small organic molecules such as nutrients, through the activity of
ends face outwards. Most proteins are embedded within, or float in, the membrane transport proteins. However, lipid-soluble substances can
lipid bilayer as a fluid mosaic. Some proteins, because of extensive pass directly through the membrane so that, for example, steroid hor-
hydrophobic regions of their polypeptide chains, span the entire width mones enter the cytoplasm freely. Their receptor proteins are either
of the membrane (transmembrane proteins), whereas others are only cytosolic or nuclear, rather than being located on the cell surface.
superficially attached to the bilayer by lipid groups. Both are integral Plasma membranes are able to generate electrochemical gradients
(intrinsic) membrane proteins, as distinct from peripheral (extrinsic) and potential differences by selective ion transport, and actively take up
membrane proteins, which are membrane-bound only through their or export small molecules by energy-dependent processes. They also
association with other proteins. Carbohydrates in the form of oligosac- provide surfaces for the attachment of enzymes, sites for the receptors


Basic structure and function of cells
5.e1
1
RETPaHC
Combinations of biochemical, biophysical and biological tech-
niques have revealed that lipids are not homogenously distributed in
membranes, but that some are organized into microdomains in the
bilayer, called ‘detergent-resistant membranes’ or lipid ‘rafts’, rich in
sphingomyelin and cholesterol. The ability of select subsets of proteins
to partition into different lipid microdomains has profound effects on
their function, e.g. in T-cell receptor and cell–cell signalling. The highly
organized environment of the domains provides a signalling, trafficking
and membrane fusion environment.


BaSIC STRuCTuRE aNd fuNCTION Of CEllS
6
1
NOITCES
of external signals, including hormones and other ligands, and sites for abundant proteins; SER is abundant in steroid-producing cells and
the recognition and attachment of other cells. Internally, plasma mem- muscle cells. A variant of the endoplasmic reticulum in muscle cells is
branes can act as points of attachment for intracellular structures, in the sarcoplasmic reticulum, involved in calcium storage and release for
particular those concerned with cell motility and other cytoskeletal muscle contraction. For further reading on the endoplasmic reticulum,
functions. Cell membranes are synthesized by the rough endoplasmic see Bravo et al (2013).
reticulum in conjunction with the Golgi apparatus.
Smooth endoplasmic reticulum
Cell coat (glycocalyx)
The smooth endoplasmic reticulum (see Fig. 1.4) is associated with
The external surface of a plasma membrane differs structurally from carbohydrate metabolism and many other metabolic processes, includ-
internal membranes in that it possesses an external, fuzzy, carbohydrate- ing detoxification and synthesis of lipids, cholesterol and steroids. The
rich coat, the glycocalyx. The cell coat forms an integral part of the membranes of the smooth endoplasmic reticulum serve as surfaces for
plasma membrane, projecting as a diffusely filamentous layer 2–20 nm the attachment of many enzyme systems, e.g. the enzyme cytochrome
or more from the lipoprotein surface. The cell coat is composed of the P450, which is involved in important detoxification mechanisms and
carbohydrate portions of glycoproteins and glycolipids embedded in is thus accessible to its substrates, which are generally lipophilic. The
the plasma membrane (see Fig. 1.3). membranes also cooperate with the rough endoplasmic reticulum
The precise composition of the glycocalyx varies with cell type; many and the Golgi apparatus to synthesize new membranes; the protein,
tissue- and cell type-specific antigens are located in the coat, including carbohydrate and lipid components are added in different structural
the major histocompatibility complex of the immune system and, in compartments. The smooth endoplasmic reticulum in hepatocytes con-


the case of erythrocytes, blood group antigens. Therefore, the glycocalyx tains the enzyme glucose-6-phosphatase, which converts glucose-6-
plays a significant role in organ transplant compatibility. The glycocalyx phosphate to glucose, a step in gluconeogenesis.
found on apical microvilli of enterocytes, the cells forming the lining
epithelium of the intestine, consists of enzymes involved in the diges- Rough endoplasmic reticulum
tive process. Intestinal microvilli are cylindrical projections (1–2 µm The rough endoplasmic reticulum is a site of protein synthesis; its
long and about 0.1 µm in diameter) forming a closely packed layer cytosolic surface is studded with ribosomes (Fig. 1.5E). Ribosomes only
called the brush border that increases the absorptive function of bind to the endoplasmic reticulum when proteins targeted for secretion
enterocytes. begin to be synthesized. Most proteins pass through its membranes and
accumulate within its cisternae, although some integral membrane pro-
Cytoplasm teins, e.g. plasma membrane receptors, are inserted into the rough
endoplasmic reticulum membrane, where they remain. After passage
Compartments and functional organization from the rough endoplasmic reticulum, proteins remain in membrane-
bound cytoplasmic organelles such as lysosomes, become incorporated
The cytoplasm consists of the cytosol, a gel-like material enclosed by
into new plasma membrane, or are secreted by the cell. Some carbohy-
the cell or plasma membrane. The cytosol is made up of colloidal pro-
drates are also synthesized by enzymes within the cavities of the rough
teins such as enzymes, carbohydrates and small protein molecules,
endoplasmic reticulum and may be attached to newly formed protein
together with ribosomes and ribonucleic acids. The cytoplasm contains
(glycosylation). Vesicles are budded off from the rough endoplasmic
two cytomembrane systems, the endoplasmic reticulum and Golgi
reticulum for transport to the Golgi as part of the protein-targeting
apparatus, as well as membrane-bound organelles (lysosomes, peroxi-
mechanism of the cell.
somes and mitochondria), membrane-free inclusions (lipid droplets,


