Physiology Past and Future

R. GREGER and U. WINDHORST

Contents in the sense that each step followed the one before, with
new questions asked because the former ones had been
1 The History of Physiology .......................... .
answered. Rather, the changes were guided by the avail-
2 The Seeds ........................................ 1
3 The Sprout ........................... . ..... . . . . . . 2 ability of new methodological tools. Consequently, and
4 The Young Science. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3embarrassingly, many of the questions asked by physiolo-
5 Schools of Physiology .. . . . . . . . . . . . . . . . . . . . . . . . . .gists
. . . at3 the turn of the century remained unanswered and
6 From Physiology to Biochemistry ............. . . . . . .. 10 were put aside, some of them until today. There is, how-
7 Physiology in Mid-life Crisis? . . . . . . . . . . . . . . . . ... . 11
. . ...
8 Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... 15 ever, also a clearly visible thread in this development. It is
the attempt to explore function at increasingly low levels of
complexity, starting at the holistic level of the organism
and proceeding through the organ, cell and membrane
1 The History of Physiology levels to one single molecule. Today, at all physiological
meetings "cell physiology," "membrane physiology," and
The history of physiology is difficult to summarize, and "molecular physiology" dominate the programs. Physiol-
we shall leave the details to more competent experts ogy has come a long way.
[3,12,15,25,30,40,43,47]. The dilemma encountered is not In this introductory chapter (which is based on several
unusual. Before the history of physiology can be consid- general references: [3, 11,12,15,21,25,30,31,36,38,40,43,4 7]),
ered, the meaning of the term has to be clear. "Physiology" we shall briefly and unsystematically discuss certain ep-
has not had a constant meaning; rather, its definition has ochs in the development of physiology and then try to
changed over the centuries. predict where this development might lead and, because
The origin of the word (from Greek ~ucns = nature and we cannot avoid doing so, say where we see the problems,
Myos = rule, or maybe logic) comes close to the Chinese and what course we feel physiology should take.
meaning of physiology = logic of life [2]. In this sense,
which was also the classical use of this word more than
2000 years ago, physiology is concerned in a very general
way with questions regarding the functional aspects of our 2 The Seeds
own nature and that surrounding us.
Much later, the development of physiology was closely re- Physiology, at the time of Aristotle (384-322 B.C.) and
lated to the development of anatomy. To cite J.W. Goethe, especially in his own writings, was based on the founda-
"Funktion ist Form in Tatigkeit gedacht" ("function is tions laid down by Hippocrates (ca. 460-377 B.C.) and
form in action"). In Goethe's day, physiology started to correlated the natural surroundings and the elements with
explore the organ functions. Experimentation began to re- our own constituents, namely the body juices. Every in-
place mere description. Logically this was the time when quiry was aimed at elucidating higher principles, which
physiology was established as a subject in its own right and were also thought to be the sources of life in general. This
chairs of physiology separate from those of anatomy were approach was called "entelechy" (from Greek TEAOS =
established in most medical faculties. aim). We shall see later that the modern brother or sister
At the same time, or maybe slightly earlier, physiology of entelechy, namely teleology (or, as some prefer:
incorporated another already well-developed and conflict- teleonomy) is still always present in our interpretations (d.
ing area, that of alchemy. Theophrastus Bombastus below: comment by E. Briicke). Despite the many facts that
Paracelsus (1493-1541) was probably the founder of this were so accurately observed by the universalist Aristotle,
branch of physiology, which then developed into physi- we are surprised to read how many misinterpretations
ological chemistry. Much later (by the end of the last cen- crept into the records of that time and have been meticu-
tury), the chemistry of life found a home of its own in the lously preserved - mainly by the Catholic church - for 2000
new specialty biochemistry. years.
The twentieth century marked another new development. Neurophysiologists must be disappointed to see that fol-
Physiology now explored the function of the cell and its lowing Aristotle the brain was regarded as a cooling device,
subcellular structures. Such developments were not guided not connected to sensory organs and not supplied with

R. Greger/V. Windhorst (Eds.)

Comprehensive Human Physiology, Vol. 1
© Springer-Verlag Berlin Heidelberg 1996
blood, or that the spinal cord was yet another type of bone Academia naturae curio sum (later Leopoldina, Halle
marrow. How much more pleasing, on the other hand, 1652); the Academia del Cimento (Firence 1657); the Royal
must it be for a cardiophysiologist to learn that the heart Society (London 1662). These societies brought together
was considered the central organ of the body. doctors of medicine and scientists working in many disci-
Much further progress in the field was made by Galen (129 plines. A new spirit of experimentation was abroad: "Meas-
to ca. 201), owing to his acquisition of extensive knowledge ure the measurable and make the as yet unmeasurable
of anatomy. However, his work was flawed by a general available to measurement" (probably by Galileo Galilei
misunderstanding, which has persisted into our own day. (1564-1642)). Many famous names and inventions come
He examined apes, pigs, dogs, etc. and concluded that what to mind on recapitulation of this century:
had been found there (anatomically) would also be true for
man. Although Galen was still under the influence of Plato, • S. Santo rio (1561-1636): perspiratio insensibilis,
Hippocrates, and Aristotle, and related function largely to thermometer
three different spirits (Greek 1tV£UI-HX; Latin spiritus), he • G. Galilei (1564-1642): gravitation, telescope, ther-
also clarified important previous misconceptions. He re- mometer, chronometer
ported that the left heart and the arteries were filled with • J. Kepler (1571-1630): optics, astronomy
blood. On the other hand, he reported openings between • W. Snellius (1591-1626): laws of diffraction
right and left ventricles and is hence responsible for the • R. Descartes (1596-1650): laws of diffraction
long delay in the correct understanding of circulation (ef. • E. Torricelli (1608-1647): barometer
below). The respiratory function was known to him. He • G.A. Borelli (1608-1679): mathematics, mechanics of
also interpreted muscle function as a consequence of the muscle (ef. Fig. 1)
innervation from the brain (Greek 1tV£UIlU 'l'crUX1K6y = • R. Boyle (1627-1691): gas laws
psychic spirit) [32]. The process of vision was still misin- • M. Malpighi (1628-1694): microscopic anatomy
terpreted, inasmuch as the light path was thought to course • C. Huygens (1629-1695): chronometer, thermometer,
in both directions and the optic chiasma was considered undulation theory of light
the center of vision. • A. von Leeuwenhoek (1632-1723): microscope
Galen had an enormous impact on medicine in general, • I Newton (1642-1727): mechanics, light theory, sound
and his views were upheld for more than 1000 years. In velocity, mathematics, optics, gravitation, color theory
• G.W. Leibniz (1646-1716): mathematics, philosophy
fact, we do not miss many achievements in physiology
when we move from the period of Galen directly to the
Renaissance. One of the important discoveries of the seventeenth cen-
tury was that of the circulation. The pulmonary circulation

3 The Sprout

One of the pioneers of the Renaissance was the "uomo

universale" Leonardo da Vinci (1452-1519): on the basis of
anatomical studies, he revised certain aspects of physiol-
ogy, such as the function of the heart, the eye, and the ear.
This new beginning after more than 1200 years of tradi-
tional Galenismus was most successfully continued in the
anatomical studies of Vesalius (1514-1564). The tables of
the human body were now precise and correct. But even
Vesalius, despite his clear description, could not com-
pletely depart from classic concepts. He described the
septum of the heart correctly: "As far as we can see none of
these indentations connects the right with the left ventri-
cle" and went on to conclude: "Thence we have to admire
the work of the Almighty that the blood flows from the
right to the left ventricle through routes that are invisible
to man."
Still, the road was paved now for vigorous progress, in the
seventeenth century, in human understanding of the
physiology of vision and of the circulation. During the
seventeenth century a new scientific spirit pervaded many
fields, including medicine. This was the century of the
foundation of scientific societies, such as the Academia dei
Lincei (Rome 1603); the Societas Ereunetica (Rostock
1622); the Academie des Sciences (Paris 1635); the Fig. 1. Giovanni Alfonso Borelli (1608-1679)

2
was understood by M. Serveto (1511-1553). The systemic called physiological chemistry or biochemistry. This inter-
circulation was logically deduced and disclosed by W. est was his hobby, his income coming from his position as
Harvey (1578 -1657). His discovery probably dates back to the leader of the French gunpowder industries. He de-
the year 1615; it was published in 1628 in Frankfurt/Main. signed the calorimeter and founded the field of energy
One of his key statements regarding the then postulated metabolism. He became a victim of the French Revolution.
direct passage of blood from the right to the left ventricle The tribunal stated (1794): "We do not need scientists any
(cf. above): " ... but there are no wholes ... ". It does not more."
come as a surprise that Harvey's discovery was not ac- The eighteenth century also saw the foundation of
cepted at once. His concept challenged and dethroned the modern neurophysiology. Electricity had just become
classic views held by Galen. amenable to experimentation (Leyden flask), and exciting
J. Kepler (1571-1630), amongst many other important dis- observations were being reported and demonstrated
coveries, also gives the first correct description of the dif- throughout Europe. Key experiments were performed by
fraction in the eye (Paralipomena in vitellionem seu A. Galvani (1737-1798). He noted that frog muscles con-
astronomia pars optica, Frankfurt/Main 1604; also cf. chap. tracted whenever a contact was made with the Leyden
49). The successful use of lenses is much older, and dates flask. Lightning exerted similar effects. His results were
back to the thirteenth century. Glasses have been used in published in 1791: "De viribus electricitatis in motu
Italy since 1280 [16]. The microscope was not invented musculari commentarius." He was able to demonstrate
until after lenses with short focus could be produced. that no external source was needed if different metals were
The first microscopes were built around 1590 in The used in the frog experiment: contractions were also ob-
Netherlands. A. von Leeuwenhoek (1632-1723) substan- served when the brass wire in contact with the spinal cord
tially improved the instruments. It is reported that his in- touched the iron support on which the frog was placed.
struments allowed for a magnification of up to 270x. His His conclusion was that the electricity was an intrinsic
and M. Malpighi's (1628-1694) work laid the foundations property of the muscle [49]. A. Volta (1745-1827) criti-
to histology. cized Galvani's interpretations, because he was able to pro-
duce electrical batteries from different metals and salt
solutions [50]. Volta was right in the sense that Galvani had
used external electrical stimulation in the above early ex-
4 The Young Science periments and from that point of view his conclusion of
intrinsic electricity was not justified. Nevertheless, Galvani
At the turn of the seventeenth century, science had gained turned out to be right in the end, because the electricity is
a momentum that was just another facet of the strong in fact intrinsic.
general movement called the Aufklarung (Englighten- Amongst many other prominent scientists of this time, A.
ment), which had been initiated by philosophers such as von Humboldt (1769-1859) and J.W. von Goethe (1749-
G.W. Leibniz (1646-1716) and was promoted by 1. Kant 1832) were inspired by these new concepts. Goethe's own
(1724-1804). There was no longer any excuse for not using position as a scientist is controversial and will not be dis-
one's own mind. In this period, sciences in general and cussed here. In the museum devoted to Goethe in Weimar,
physiology in particular could flourish. the interested reader will find expressions of the highest
One center of excellence in those days was Leyden. In 1708, appreciation, but also of devastating criticism (e.g., from
H. Boerhaave (1668-1738) published his view of physiol- du Bois-Reymond; cf. below). In one of Goethe's own state-
ogy in the Institutiones medicinae, probably the first stu- ments about science we find a sentence that is not only
dent text of physiology. His book was translated into characteristic of this time but also an inspiring truism:
English and French. The German title of his book "Auch in den Wissenschaften kann man letztlich nichts
Phisiologia (1754) introduced the use of this word to indi- wissen, es will gethan sein" [In science, too, nothing can be
cate the field. It has been retained ever since. known; it has to be done J.
One of the most famous pupils of Boerhaave was A. von
Haller (1708-1777), who is respected by both anatomists
and physiologists as an outstanding pioneer. At the age of
28 he became professor of botany, anatomy, and medicine 5 Schools of Physiology
at the University of Gottingen, which he helped to found.
His contributions are indeed remarkable and, like those of In the nineteenth century, physiology continued to flourish
many of the physiologists to be discussed below, are prob- and became an independent science in most medical facul-
ably also related to the fact that he worked very hard: ties. This occurred in most places around the middle of
something like 20 hours a day every day [40j. Haller's ap- the century, with the opening of physiology laboratories
proach was based entirely on morphological examination. and the installation of chairs (If physiology. The first physi-
This approach was called Anatomia animata (cf.: ology laboratory was probably that opened in Freiburg in
"... Form in Tatigkeit gedacht ... "). 1821 by C.A.S. Schultze (1795-1877) [33]. One of the next
Another important scientist of this time was A.L. Lavoisier laboratories dedicated exclusively to physiology was
(1743-1794). He was interested predominantly in chemis- that oO.E. Purkinje (1787-1869) in Breslau. Several other
try and physics and was a promoter of what would later be universities followed shortly thereafter, although in many