glycogen and pigments) and the cytoskeleton. The nuclear contents, Ribosomes, polyribosomes
the nucleoplasm, are separated from the cytoplasm by the nuclear
and protein synthesis
envelope.
Ribosomes are macromolecular machines that catalyse the synthesis of
Endoplasmic reticulum proteins from amino acids; synthesis and assembly into subunits takes
The endoplasmic reticulum is a system of interconnecting membrane- place in the nucleolus and includes the association of ribosomal RNA
lined channels within the cytoplasm (Fig. 1.4). These channels take (rRNA) with ribosomal proteins translocated from their site of synthesis
various forms, including cisternae (flattened sacs), tubules and vesicles. in the cytoplasm. The individual subunits are then transported into the
The membranes divide the cytoplasm into two major compartments. cytoplasm, where they remain separate from each other when not
The intramembranous compartment, or cisternal space, is where secre- actively synthesizing proteins. Ribosomes are granules approximately
tory products are stored or transported to the Golgi complex and cell 25 nm in diameter, composed of rRNA molecules and proteins assem-
exterior. The cisternal space is continuous with the perinuclear space. bled into two unequal subunits. The subunits can be separated by their
Structurally, the channel system can be divided into rough or granu- sedimentation coefficients (S) in an ultracentrifuge into larger 60S and
lar endoplasmic reticulum (RER), which has ribosomes attached to its smaller 40S components. These are associated with 73 different pro-
outer, cytosolic surface, and smooth or agranular endoplasmic reticu- teins (40 in the large subunit and 33 in the small), which have structural
lum (SER), which lacks ribosomes. The functions of the endoplasmic and enzymatic functions. Three small, highly convoluted rRNA strands
reticulum vary greatly and include: the synthesis, folding and transport (28S, 5.8S and 5S) make up the large subunit, and one strand (18S) is
of proteins; synthesis and transport of phospholipids and steroids; and in the small subunit.


storage of calcium within the cisternal space and regulated release into A typical cell contains millions of ribosomes. They may form groups
the cytoplasm. In general, RER is well developed in cells that produce (polyribosomes or polysomes) attached to messenger RNA (mRNA),
which they translate during protein synthesis for use outside the system
of membrane compartments, e.g. enzymes of the cytosol and cytoskel-
etal proteins. Some of the cytosolic products include proteins that can
be inserted directly into (or through) membranes of selected organelles,
such as mitochondria and peroxisomes. Ribosomes may be attached to
the membranes of the rough endoplasmic reticulum (see Fig. 1.5E).
In a mature polyribosome, all the attachment sites of the mRNA are
occupied as ribosomes move along it, synthesizing protein according
to its nucleotide sequence. Consequently, the number and spacing of
ribosomes in a polyribosome indicate the length of the mRNA mole-
cule and hence the size of the protein being made. The two subunits
have separate roles in protein synthesis. The 40S subunit is the site of
attachment and translation of mRNA. The 60S subunit is responsible
for the release of the new protein and, where appropriate, attachment
to the endoplasmic reticulum via an intermediate docking protein that
directs the newly synthesized protein through the membrane into the
cisternal space.
Golgi apparatus (Golgi complex)
Fig . 1 .4 Smooth endoplasmic reticulum with associated vesicles . The The Golgi apparatus is a distinct cytomembrane system located near the
dense particles are glycogen granules . (Courtesy of Rose Watson, Cancer nucleus and the centrosome. It is particularly prominent in secretory
Research UK .) cells and can be visualized when stained with silver or other metallic


Basic structure and function of cells
6.e1
1
RETPaHC
The glycocalyx plays a significant role in maintenance of the integrity
of tissues and in a wide range of dynamic cellular processes, e.g. serving
as a vascular permeability barrier and transducing fluid shear stress to
the endothelial cell cytoskeleton (Weinbaum et al 2007). Disruption of
the glycocalyx on the endothelial surface of large blood vessels precedes
inflammation, a conditioning factor of atheromatosis (e.g. deposits of
cholesterol in the vascular wall leading to partial or complete obstruc-
tion of the vascular lumen).
Protein synthesis on ribosomes may be suppressed by a class of RNA
molecules known as small interfering RNA (siRNA) or silencing RNA.
These molecules are typically 20–25 nucleotides in length and bind (as
a complex with proteins) to specific mRNA molecules via their comple-
mentary sequence. This triggers the enzymatic destruction of the mRNA
or prevents the movement of ribosomes along it. Synthesis of the
encoded protein is thus prevented. Their normal function may have
antiviral or other protective effects; there is also potential for developing
artificial siRNAs as a therapeutic tool for silencing disease-related genes.


Cell structure
7
1
RETPaHC
A B
N
GG
V
GG M
C Phagocytic pathway Secretory pathway Membrane recycling Receptor-mediated endocytosis
Clathrin-coated pit
Early endosome
Late endosome
Lysosomal
fusion
Secondary lysosome
Residual body
Vesicle shuttling
between cisternae trans-Golgi network
Golgi cisternae
cis-Golgi network
Rough endoplasmic
reticulum
D E
G
R
Fig . 1 .5 The Golgi apparatus and functionally related organelles . A, Golgi apparatus (G) adjacent to the nucleus (N) (V, vesicle) . B, A large residual body
(tertiary lysosome) in a cardiac muscle cell (M, mitochondrion) . C, The functional relationships between the Golgi apparatus and associated cellular
structures . D, A three-dimensional reconstruction of the Golgi apparatus in a pancreatic β cell showing stacks of Golgi cisternae from the cis-face (pink)
and cis-medial cisternae (red, green) to the trans-Golgi network (blue, yellow, orange–red); immature proinsulin granules (condensing vesicles) are
shown in pale blue and mature (crystalline) insulin granules in dark blue . The flat colour areas represent cut faces of cisternae and vesicles . E, Rough
endoplasmic reticulum (R), associated with the Golgi apparatus (G) . (D, Courtesy of Dr Brad Marsh, Institute for Molecular Bioscience, University of
Queensland, Brisbane . A,B,E From human tissue, courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .)