3
other instances physiology was still housed in anatomical
institutes. As it is today, laboratory space was always ex-
tremely short, and many classic experiments were there-
fore performed in the private rooms and homes of the
investigators.
The maturation of this new specialty was also reflected in
the appearance of periodicals dealing exclusively with
physiology (Germany 1795; France 1821; England 1878;
Scandinavia 1891; USA 1898). It should be mentioned
here that in Germany a physiology periodical was started
in 1795 by C. Rei!. This journal later became a joint
journal for anatomy, physiology and medical science
(Archiv fur Anatomie, Physiologie und wissenschaftliche
Medizin) for a time, but has been a physiology journal
only again since 1877. In France the first physiology jour-
nal was started 1821 by F. Magendie (1783-1855, Fig. 2; cf.
below).
Around 1870-1890, physiological societies were founded
in the various countries, either as sections of more global
societies or as completely independent societies (1876
British Physiological Society; 1887 American Physiological
Society) [3,38,40j.
Still, at the very beginning of the nineteenth century physi-
ology went through a "romantic period" under the influ-
ence of F.W.J. Schelling (1775-1854), for example. It was a
time of philosophical universalism and gross extrapolation
from the cosmos to the body. Magnetism and electricity Fig. 3. Johannes Muller (1801-1858). (From [40])
inspired a large number of scientists. For a little while
recent achievements of physiology, such as the under-
standing of the circulation, were questioned on a philo- sophical basis. As J.B. Wilbrand (1779-1846) put it: "I deny
the existence of the circulation of blood." He believed that
blood underwent a metamorphosis when it reached the
periphery, to become tissue.
Fortunately enough, this period did not last long as it was
terminated by such experimentalists as F. Magendie (cf.
Fig. 2), who worked for many years in Paris. Magendie
based every conclusion on experimental observation and
was a strict opponent of any, even the slightest, extrapola-
tion. His famous work was the Precis elementaire de
physiologie (1816-1817) [42]. J.E. Purkinje (1787-1869)
was another example of a restless experimentalist. He
worked on vision, but he was also a good microscopist
(Purkinje cells in the cerebellum) and anatomist (Purkinje
fibers in the heart). Ironically, Purkinje and his group of
students were most productive while they had no space
and had to perform all their experiments in one room in
the anatomical institute or in Purkinje's home. The pro-
ductivity died off when he found unique new facilities in
his new institute in Breslau in 1839.
Below we briefly present a few of the century's most fa-
mous physiologists (and their schools) and the areas in
which they mainly worked. Space does not allow any at-
tempt to be comprehensive, and for our present purposes
this would in any case be unnecessary.
J. Muller (1801-1858, cf. Fig. 3) had an enormous impact
on physiology, not only in Germany but also in many other
countries. His approach was still strongly anatomically ori-
ented, and he believed more in observation than in experi-
Fig. 2. Fran~ois Magendie (1783-1855). (From [40]) ment. In his inaugural lecture as a "privatdocent" in 1824,

4
when he was only 23 years old, he made this point by
saying: " ... we have to press nature only hard enough and
we shall obtain an answer from the suffering victim." One
of Muller's important discoveries was the understanding of
the secretory process in glands. In 1833, Muller was ap-
pointed to the chair of anatomy and physiology in Berlin.
He wrote a two-volume handbook of physiology (1834 and
1837). Muller did not appreciate invasive experimentation
such as was practised by his French colleagues Magendie
and others (cf. above) and continued later by C. Bernard
(1813-1878; cf. Fig. 4 below). He was no "vivisectionist,"
appearing rather to be influenced by vitalism to some
extent.
C. Ludwig (1816-1895; cf. Fig. 5) may have had an even
more inspiring influence on physiology than Miiller [40].
He can probably be regarded as one of the founders of
the strictly quantitative approach. In fact one of his early
inventions, the kymograph (1856), was a key tool in physi-
ology for some 100 years. It is still found in the basements
of many institutes. In fact, we both used it as students in
our physiology classes. In 1865, Ludwig was appointed to
the chair of physiology in Leipzig after having been in
Marburg, Zurich and Vienna. In 1869, his new institute
was opened in Leipzig with, at that time, unique facilities.
He attracted an enormous number of students (over 200)
from within and outside Germany. His institute became
world-famous for its productivity in many areas: innerva-
tion of the heart, effect of pressoreceptors, blood gases, Fig. 5. Carl Ludwig (1816-1895). (From [15])
and metabolism of isolated organs [14]. At that time a

sabbatical in his laboratory was part of the curriculum in

physiology.
Both Muller and Ludwig founded schools, and it is amaz-
ing how many of to day's physiologists proudly claim to be
a scientific great-great-grand-child of one of them or at
least of someone who worked with them.
Among the scientific "children" and "grandchildren" of J.
Muller were:

• J. Henle (1809-1885): Berlin, Zurich, Heidelberg,

Giittingen: microscopic anatomy. With his work
Handbuch der rationalen Pathologie (1855) he set the
stage for pathophysiology. Pupils: A. Koelliker; J.
Moleschott.
• T. Schwann (1810-1882): Berlin, Leuven, Liege: pepsin;
general cell structures. Schwann, after moving to Leuven
(1839) and to Liege (1858), had little success. This was
probably due to the fact that physiology in Belgium was
poorly developed and supported at that time.
• E. du Bois-Reymond (1818-1896) [11]: Berlin: "thie-
rische Elektrizitat" (animal electricity); critic of the "vis
vitalis." Pupils: J. Bernstein; A. von Bezold; J. Gad; R.
Heidenhain; L. Hermann; J.F. Heymans; E. Pfluger; 1.
Rosenthal.
• E. Brucke (1819-1892): Berlin, Konigsberg, Vienna: sen-
sory physiology, gastrointestinal physiology. Like du
Bois-Reymond and Ludwig, Brlicke was a fighter against
Fig. 4. Claude Bernard (1813-1878). (From [40]) vitalism, yet he was very self-critical when confessing:

5
 "Teleology is a lady without whom no biologist can live, • G. Hufner (1840-1908): Leipzig, Tubingen: hemoglobin.
yet he is afraid to be seen with her in public." Pupils: Hufner was one of the promoters of physiological chem-
S. Exner; F. Holmgren; A. Kreidl; W. Kuhne; T. istry. Pupils: K. Burke; K. Hurthle.
Lauder-Brunton; A. Rollett; J.M. Setschenow; M. von • E. Drechsel (1843-1897): Leipzig, Bern: urea metabo-
Vintschgau. lism; fat metabolism. Like Hufner he was one of the
• H. von Helmholtz (1821-1894): Potsdam, Berlin, pioneers of biochemistry. Pupils: M. Siegfried; E.
Konigsberg, Bonn, Heidelberg, Berlin: Muscle metabo- Fischer.
lism; nerve conduction; ophthalmoscope; hearing; vi- • M. von Frey (1852-1932): Leipzig, Zurich, Wurzburg:
sion; electrodynamics. Pupils: J. Bernstein; S. Exner; A. muscle metabolism (lactate); pulse; tactile senses. Pu-
Konig; J. von Kries; H. Kronecker. pils: J. Bizzozero; P. Hoffmann; E. Overton; H. Rein;
• E. Haeckel (1838-1919): Berlin: evolutional theory; Y. Renqvist-Reenp1Hi.; F. Schellong; H. Schriever; H.
monism. Pupil: M. Verworn. Strughold; E. Wohlisch.
• J. ,:"on Kries (1853-1928, also cf. above): Leipzig, Berlin,
The scientific "children" and "grandchildren" of C. Leipzig, Freiburg; muscle excitation; conduction in
Ludwig: the heart; sensory physiology; protanopia
deuteranopia. Von Kries was only 27 years of age when
• A. Fick (1829-1901, cf. Fig. 6): Marburg, Berlin, Zurich, he was appointed professor of physiology in Freiburg .
Wurzburg: muscle function; diffusion; medical physics; During the last 25 years of his scientific life he, like many
electrical excitability; nutrition. Pupils: M.G. Blix; R. other physiologists before and after him, turned to phi-
Boehm; J. Gad; A. Gurber; J. Loeb; F. Schenk. losophy. Pupils: E. Mangold; R. Metzner; W. Nagel; H.
• I.M. Setschenow (1829-1905, also cf. above): Berlin, Piper; E. von Skramlik; W. Trendelenburg; V. von
Zurich, Vienna, Graz: reflexes. Weizacker.
• H. Kronecker (1839-1914): Leipzig, Berlin, Bern: stri- • M. Rubner (1854-1932): Munich, Leipzig, Munich;
ated muscle; high altitude. Kronecker, as a result of his Marburg; Berlin: metabolism; nutrition; climatology.
friendship with other European colleagues, was one of Pupils: E. Atzler; A. Kohlrausch; O. Krummacher; G.
the initiators of the First International Congress of Lehmann; K. Thomas.
Physiology (Basel 1888). Pupils: L. Asher; S. von Basch; • O. Frank (1865-1944): Leipzig, GieBen, Munich: physi-
A.R. Cushny; F. Gotch; S.J. Meltzer. ology of circulation; manometry; isolated heart. Pupils:
P. Broemser; J. Seemann; E. von Skramlik; H. Straub; R.
Wagner; K. Wezler; c.J. Wiggers.

A special category of coworkers in Ludwig's laboratory

is made up of physiologists from other countries. I.M.
Setschenow (1829-1905) has already been listed above. He
was the first Russian coworker. Other foreign collaborators
will be listed below, which gives us a good opportunity to
highlight a network of interaction between the physiol-
ogists in other European countries and in the United
States:

• F. Holmgren (1831-1897): Uppsala, Vienna (with

Brucke and Ludwig), Berlin (with du Bois-Reymond),
Heidelberg (with Helmholtz). He had the specific inten-
tion of establishing physiology in his own country. After
many years in the above laboratories he returned to
Uppsala. His key interest was retinal physiology. He was
the founder of the Scandinavian Journal of Physiology
(1891). Pupil: O. Hammarsten (d. below).
• C. Loven (1835-1904): Stockholm, Leipzig (with
Ludwig): innvervation of vasculature. He established the
first physiology chair in Stockholm in 1874. Pupil:
R.A.A. Tigerstedt (d. below).
• L. Luciani (1840-1919): Bologna, Leipzig (with Ludwig),
Parma, Siena, Florence, Rome: heart; starvation; cere-
bellum. His stay with Ludwig must have been very im-
portant as he states: " ... this was the most important
period of my scientific life ... " Luciani was convinced
of the impossibility of separating physiology and
Fig. 6. Adolf Fick (1829-1901). (From [40]) pathology.

6
• O. Hammersten (1841-1932) : Uppsala, Leipzig (with
Ludwig), Uppsala: coagulation, protein chemistry. He
was one of the pioneers of biochemistry. Pupils: S.
Arrhenius; l. Bang.
• A. Mosso (1846-1910): Torino, Paris (with Bernard),
Leipzig (with Ludwig), Torino: high altitude; exercise.
• R.A.A. Tigerstedt (1853-1923): Stockholm, Leipzig
(with Ludwig): circulation; metabolism. His publica-
tions, namely those on physiological methods, have long
been standard sources of reference. Pupils: E.M.
Lindhagen; J.E. Johansson; e.G. Stantesson; E.M.P.
Widmark.
• W.H. Gaskell (1847-1914): Cambridge, Leipzig (with
Ludwig), Cambridge: regulation of blood vessels in
exercise; cardiac innervation; sympathergic inner-
vation.
• l.P. Pavlov (1849-1936, cf. Fig. 7): Petersburg, Breslau
(with Heidenhain), Leipzig (with Ludwig), Petersburg:
gastrointestinal innervation and reflexes; conditioned
reflexes; central sensory physiology; sleep. He was the
first Nobel laureate in the field of physiology (ef. below
Table 1). He had a prodigious number of pupils; at times
he had 50 assistants working with him in a well-
equipped laboratory [51].
• C. Bohr (1855-1911): Copenhagen, Leipzig (with
Ludwig), Copenhagen: blood gases; CO 2 effect on 0 ,
binding by hemoglobin. Pupils: K. Hasselbalch; A.
Krogh.
Fig. 8. Peter Ludwig Panum (1820-1885). (From [40])

A few other schools must be mentioned. F. Magendie

(1783-1855, cf. Fig. 2) was the founder of a new and very
strong experimental branch in physiology [25]. His succes-
sor in Paris was C. Bernard (1813-1878, cf. Fig. 4). Bernard
discovered glycogen and the glycogenolysis in the liver
(1855). He worked on exocrine secretion, on anesthetics,
the innervation of vessels and much more. He is also
known for the introduction of the concept of the "milieu
interieur" [21]. He had several famous pupils and guest
workers:

• P.L. Panum (1820-1885, cf. Fig. 8): Paris (with Bernard),

Copenhagen: blood coagulation, blood transfusion. He
was the founder of physiology in Denmark.
• L. Pasteur (1822-1895): Paris: He was not in fact a pupil
of anybody, but on many occasions acknowledged the
marked impact that Bernard had on his work.
• L. Vella (1825-1886): Paris (with Bernard), Modena,
Bologna.
• J.e. Dalton (1825-1889): Paris (with Bernard), Buffalo,
Vermont, New York: glucose metabolism, bile forma-
tion. He was one of the pioneers of American physiology
[3,38).
• J. Burdon-Sanderson (1828 - 1905, cf. below).
• S.W. Mitchell (1829-1914): Paris (with Bernard), Phila-
delphia. He was one of the founder members of the
Fig. 7. Ivan Petrovitsch Pavlov (1849-1936). (From [40]) American Physiological Society [3,38].

7
 Bernard's successor at the College de France was C.E.
Brown-Sequard (1818-1894). He worked in neuro-
physiology (hemiparesis, epilepsy).
Physiology in Great Britain had a less smooth start [47].
One of the most important founding fathers was M. Foster
(1836-1907, cf. Fig. 9). Foster was hired by W. Sharpey
(1802-1880), who was anatomist at the University College
in London. Foster established a physiology course there.
Later Foster moved to Cambridge (1870). J. Burdon-
Sanderson (1828-1905) was Foster's, and later Sharpey's,
successor as the first physiologist (1874). He was a guest
worker in Bernard's laboratory, working on infectious dis-
eases and also on cardiac electrophysiology. Later he
moved to Oxford (1887). The laboratories in Cambridge
(Foster) and London (Burdon-Sanderson) attracted a large
number of young pupils, many of whom also spent some
time with Bernard (Paris), BrUcke (Vienna), KUhne
(Heidelberg), and Ludwig (Leipzig). A few of these should
be mentioned:

• W.H. Gaskell (1847-1915): Cambridge, Leipzig (with

Ludwig), Cambridge: heart and vasculature; cardiac in-
nervation; heart automatism.
• H. Newell-Martin (1848-1896): Cambridge (with Fos-
ter), Baltimore: isolated mammalian heart. He was one
of the pioneers of physiology in the United States [3,38].
• J. Newport Langley (1852-1925): Cambridge: He was a
pioneer of autonomous innervation and its pharmaco-
Fig. 9. Michael Foster (1836-1907). (From [40]) logical control. He became Foster's successor.
• F.G. Hopkins (1861-1947): Cambridge: worked mostly
on biochemical questions together with W.M. Fletcher
in Foster's laboratory. His interests were muscle me-
tabolism, tryptophan, glutathion. He was appointed to a
chair of biochemistry in Cambridge and received the
• P. Bert (1830-1886): Paris, Tonking: effects of com- Nobel prize in 1921.
pressed and decompressed air. • W.M. Bayliss {1866-1924): London, Oxford, London:
• L.A. Ranvier (1835-1922): Paris: He became the most collaborated closely with his brother-in-law and
famous histologist in France. friend E.H. Starling (cf. Fig. 10). Both made
• N. Grehant (1837-1909): Paris: blood vessels. important discoveries: secretin, explanation of T-wave
• W. KUhne (1837-1900): Berlin (with du Bois-Reymond), in the electrocardiogram, vasomotor reflexes. If Bayliss
Vienna (with BrUcke), Paris (with Bernard), Leipzig had not failed his anatomy examination, he would
(with Ludwig), Amsterdam, Heidelberg. He received his probably have continued in medicine and not turned to
education in most of the famous laboratories of that physiology.
time: nerve conduction in both directions, end plate etc. • E.H. Starling {1866-1927, cf. Fig. 10): Heidelberg (with
• E. de Cyon (1843-1912): Paris (with Bernard), Peters- KUhne), Breslau (with Heidenhain), London: colloid os-
burg, Paris, Leipzig (with Ludwig): electrotherapy, motic pressure, heart-lung preparation, etc. In a speech
nystagmus, depressor nerve. at the International Congress of Physiology (1926) he
• A.J. Dastre (1844-1917): Paris: anesthesia, vasomotor commented on the motives for going into physiology.
nerves. For his countrymen he states: " ... because it is the hard-
• J.P. Morat (1846-1920): Paris (with Bernard), Lille, est and the finest game ... "
Lyon: vasomotor nerves.
• A. Mosso (1846-1910, d. above). One of Newport Langley's pupils was C.S. Sherrington
• I.R. Tarchanow (1848-1908): Paris (with Bernard), {1859-1952). He turned to neurophysiology and was
Petersburg. mostly interested in the " ... integrative action of the nerv-
• C. Richet (1850-1935): Paris: He discovered the ous system." Together with E.D. Adrian (1889-1977) he
anaphylaxis and was honored with the Nobel prize in received the Nobel prize in 1932 (cf. Table 1).
1913 (d. below: Table 1). At the end of this section, let us briefly mention the seeds of
• J.A. d'Arsnoval (1851-1914): Paris: calorimetry; AC American physiology, not because it was very strong dur-
therapy. ing the last century, but because American physiology

8
 • J.G. Curtis (1844-1913): Harvard, New York: He joined
Dalton's laboratory in 1883 and became his successor.
• H. Newell-Martin (1848-1896, cf. above).
• R.H. Chittenden (1856-1943): Yale, Heidelberg (with
Kuhne), Yale. He obtained the first degree in physiologi-
cal chemistry in the United States, and is a founder of
this subject in his country: protein chemistry, enzymes,
nutrition.