BaSIC STRuCTuRE aNd fuNCTION Of CEllS
8
1
NOITCES
salts. Traffic between the endoplasmic reticulum and the Golgi appara- Endocytic (internalization) pathway
tus is bidirectional and takes place via carrier vesicles derived from the
The endocytic pathway begins at the plasma membrane and ends in
donor site that bud, tether and fuse with the target site.
lysosomes involved in the degradation of the endocytic cargo through
Golgins are long coiled-coil proteins attached to the cytoplasmic
the enzymatic activity of lysosomal hydrolases. Endocytic cargo is
surface of cisternal membranes, forming a fibrillar matrix surrounding
internalized from the plasma membrane to early endosomes and
the Golgi apparatus to stabilize it; they have a role in vesicle trafficking
then to late endosomes. Late endosomes transport their cargo to lyso-
(for further reading on golgins, see Munro 2011). The Golgi apparatus
somes, where the cargo material is degraded following fusion and
has several functions: it links anterograde and retrograde protein and
mixing of contents of endosomes and lysosomes. Early endosomes
lipid flow in the secretory pathway; it is the site where protein and lipid
derive from endocytic vesicles (clathrin-coated vesicles and caveolae).
glycosylation occurs; and it provides membrane platforms to which
Once internalized, endocytic vesicles shed their coat of adaptin and
signalling and sorting proteins bind.
clathrin, and fuse to form an early endosome, where the receptor
Ultrastructurally, the Golgi apparatus (Fig. 1.5A) displays a contin-
molecules release their bound ligands. Membrane and receptors from
uous ribbon-like structure consisting of a stack of several flattened
the early endosomes can be recycled to the cell surface as exocytic
membranous cisternae, together with clusters of vesicles surrounding
vesicles.
its surfaces. Cisternae differ in enzymatic content and activity. Small
Clathrin-dependent endocytosis occurs at specialized patches of
transport vesicles from the rough endoplasmic reticulum are received
plasma membrane called coated pits; this mechanism is also used to


at one face of the Golgi stack, the convex cis-face (entry or forming
internalize ligands bound to surface receptor molecules and is also
surface). Here, they deliver their contents to the first cisterna in the
termed receptor-mediated endocytosis. Caveolae (little caves) are struc-
series by membrane fusion. From the edges of this cisterna, the protein
turally distinct pinocytotic vesicles most widely used by endothelial and
is transported to the next cisterna by vesicular budding and then
smooth muscle cells, when they are involved in transcytosis, signal
fusion, and this process is repeated across medial cisternae until the
transduction and possibly other functions. In addition to late endo-
final cisterna at the concave trans-face (exit or condensing surface) is
somes, lysosomes can also fuse with phagosomes, autophagosomes
reached. Here, larger vesicles are formed for delivery to other parts of
and plasma membrane patches for membrane repair. Lysosomal hydro-
the cell.
lases process or degrade exogenous materials (phagocytosis or hetero-
The cis-Golgi and trans-Golgi membranous networks form an inte-
phagy) as well as endogenous material (autophagy). Phagocytosis
gral part of the Golgi apparatus. The cis-Golgi network is a region of
consists of the cellular uptake of invading pathogens, apoptotic cells
complex membranous channels interposed between the rough endo-
and other foreign material by specialized cells. Lysosomes are numerous
plasmic reticulum and the Golgi cis-face, which receives and transmits
in actively phagocytic cells, e.g. macrophages and neutrophil granulo-
vesicles in both directions. Its function is to select appropriate proteins
cytes, in which lysosomes are responsible for destroying phagocytosed
synthesized on the rough endoplasmic reticulum for delivery by vesicles
particles, e.g. bacteria. In these cells, the phagosome, a vesicle poten-
to the Golgi stack, while inappropriate proteins are shuttled back to the
tially containing a pathogenic microorganism, may fuse with several
rough endoplasmic reticulum.
lysosomes.
The trans-Golgi network, at the other side of the Golgi stack, is also


Autophagy involves the degradation and recycling within an
a region of interconnected membrane channels engaged in protein
autophagosome of cytoplasmic components that are no longer needed,
sorting. Here, modified proteins processed in the Golgi cisternae are
including organelles. The assembly of the autophagosome involves
packaged selectively into vesicles and dispatched to different parts of
several proteins, including autophagy-related (Atg) proteins, as well as
the cell. The packaging depends on the detection, by the trans-Golgi
Hsc70 chaperone, that translocate the substrate into the lysosome (Boya
network, of particular amino-acid signal sequences, leading to their
et al 2013). Autophagosomes sequester cytoplasmic components and
enclosure in membranes of appropriate composition that will further
then fuse with lysosomes without the participation of a late endosome.
modify their contents, e.g. by extracting water to concentrate them
The 26S proteasome (see below) is also involved in cellular degradation
(vesicles entering the exocytosis pathway) or by pumping in protons to
but autophagy refers specifically to a lysosomal degradation–recycling
acidify their contents (lysosomes destined for the intracellular sorting
pathway. Autophagosomes are seen in response to starvation and cell
pathway).
growth.
Within the Golgi stack proper, proteins undergo a series of sequen-
Late endosomes receive lysosomal enzymes from primary lysosomes
tial chemical modifications by Golgi resident enzymes synthesized
derived from the Golgi apparatus after late endosome–lysosome mem-
in the rough endoplasmic reticulum. These include: glycosylation
brane tethering and fusion followed by diffusion of lysosomal contents
(changes in glycosyl groups, e.g. removal of mannose, addition of
into the endosomal lumen. The pH inside the fused hybrid organelle,
N-acetylglucosamine and sialic acid); sulphation (addition of sulphate
now a secondary lysosome, is low (about 5.0) and this activates lyso-
groups to glycosaminoglycans); and phosphorylation (addition of
somal acid hydrolases to degrade the endosomal contents. The products
phosphate groups). Some modifications serve as signals to direct pro-
of hydrolysis either are passed through the membrane into the cytosol,


teins and lipids to their final destination within cells, including lyso-
or may be retained in the secondary lysosome. Secondary lysosomes
somes and plasma membrane. Lipids formed in the endoplasmic
may grow considerably in size by vesicle fusion to form multivesicular
reticulum are also routed for incorporation into vesicles.
bodies, and the enzyme concentration may increase greatly to form
large lysosomes (Fig. 1.5B).
Exocytic (secretory) pathway
Secreted proteins, lipids, glycoproteins, small molecules such as amines
Lysosomes
and other cellular products destined for export from the cell are trans-
ported to the plasma membrane in small vesicles released from the Lysosomes are membrane-bound organelles 80–800 nm in diameter,
trans-face of the Golgi apparatus. This pathway either is constitutive, in often with complex inclusions of material undergoing hydrolysis (sec-
which transport and secretion occur more or less continuously, as with ondary lysosomes). Two classes of proteins participate in lysosomal
immunoglobulins produced by plasma cells, or it is regulated by exter- function: soluble acid hydrolases and integral lysosomal membrane
nal signals, as in the control of salivary secretion by autonomic neural proteins. Each of the 50 known acid hydrolases (including proteases,
stimulation. In regulated secretion, the secretory product is stored tem- lipases, carbohydrases, esterases and nucleases) degrades a specific sub-
porarily in membrane-bound secretory granules or vesicles. Exocytosis strate. There are about 25 lysosomal membrane proteins participating
is achieved by fusion of the secretory vesicular membrane with the in the acidification of the lysosomal lumen, protein import from the
plasma membrane and release of the vesicle contents into the extracel- cytosol, membrane fusion and transport of degradation products to the
lular domain. In polarized cells, e.g. most epithelia, exocytosis occurs cytoplasm. Material that has been hydrolysed within secondary lyso-
at the apical plasma membrane. Glandular epithelial cells secrete into somes may be completely degraded to soluble products, e.g. amino
a duct lumen, as in the pancreas, or on to a free surface, such as the acids, which are recycled through metabolic pathways. However, degra-


lining of the stomach. In hepatocytes, bile is secreted across a very small dation is usually incomplete and some debris remains. A debris-laden
area of plasma membrane forming the wall of the bile canaliculus. This vesicle is called a residual body or tertiary lysosome (see Fig. 1.5B), and
region is defined as the apical plasma membrane and is the site of may be passed to the cell surface, where it is ejected by exocytosis;
exocrine secretion, whereas secretion of hepatocyte plasma proteins alternatively, it may persist inside the cell as an inert residual body.
into the blood stream is targeted to the basolateral surfaces facing the Considerable numbers of residual bodies can accumulate in long-lived
sinusoids. Packaging of different secretory products into appropriate cells, often fusing to form larger dense vacuoles with complex lamellar
vesicles takes place in the trans-Golgi network. Delivery of secretory inclusions. As their contents are often darkly pigmented, this may
vesicles to their correct plasma membrane domains is achieved by change the colour of the tissue; e.g. in neurones, the end-product of
sorting sequences in the cytoplasmic tails of vesicular membrane lysosomal digestion, lipofuscin (neuromelanin or senility pigment),
proteins. gives ageing brains a brownish-yellow colouration. Lysosomal enzymes


Basic structure and function of cells
8.e1
1
RETPaHC
Carrier vesicles in transit from the endoplasmic reticulum to the
Golgi apparatus (anterograde transport) are coated by coat protein
complex II (COPII), whereas COPI-containing vesicles function in the
retrograde transport route from the Golgi apparatus (reviewed in Spang
(2013)).
The membranes contain specific signal proteins that may allocate
them to microtubule-based transport pathways and allow them to dock
with appropriate targets elsewhere in the cell, e.g. the plasma mem-
brane in the case of secretory vesicles. Vesicle formation and budding
at the trans-Golgi network involves the addition of clathrin on their
external surface, to form coated pits.
Specialized cells of the immune system, called antigen-presenting
cells, degrade protein molecules, called antigens, transported by the
endocytic pathway for lysosomal breakdown, and expose their frag-
ments to the cell exterior to elicit an immune response mediated ini-
tially by helper T cells.