This summary of some of the most important schools of

physiology should give an impression of the enormous
growth of this science during the nineteenth century. The
above list of names is probably known to most physiology
students today from the respective technical terms. This
brief listing is also intended to highlight how physiology
has tackled the study of the function of the body in general
and the specific organ functions. Obviously and tradition-
ally, the main focuses of interest were the functions of the
heart, the circulation, and sensory physiology. New impor-
tant fields in this century have been excretory gland func-
tion, neurophysiology, the autonomic nervous system,
muscle physiology, and blood physiology. Physiology has
also started to divide into a chemical and a more physical
branch. This issue will have to be discussed briefly in the
next section.
What were the reasons for this success? One certainly was
the zeitgeist, namely the intellectual departure from mere
description of morphology to observation and, even more
importantly, experiment. A second was the ability to per-

Fig. 10. Ernest Henry Starling (1866-1927). (From [40])

started to flourish at the turn of the century and has

been going from strength to strength ever since
[1,6,9,10,13,19,22,24,26,28,34,35,37,39,46). Important
founders of American physiology were [3,38,48]:

• R. Dunglison (1728-1869): London, Virginia, Baltimore,

Philadelphia. He was appointed to the chair of anatomy,
physiology, surgery, materia medica, pharmacy, and
history of medicine at the University of Virginia in 1825.
He was an excellent teacher and wrote a textbook enti-
tled Human Physiology in 1832. For a time, through col-
laboration with W. Beaumont (1785 -1853, cf. Fig. II), he
was involved in studies on gastric secretion [46J.
• W. Beaumont (1785-1853, cf. Fig. 11): Washington: gas-
tric secretion. He was a surgeon who had the chance of
studying the gastric juice of a soldier with a fistula [52]
(ef. above) .
• J.e. Dalton (1825-1889), cf. above) .
• S.W. Mitchell (1829-1914, cf. above).
• H.P. Bowditch (1840-1911): Harvard, Leipzig (with
Ludwig), Harvard. He improved on Ludwig's
kymograph, description of the "Treppe" and the "all-or-
none law." Bowditch was the first president of the
American Society of Physiology (1887-1889). Fig. ll. William Beaumont (1785-1853). (From [40J)

9
 form new types of experiments with the availability of laureate. Nonetheless, he became chairman of chemistry
chemical and physical methods. In this respect the intro- only 1 year later. Liebig established the most famous
duction of anesthesia by the middle of the century had an laboratory of this kind at that time. In its relevance for
enormous impact. "Vivisection" changed its meaning from biochemistry his laboratory in Giessen was comparable
operations on the nonanesthetized to painless experimen- to that of Ludwig for physiology. Liebig was very rigorous
tation under anesthesia. A third important point was the in his analysis. His intention, which he achieved, was
parallel progress made in many other fields, such as to abandon old misinterpretations and to erect a new
anatomy, histology, pathology, bacteriology, biology, and systematic classification of organic compounds.
physics, and chemistry. A fourth was the strong linkage Liebig left Giessen in 1852 to accept the chair in Munich.
between zoology and physiology. His lectures were famous. They were even social events.
The creation of marine biology stations had a marked im- Many of his speculations were wrong, but they were
pact on the success of physiology during the last century, nonetheless the basis of subsequent experimental
as it still has today. The first one was that in Napoli examination.
("stazione"), which was founded in 1870 by A. Dohrn In Germany Hoppe-Seyler (1825-1895) was another
(1840-1909), a physiologist from Jena who closely collabo- pioneer of this young science. He already lectured
rated with du Bois-Reymond [11]. Modern in "zoochemia cum demonstrationibus" and "chemia
neurophysiology was established and spread out from physiologia et pathologia" in Greifswald (1855). Later he
there. This stazione is still a very important physiology moved to Berlin (with Virchow), where he was appointed
laboratory in Italy (cf. Chap. 110). The marine biology to the chair of applied chemistry [23]. His work focused
laboratory in Plymouth (Great Britain) and that in on hemoglobin. He moved to Strasbourg in 1872, taking
Woods Hole (established in 1892) are closely linked (for the chair of physiological chemistry. He continued his
example) with the pioneering studies on squid axon work most successfully on lipids: lecithin, cholesterol,
(e.g., A.L. Hodgkin and A.F. Huxley [20]). The marine proteins in the nucleus, etc. In 1877 he founded the peri-
biology laboratory in Mount Desert Island in Maine odical Zeitschrift fur physiologische Chemie. One of his
(MDIBL, founded in 1898) has become one of the world famous pupils, W. KUhne (1837-1900), has already been
centers of renal and epithelial physiology during this
century. One of the pioneers at the MDIBL, H.W. Smith
(1895-1962), was one of the founders of renal physiology
[15,41]. His famous book "From Fish to Philosopher" [45]
is just another example for the fact that physiology has
always been a science aimed at a profound and broad
understanding.

6 From Physiology to Biochemistry

It is obvious that biochemistry has its roots in organic and

in medical and animal chemistry. However, as mentioned
above, biochemistry has also logically emerged from the
chemical approach to physiology. The most important
roots of organic chemistry in the eighteenth century
were certainly in France [31,40]. Early in the nineteenth
century one of the important pioneers of this branch of
physiology was J.J. Berzelius (1779-1848), who was ap-
pointed professor of medicine and pharmacy in Stockholm
in 1807.
Berzelius had famous pupils, amongst whom 1. Gmelin
(1788-1853), later professor of medicine and chemistry in
Heidelberg (1817), and F. Wohler (1800-1882), later pro-
fessor of chemistry in Gottingen, should be mentioned.
Wohler is famous for the synthesis of urea, which de-
stroyed the dogma that organic compounds could only be
synthesized by living organisms.
The most outstanding pioneer of biochemistry of this pe-
riod was probably J. Liebig (1803-1873, cf. Fig. 12). Liebig
worked in Paris with J.L. Gay-Lussac. When he was ap-
pointed professor in Giessen at only 21 years of age, he did
not have a postgraduate degree; nor was he even a bacca- Fig. 12. Justus von Liebig (1803-1873). (From [40])