Cell structure
9
1
RETPaHC
may also be secreted – often as part of a process to alter the extracellular A
matrix, as in osteoclast-mediated erosion during bone resorption. For
further reading on lysosome biogenesis, see Saftig and Klumperman
(2009).
lysosomal dysfunction
Lysosomal storage diseases (LSDs) are a consequence of lysosomal
dysfunction. Approximately 60 different types of LSD have been identi-
fied on the basis of the type of material accumulated in cells (such as
mucopolysaccharides, sphingolipids, glycoproteins, glycogen and lipo-
fuscins). LSDs are characterized by severe neurodegeneration, mental
decline, and cognitive and behavioural abnormalities. Autophagy
impairment caused by defective lysosome–autophagosome coupling
triggers a pathogenic cascade by the accumulation of substrates that
contribute to neurodegenerative disorders including Parkinson’s dis-
ease, Alzheimer’s disease, Huntington’s disease and several tau-opathies.
Many lysosomal storage diseases are known, e.g. Tay–Sachs disease
(GM2 gangliosidosis), in which a faulty β-hexosaminidase A leads to
the accumulation of the glycosphingolipid GM2 ganglioside in neu-
rones, causing death during childhood. In Danon disease, a vacuolar
skeletal myopathy and cardiomyopathy with neurodegeneration in
hemizygous males, lysosomes fail to fuse with autophagosomes because
of a mutation of the lysosomal membrane protein LAMP-2 (lysosomal B
associated membrane protein-2).
26S proteasome
Outer membrane
A protein can be degraded by different mechanisms, depending on
the cell type and different pathological conditions. Furthermore, the
same substrate can engage different proteolytic pathways (Park and Inner membrane
Cuervo 2013). Three major protein degradation mechanisms operate
in eukaryotic cells to dispose of non-functional cellular proteins: Cristae (folds)
the autophagosome–lysosomal pathway (see above); the apoptotic
procaspase–caspase pathway (see below); and the ubiquitinated Elementary
particles
protein–26S proteasome pathway. The 26S proteasome is a multicata-


lytic protease found in the cytosol and the nucleus that degrades intra-
cellular proteins conjugated to a polyubiquitin chain by an enzymatic
cascade. The 26S proteasome consists of several subunits arranged into
two 19S polar caps, where protein recognition and adenosine 5′-
triphosphate (ATP)-dependent target processing occur, flanking a 20S
central barrel-shaped structure with an inner proteolytic chamber
(Tomko and Hochstrasser 2013). The 26S proteasome participates in
the removal of misfolded or abnormally assembled proteins, the deg-
radation of cyclins involved in the control of the cell cycle, the process-
ing and degradation of transcription regulators, cellular-mediated Fig . 1 .6 A, Mitochondria in human cardiac muscle . The folded cristae
immune responses, and cell cycle arrest and apoptosis. (arrows) project into the matrix from the inner mitochondrial membrane .
B, The location of the elementary particles that couple oxidation and
Peroxisomes
phosphorylation reactions . (A, Courtesy of Dr Bart Wagner,
Peroxisomes are small (0.2–1 µm in diameter) membrane-bound Histopathology Department, Sheffield Teaching Hospitals, UK .)
organelles present in most mammalian cells. They contain more than
50 enzymes responsible for multiple catabolic and synthetic biochemi-
cal pathways, in particular the β-oxidation of very-long-chain fatty Mitochondria
acids (>C22) and the metabolism of hydrogen peroxide (hence the In the electron microscope, mitochondria usually appear as round or
name peroxisome). Peroxisomes derive from the endoplasmic reticu- elliptical bodies 0.5–2.0 µm long (Fig. 1.6), consisting of an outer
lum through the transfer of proteins from the endoplasmic reticulum mitochondrial membrane; an inner mitochrondrial membrane, sepa-
to peroxisomes by vesicles that bud from specialized sites of the endo- rated from the outer membrane by an intermembrane space; cristae,
plasmic reticulum and by a lipid non-vesicular pathway. All matrix infoldings of the inner membrane that harbour ATP synthase to gener-


proteins and some peroxisomal membrane proteins are synthesized by ate ATP; and the mitochondrial matrix, a space enclosed by the inner
cytosolic ribosomes and contain a peroxisome targeting signal that membrane and numerous cristae. The permeability of the two mito-
enables them to be imported by proteins called peroxins (Braverman chondrial membranes differs considerably: the outer membrane is
et al 2013, Theodoulou et al 2013). Mature peroxisomes divide by freely permeable to many substances because of the presence of large
small daughter peroxisomes pinching off from a large parental non-specific channels formed by proteins (porins), whereas the inner
peroxisome. membrane is permeable to only a narrow range of molecules. The pres-
Peroxisomes often contain crystalline inclusions composed mainly ence of cardiolipin, a phospholipid, in the inner membrane may con-
of high concentrations of the enzyme urate oxidase. Oxidases use tribute to this relative impermeability.
molecular oxygen to oxidize specific organic substrates (such as L-amino Mitochondria are the principal source of chemical energy in most
acids, D-amino acids, urate, xanthine and very-long-chain fatty acids) cells. Mitochondria are the site of the citric acid (Krebs’) cycle and the
and produce hydrogen peroxide that is detoxified (degraded) by per- electron transport (cytochrome) pathway by which complex organic
oxisomal catalase. Peroxisomes are particularly numerous in hepato- molecules are finally oxidized to carbon dioxide and water. This process
cytes. Peroxisomes are important in the oxidative detoxification of provides the energy to drive the production of ATP from adenosine
various substances taken into or produced within cells, including diphosphate (ADP) and inorganic phosphate (oxidative phosphoryla-
ethanol. Peroxin mutation is a characteristic feature of Zellweger syn- tion). The various enzymes of the citric acid cycle are located in the
drome (craniofacial dysmorphism and malformations of brain, liver, mitochondrial matrix, whereas those of the cytochrome system and
eye and kidney; cerebrohepatorenal syndrome). Neonatal leukodystro- oxidative phosphorylation are localized chiefly in the inner mitochon-


phy is an X-linked peroxisomal disease affecting mostly males, caused drial membrane.
by deficiency in β-oxidation of very-long-chain fatty acids. The build-up The intermembrane space houses cytochrome c, a molecule involved
of very-long-chain fatty acids in the nervous system and suprarenal in activation of apoptosis.
glands determines progressive deterioration of brain function and The number of mitochondria in a particular cell reflects its general
suprarenal insufficiency (Addison’s disease). For further reading, see energy requirements; e.g. in hepatocytes there may be as many as 2000,
Braverman et al (2013). whereas in resting lymphocytes there are usually very few. Mature


Basic structure and function of cells
9.e1
1
RETPaHC
The transcription factor EB (TFEB) is responsible for regulating lyso-
somal biogenesis and function, lysosome-to-nucleus signalling and
lipid catabolism (for further reading, see Settembre et al (2013)). If any
of the actions of lysosomal hydrolases, of the lysosome acidification
mechanism or of lysosomal membrane proteins fails, the degradation
and recycling of extracellular substrates delivered to lysosomes by the
late endosome and the degradation and recycling of intracellular sub-
strates by autophagy lead to progressive lysosomal dysfunction in
several tissues and organs.
Experimentally, TFEB activation can reduce the accumulation of
the pathogenic protein in a cellular model of Huntington’s disease (a
neurodegenerative genetic disorder that affects muscle coordination)
and improves the Parkinson’s disease phenotype in a murine model.
Cristae are abundant in mitochondria seen in cardiac muscle
cells and in steroid-producing cells (in the suprarenal cortex, corpus
luteum and Leydig cells). The protein steroidogenic acute regulatory
protein (StAR) regulates the synthesis of steroids by transporting
cholesterol across the outer mitochondrial membrane. A mutation
in the gene encoding StAR causes defective suprarenal and gonadal
steroidogenesis.


BaSIC STRuCTuRE aNd fuNCTION Of CEllS
10
1
NOITCES
erythrocytes lack mitochondria altogether. Cells with few mitochondria ent and its electronic charge, and the potential difference across the
generally rely largely on glycolysis for their energy supplies. These membrane. These factors combine to produce an electrochemical gradi-
include some very active cells, e.g. fast twitch skeletal muscle fibres, ent, which governs ion flux. Channel proteins are utilized most effec-
which are able to work rapidly but for only a limited duration. Mito- tively by the excitable plasma membranes of nerve cells, where the
chondria appear in the light microscope as long, thin structures in the resting membrane potential can change transiently from about −80 mV
cytoplasm of most cells, particularly those with a high metabolic rate, (negative inside the cell) to +40 mV (positive inside the cell) when
e.g. secretory cells in exocrine glands. In living cells, mitochondria stimulated by a neurotransmitter (as a result of the opening and sub-
constantly change shape and intracellular position; they multiply by sequent closure of channels selectively permeable to sodium and
growth and fission, and may undergo fusion. potassium).
The mitochondrial matrix is an aqueous environment. It contains a Carrier proteins bind their specific solutes, such as amino acids, and
variety of enzymes, and strands of mitochondrial DNA with the capacity transport them across the membrane through a series of conforma-
for transcription and translation of a unique set of mitochondrial genes tional changes. This latter process is slower than ion transport through
(mitochondrial mRNAs and transfer RNAs, mitochondrial ribosomes membrane channels. Transport by carrier proteins can occur either pas-
with rRNAs). The DNA forms a closed loop, about 5 µm across; several sively by simple diffusion, or actively against the electrochemical gradi-
identical copies are present in each mitochondrion. The ratio between ent of the solute. Active transport must therefore be coupled to a source
its bases differs from that of nuclear DNA, and the RNA sequences also of energy, such as ATP generation, or energy released by the coordinate
differ in the precise genetic code used in protein synthesis. At least 13 movement of an ion down its electrochemical gradient. Linked trans-


respiratory chain enzymes of the matrix and inner membrane are port can be in the same direction as the solute, in which case the carrier
encoded by the small number of genes along the mitochondrial DNA. protein is described as a symporter, or in the opposite direction, when
The great majority of mitochondrial proteins are encoded by nuclear the carrier acts as an antiporter.
genes and made in the cytosol, then inserted through special channels
in the mitochondrial membranes to reach their destinations. Their Translocation of proteins across
membrane lipids are synthesized in the endoplasmic reticulum. intracellular membranes
It has been shown that mitochondria are of maternal origin because Proteins are generally synthesized on ribosomes in the cytosol or on
the mitochondria of spermatozoa are not generally incorporated the rough endoplasmic reticulum. A few are made on mitochondrial
into the ovum at fertilization. Thus mitochondria (and mitochondrial ribosomes. Once synthesized, many proteins remain in the cytosol,
genetic variations and mutations) are passed only through the where they carry out their functions. Others, such as integral membrane
female line. proteins or proteins for secretion, are translocated across intracellular
Mitochondria are distributed within a cell according to regional membranes for post-translational modification and targeting to their
energy requirements, e.g. near the bases of cilia in ciliated epithelia, in destinations. This is achieved by the signal sequence, an addressing
the basal domain of the cells of proximal convoluted tubules in the system contained within the protein sequence of amino acids, which is
renal cortex (where considerable active transport occurs) and around recognized by receptors or translocators in the appropriate membrane.
the proximal segment, called middle piece, of the flagellum in sperma- Proteins are thus sorted by their signal sequence (or set of sequences
tozoa. They may be involved with tissue-specific metabolic reactions, that become spatially grouped as a signal patch when the protein folds
e.g. various urea-forming enzymes are found in liver cell mitochondria. into its tertiary configuration), so that they are recognized by and enter
Moreover, a number of genetic diseases of mitochondria affect particu- the correct intracellular membrane compartment.
lar tissues exclusively, e.g. mitochondrial myopathies (skeletal muscle)
and mitochondrial neuropathies (nervous tissue). For further informa-
Cell signalling