10
mentioned above. For further details of the development Table 1. Nobel prize laureates (1901-1993) working in physiol-
ogy. For the sake of simplification only one more general area is
of this new science in Europe and abroad the reader is
given per year
referred to other publications [18,23,27,29,31,36,44].
Chairs of physiological chemistry had been established in Year Name(s) Area
most medical faculties by the turn of the century. At the
same time specialized societies were founded in many 1904 l.P. Pawlow Control of digestion
1911 A. Gullstrand Optic properties of the eye
countries.
1913 C.R. Richet Anaphylaxis
For the independence of this new science the name "physi- 1914 R. Barany Vestibular function
ological" chemistry was inappropriate, inasmuch as it sug- 1920 A. Krogh Microcirculation
gested that this was nothing but the use of chemical 1924 W. Einthoven Electrocardiogram
approaches in physiology, i.e., just one section of phy- 1932 C.S. Sherrington
E.D. Adrian Reflexes and nerve
siology. The new concept of biochemistry or biological function
chemistry was broader and was therefore generally 1938 C.J.F. Heymans Presso-chemoreceptors
accepted. 1944 J. Erlanger
Starting from one end, biochemists have worked and gone H.S. Gasser Nerve fibers
1945 W.R. Hess CNS mechanisms and
their way for more than 50 years and have approached
A.C. de Abreu neurosurgery
increasingly complex systems. On the other hand, many Freire Egas
physiologists have approached from the other direction, Moniz
simplifying their systems and trying to get down to the 1961 G. von Bekesy Inner ear
molecular level: "molecular physiology." Hence, some 1963 J.C. Eccles
A.F. Huxley
fields in physiology and in biochemistry can no longer be A.L. Hodgkin Neurophysiology and
distinguished. In fact, they are starting to merge (d. be- nerve function
low). 1967 G. Wald
H.K. Hartline
R. Granit Visual receptors and
central processing
1973 K. von Frisch
7 Physiology in Mid-life Crisis? K. Lorenz
N. Tinbergen Behavioral physiology
Physiology is flourishing more and more strongly as the 1974 A. Claude
C. de Duve
turn of this century draws near. The subject is now well G.A. Palade Cellular and subcellular
established in almost every medical faculty (school). A se- physiology
ries of reviews, published on the occasion of the 100th 1977 R. Guillemin
anniversary of the American Physiological Society, beauti- A.V. Schelly
R.S. Yalow Neurobiology
fully summarize the development in the departments in
1981 R.W. Sperry
North America [1,9,10,13,19,22,24,26,28,34,35,39,46]. The D.H. Hubel
reader is also referred to a large number of autobiogra- T. Wiesel Central neuronal
phies published regularly as introductory chapters in processing
Annual Reviews of Physiology. 1986 S. Cohen
R. Lewi-Montalcini Growth factors
Everything is fine, then? Or isn't there a prevailing sense of 1991 E. Neher
uneasiness? If so, what is it about? What are the reasons for B. Sakmann Patch clamp and single ion
it? channel analysis

Specialization. As seen above, the boundaries between

physiology and other sciences are in a permanent state of
flux, with some special fields entering and others leaving it.
A look through the records of the Nobel prize winners in reflects the fact that most scientific work is conducted in
physiology and medicine from 1901 to 1993 shows that the form of cooperative studies, often with specialists from
physiology itself is well represented throughout this period different fields.
(Table 1): If a physiologist of the last century, say Carl Ludwig, were
Obviously, however, the classification used here is subjec- to look at the list of Nobel laureates and their fields of
tive: just 25% of the laureates of the prize for "physiology research, he would have difficulty in understanding the
and medicine" were or are working in physiology proper; specialization and, even if he had more details explained,
20% in biochemistry; 12% in immunology; 12% in genet- he would probably ask: "Why do you call this biochemis-
ics; 12% in clinical areas; 9% in pharmacology; 7% in virol- try? It is physiology! Why does one call functions of the
ogy; 3% in anatomy. This indicates that field boundaries blood and blood cells immunology? Is this not physiology
are permeable. One trend that is characteristic of this cen- proper?" These questions draw attention to the fact that
tury is also apparent from Table 1: very few discoveries can physiology has again undergone profound changes. Many
be ascribed to one single person. These days, more than problems that in the mid-nineteenth century would have
one prize winner is usually elected each year. This also been tackled by a physiologist are now topics within new

11
disciplines. In addition, the progress in physiology and Pf/iigers Archiv). We counted the number of journals con-
related sciences has generated entirely new areas of taining reports on physiology that are listed in the 1993
research. issue of "Life Sciences" in Current Contents; we arrived at
The first half of this century has seen an enormous increase the impressive number of 481.
in our knowledge of system physiology. This makes up a To make this point more clearly, we have analyzed the
large part of the material we teach our students today, and Medline library for the past 12 years and searched for a few
it is the basis of pathophysiology and clinical medicine. items (keywords). Figure 13 shows the results. "Physiol-
With respect to research, specialization and "ultra-spe- ogy" as a term is strongly represented, with an incidence of
cialization" [5] have become seemingly inevitable, because 27,420 in 1982 and 50,055 in 1993. The doubling of citations
of the diversity of certain sections of physiology and of new probably simply reflects the ever-increasing output in sci-
methods. Even more importantly, the results in the various ence, although, in the case of physiology, a saturation
areas of physiology have literally exploded. A general over- started to become apparent in 1989. The term "system
view has become increasingly difficult, if not impossible. physiology," chosen as an indicator of organ-oriented re-
In many departments, new sections have been opened: search, has been keyworded 1500-2100 times over the last
neurophysiology, circulatory physiology, renal physiology, few years, and similarly in the early 1980s. However, in
etc. From this perspective the complete autonomy of areas relation to the increase in physiological literature, system
such as biochemistry, genetics, and immunology appears physiology has lost ground over the last 12 years, from the
not as a loss, but as a timely self-identification of these new relative number of 45 per million to around 30 per million.
areas of research. The term "molecular physiology" has followed just the
This specialization is also readily apparent at the level of opposite trend: it has increased from zero to 3.6 per million
publications: single-author textbooks of physiology have over this period, even though this technical term has only
become a great exception. The number of journals has been around since 1986. Similarly, the term "transduction"
increased steadily, and their titles reflect the degree of had a representation of only 8 per million in 1982, but has
specificity of their topics. Even some of the traditional been rising ever since, reaching 57 per million in 1993. It is
journals of physiology have felt compelled to start inde- not surprising that the term "molecular biology" demon-
pendent sections (e.g., American Journal of Physiology, strates a qualitatively comparable time course: it climbed
from close to nothing (2.5 per million) to 63 per million in
1993. These data appear to indicate two trends: a progres-
sive split into more restricted fields and a concomitant
A reductionism.
100000 physiology
IJl What about the "new" field of pathophysiology? Is it still
c peR
0 10000 part of physiology, as conceived of above as the study of
§ "the logic of life"? Pathophysiology is starting to separate
'0 1000 from physiology, which we perceive as an inappropriate
'0 and dangerous development. For several centuries, physi-
"- lOa
CIl
.0
ology has provided the basis for the understanding of pa-
E 10
thology. If pathophysiology were to be separated from
:::I
c physiology, it would be like amputating a limb from its
body and sentencing the limb to death, without any blood
B3 B4 B5 B6 B7 BB B9 90 91 92 93 supply. Physiology in itself is the basis for understanding
Year disease. Besides, the separation of physiology and
pathophysiology would lead to the dilemma that all prob-
B lems of integration would tend to move to the latter while
80 physiology would drift away into ultraspecializaion.
molecular biology
0
0 Reductioni m. Specialization is inevitable, as a conse-
0 60
quence of the enormous progress in science and draws its
Q) justification from the success in so many different areas.
a. 40
.... Hence, we ought to be grateful and not complain. The real
ClJ
.0 dilemma is probably of a different nature: we have no rea-
E 20 son to complain that immunology and biophysics are sub-
:::I
C jects in their own right, but we must be concerned that
many results obtained cannot be understood at the organ
0
level. The inability of a physiologist to reconstruct organ
82 83 84 85 86 87 88 89 90 91 92 93
function completely on the basis ofhis/her results may be
Year regarded as inevitable and hence acceptable. The point we
want to make is another one: are we really and seriously
Fig. 13A,B. Citations in Medline from 1982 to 1991. Frequency trying to arrive at such reconstructions; are there not too
per year is plotted against year few attempts to bridge the gap between low and high hier-