tion on mitochondrial genetics and disorders, see Chinnery and Hudson
(2013).
Cellular systems in the body communicate with each other to coordi-
Cytosolic inclusions nate and integrate their functions. This occurs through a variety of
The aqueous cytosol surrounds the membranous organelles described processes known collectively as cell signalling, in which a signalling
above. It also contains various non-membranous inclusions, including molecule produced by one cell is detected by another, almost always by
free ribosomes, components of the cytoskeleton, and other inclusions, means of a specific receptor protein molecule. The recipient cell trans-
such as storage granules (e.g. glycogen), pigments (such as lipofuscin duces the signal, which it most often detects at the plasma membrane,
granules, remnants of the lipid oxidative mechanism seen in the supra- into intracellular chemical messages that change cell behaviour.
renal cortex) and lipid droplets. The signal may act over a long distance, e.g. endocrine signalling
through the release of hormones into the blood stream, or neuronal
lipid droplets synaptic signalling via electrical impulse transmission along axons
Lipid droplets are spherical bodies of various sizes found within many and subsequent release of chemical transmitters of the signal at syn-
cells, but are especially prominent in the adipocytes (fat cells) of apses or neuromuscular junctions. A specialized variation of endocrine
adipose connective tissue. They do not belong to the Golgi-related vacu- signalling (neurocrine or neuroendocrine signalling) occurs when neu-
olar system of the cell. They are not membrane-bound, but are droplets rones or paraneurones (e.g. chromaffin cells of the suprarenal medulla)
of lipid suspended in the cytosol and surrounded by perilipin proteins, secrete a hormone into interstitial fluid and the blood stream.
which regulate lipid storage and lipolysis. See Smith and Ordovás Alternatively, signalling may occur at short range through a paracrine
(2012) for further reading on obesity and perilipins. In cells specialized mechanism, in which cells of one type release molecules into the inter-
for lipid storage, the vacuoles reach 80 µm or more in diameter. They stitial fluid of the local environment, to be detected by nearby cells of


function as stores of chemical energy, thermal insulators and mechani- a different type that express the specific receptor protein. Neurocrine
cal shock absorbers in adipocytes. In many cells, they may represent cell signalling uses chemical messengers found also in the central
end-products of other metabolic pathways, e.g. in steroid-synthesizing nervous system, which may act in a paracrine manner via interstitial
cells, where they are a prominent feature of the cytoplasm. They may fluid or reach more distant target tissues via the blood stream. Cells
also be secreted, as in the alveolar epithelium of the lactating breast. may generate and respond to the same signal. This is autocrine signal-
ling, a phenomenon that reinforces the coordinated activities of a group
Transport across cell membranes of like cells, which respond together to a high concentration of a local
Lipid bilayers are increasingly impermeable to molecules as they signalling molecule. The most extreme form of short-distance signalling
increase in size or hydrophobicity. Transport mechanisms are therefore is contact-dependent (juxtacrine) signalling, where one cell responds to
required to carry essential polar molecules, including ions, nutrients, transmembrane proteins of an adjacent cell that bind to surface recep-
nucleotides and metabolites of various kinds, across the plasma mem- tors in the responding cell membrane. Contact-dependent signalling
brane and into or out of membrane-bound intracellular compartments. also includes cellular responses to integrins on the cell surface binding
Transport is facilitated by a variety of membrane transport proteins, to elements of the extracellular matrix. Juxtacrine signalling is impor-
each with specificity for a particular class of molecule, e.g. sugars. Trans- tant during development and in immune responses. These different
port proteins fall mainly into two major classes: channel proteins and types of intercellular signalling mechanism are illustrated in Figure 1.7.
carrier proteins. For further reading on cell signalling pathways, see Kierszenbaum and
Channel proteins form aqueous pores in the membrane, which open Tres (2012).
and close under the regulation of intracellular signals, e.g. G-proteins,
Signalling molecules and their receptors
to allow the flux of solutes (usually inorganic ions) of specific size and
charge. Transport through ion channels is always passive, and ion flow The majority of signalling molecules (ligands) are hydrophilic and so


through an open channel depends only on the ion concentration gradi- cannot cross the plasma membrane of a recipient cell to effect changes


Basic structure and function of cells
10.e1
1
RETPaHC
Mitochondrial ribosomes are smaller and quite distinct from those
of the rest of the cell in that they (and mitochondrial nucleic acids)
resemble those of bacteria. This similarity underpins the theory that
mitochondrial ancestors were oxygen-utilizing bacteria that existed in
a symbiotic relationship with eukaryotic cells unable to metabolize the
oxygen produced by early plants. As mitochondria are formed only
from previously existing ones, it follows that all mitochondria in the
body are descended from those in the cytoplasm of the fertilized ovum.


Cell structure
11
1
RETPaHC
A Endocrine B Paracrine
Short-range signalling
molecule
Endocrine cell A
Endocrine cell B Receptor Y Sig cn ea ll lling
Receptor X
Target
cells
Target cell B
Different
Target cell A
Blood stream hormones
C Autocrine D Synaptic
Neurone
Synapse
Membrane receptor Axon
Hormone or Cell body Neurotransmitter Target cell
growth factor
E Neurocrine F Contact-dependent
Neuroendocrine Neuropeptide
Stimulus cell or amine Signalling cell Target cell
Blood vessel
Membrane-bound
Distant target cell signal molecule
Fig . 1 .7 The different modes of cell–cell signalling .
inside the cell unless they first bind to a plasma membrane receptor among signalling molecules in having no specific receptor protein; it
protein. Ligands are mainly proteins (usually glycoproteins), polypep- acts directly on intracellular enzymes of the response pathway.
tides or highly charged biogenic amines. They include: classic peptide
hormones of the endocrine system; cytokines, which are mainly of Receptor proteins
haemopoietic cell origin and involved in inflammatory responses and There are some 20 different families of receptor proteins, each with
tissue remodelling (e.g. the interferons, interleukins, tumour necrosis several isoforms responding to different ligands. The great majority of
factor, leukaemia inhibitory factor); and polypeptide growth factors these receptors are transmembrane proteins. Members of each family
(e.g. the epidermal growth factor superfamily, nerve growth factor, share structural features that indicate either shared ligand-binding char-
platelet-derived growth factor, the fibroblast growth factor family, trans- acteristics in the extracellular domain or shared signal transduction
forming growth factor beta and the insulin-like growth factors). properties in the cytoplasmic domain, or both. There is little relation-
Polypeptide growth factors are multifunctional molecules with more ship either between the nature of a ligand and the family of receptor
widespread actions and cellular sources than their names suggest. They proteins to which it binds and activates, or the signal transduction
and their receptors are commonly mutated or aberrantly expressed in strategies by which an intracellular response is achieved. The same


certain cancers. The cancer-causing gene variant is termed a transform- ligand may activate fundamentally different types of receptor in differ-
ing oncogene and the normal (wild-type) version of the gene is a cel- ent cell types.
lular oncogene or proto-oncogene. The activated receptor acts as a Cell surface receptor proteins are generally grouped according to
transducer to generate intracellular signals, which are either small dif- their linkage to one of three intracellular systems: ion channel-linked
fusible second messengers (e.g. calcium, cyclic adenosine monophos- receptors; G-protein coupled receptors; and receptors that link to
phate or the plasma membrane lipid-soluble diacylglycerol), or larger enzyme systems. Other receptors do not fit neatly into any of these
protein complexes that amplify and relay the signal to target control categories. All the known G-protein coupled receptors belong to a
systems. structural group of proteins that pass through the membrane seven
Some signals are hydrophobic and able to cross the plasma mem- times in a series of serpentine loops. These receptors are thus known as
brane freely. Classic examples are the steroid hormones, thyroid hor- seven-pass transmembrane receptors or, because the transmembrane
mones, retinoids and vitamin D. Steroids, for instance, enter cells regions are formed from α-helical domains, as seven-helix receptors.
non-selectively, but elicit a specific response only in those target cells The best known of this large group of phylogenetically ancient receptors
that express specific cytoplasmic or nuclear receptors. Light stimuli also are the odorant-binding proteins of the olfactory system; the light-
cross the plasma membranes of photoreceptor cells and interact intra- sensitive receptor protein, rhodopsin; and many of the receptors for
cellularly, at least in rod cells, with membrane-bound photosensitive clinically useful drugs. A comprehensive list of receptor proteins, their
receptor proteins. Hydrophobic ligands are transported in the blood activating ligands and examples of the resultant biological function is
stream or interstitial fluids, generally bound to carrier proteins, and they given in Pollard and Earnshaw (2008).
often have a longer half-life and longer-lasting effects on their targets
than do water-soluble ligands. Intracellular signalling
A separate group of signalling molecules able to cross the plasma A wide variety of small molecules carry signals within cells, conveying


membrane freely is typified by the gas, nitric oxide. The principal target the signal from its source (e.g. activated plasma membrane receptor) to
of short-range nitric oxide signalling is smooth muscle, which relaxes its target (e.g. the nucleus). These second messengers convey signals as
in response. Nitric oxide is released from vascular endothelium as a fluctuations in local concentration, according to rates of synthesis and
result of the action of autonomic nerves that supply the vessel wall degradation by specific enzymes (e.g. cyclases involved in cyclic nucle-
causing local relaxation of smooth muscle and dilation of vessels. This otide (cAMP, cGMP) synthesis), or, in the case of calcium, according to
mechanism is responsible for penile erection. Nitric oxide is unusual the activities of calcium channels and pumps. Other, lipidic, second


BaSIC STRuCTuRE aNd fuNCTION Of CEllS
12
1
NOITCES
messengers such as phosphatidylinositol, derive from membranes and are microfilaments (7 nm thick), microtubules (25 nm thick) and inter-
may act within the membrane to generate downstream effects. For mediate filaments (10 nm thick). Other important components are
further consideration of the complexity of intracellular signalling path- proteins that bind to the principal filamentous types to assemble or
ways, see Pollard and Earnshaw (2008). disassemble them, regulate their stability or generate movement. These
include actin-binding proteins such as myosin, which in some cells can
Cytoskeleton assemble into thick filaments, and microtubule-associated proteins.
Pathologies involving cytoskeletal abnormalities include ciliopathies
(resulting from the abnormal assembly and function of centrioles, basal
The cytoskeleton is a three-dimensional network of filamentous intra-
bodies and cilia); neurodegenerative diseases (a consequence of defec-
cellular proteins of different shapes, sizes and composition distributed
tive anterograde transport of neurotransmitters along microtubules in
throughout the cytoplasm. It provides mechanical support, maintains
axons); and sterility (determined by defective or absent microtubule-
cell shape and rigidity, and enables cells to adopt highly asymmetric or
associated dynein in axonemes, e.g. Kartagener’s syndrome).
irregular profiles. It plays an important part in establishing structural
polarity and different functional domains within a cell. It also provides
Actin filaments (microfilaments)
mechanical support for permanent projections from the cell surface (see
below), including persistent microvilli and cilia, and transient proc- Actin filaments are flexible filaments, 7 nm thick (Fig. 1.8). Within
esses, such as the thin finger-like protrusions called filopodia (0.1– most cell types, actin constitutes the most abundant protein and in
0.3 µm) and lamellipodia (0.1–0.2 µm). Filopodia consist of parallel some motile cells its concentration may exceed 200 µM (10 mg protein