12
archicallevels of understanding? Is the trend not generally set, not only among scientists, but also in funding agencies
reductionistic? As we are not successful in reconstruction, (see below): "One reason this kind of challenge is stimulat-
what is the reaction? We simply proceed with the dissec- ing is that answers cannot be expected solely from deduc-
tion and call ourselves "molecular physiologists." This atti- tive analysis, but call for creative leaps followed by
tude bears the additional advantage of being fashionable. vigorous efforts to disprove each hypothesis" [4]. Creative
Forget old-fashioned physiology, do it all over again leaps do not generally come along as a bounty, so that
mutatis mutandis, and call it the molecular approach. It is creating a theory and disproving it, or - against Popper -
interesting to search for the signs and symptoms of this trying to find support for it, may be time-consuming and
reaction. It finds its expression in the United States, but hazardous to the career in our increasingly fast and breath
also in Europe, in the renaming of well-established physi- less world (see below).
ology departments. They now call themselves departments A third reason for indulging in reductionism is the notori-
of "cellular physiology"; "molecular and cellular physiol- ous difficulty of running and interpreting experiments on
ogy"; "molecular physiology," etc. But there should be no . whole-animal preparations. Experiments on intact animals
doubt that a higher level of understanding requires putting are difficult to perform, have a lower yield, and require
things that have been split up together again. From this much patience and stamina; as well as all this, interpreta-
perspective it would appear desirable, maybe even neces- tion of the results has to take into account the complexity
sary, that the same laboratory as elaborates the function of of the organism. The analytical approach of physiological
a molecule should also engage in the examination of this experimentation implies that the experiment is designed in
function at higher levels. Even if not all individuals in the such a way that many parameters are controlled. This in
laboratory are able to bridge the gaps, some should be able itself leads research away from a complex to a more re-
to do so. The ephemeral jumping from one new and fash- duced system.
ionable method to another is dangerous, costly, and de- In this venue, the most negative projection would be a
structive (see below). Does it not appear almost as reductionist physiologist who is interested in his small
ridiculous as a man of 50 dressing like a 25-year-old to world only and enjoys his or her microcosm and experi-
attract a young woman of 20? ments throughout his/her academic years without ever
These concerns are especially conspicuous in the asking what it all means to the organism.
neurosciences [7], as beautifully phrased by T.H. Bullock But the pendulum appears to be swinging back: "While
[4]: "We should remind ourselves, however, that the vast molecular and cellular componentry forges ahead, I hear
increase in knowledge still leaves us fundamentally igno- from all sides a resurgence of interest in integrative sys-
rant of how brain cells work together - to achieve recogni- tems level research" [4]. Whole-animal experiments have
tion, evaluation of sensory input, selection, and continued in many areas of physiology. Examples are stud-
coordination of response. We are rich in knowledge of ies on CNS function and development, and studies on the
mechanisms at the level of components: molecular, regulation of circulation, kidney function, respiration, and
intracellular, even some circuits. We are still poor in un- volume status. Many of the subsequent chapters give an
derstanding higher levels, for example, cerebellum, impression of how much new information has been gained
striatum and cerebral cortex or feature extraction, reper- in whole-animal experiments. For the above reasons these
toire selection, and motor control, and still poorer in re- achievements have not received as much attention as the
spect to volition, cognition, and learning, in spite of results obtained with reductionistic methods. But it may be
spectacular advances in each of these areas." predicted that in a few years time, integrative physiology
The trend toward reductionism in the neurosciences has will be on the upswing again, because a heap of uncon-
been supported by scientists shying away from theory: nected details at low hierarchical levels is devoid of the
"Theorizing about brain functions is often considered sense provided by the umbrella of general framework and
slightly disreputable and anyhow a waste of time - perhaps theory.
even 'philosophical'." A neuroscientist randomly plucked
out of the crowd at the Society for Neuroscience meetings Method-oriented v Problem-oriented Research. Another
and asked about the role of theories in the discipline will interesting feature is also apparent from the above figures
probably answer with one of the ideas: (1) "The time for on citations. New and ingenious methods now spread with
theories has not yet arrived, since not enough is known incredible speed. The patch clamp method, in its mature
about the structural detail"; (2) "What is available by way form [17], was published in 1981. The number of papers
of theory is too abstract, is untestable, and is anyhow irrel- citing the term "patch clamp" was 14 in 1982. In 1991 it was
evant to experimental neuroscience"; (3) "You cannot get a a respectable 538. Similarly the polymerase chain reaction
grant for that sort of monkey business." Nonetheless, such (peR) was first described by Mullins (Nobel laureate of
efforts are badly needed: "Without denigrating the popular 1993) and his group in 1986. That year the term was cited 3
search for basic cellular components and fundamental times. In 1993 this number had increased to 6439. It is
common denominators, a true understanding of brain interesting to examine separately how physiology utilizes
function in higher animals has to include the emergent this technique. The combination of the terms physiology
levels of system complexity" [4]. Mutatis mutandis, this and peR makes up 0% of all peR citations in 1986 and
also applies to other fields. Admittedly, the challenge of 1987. In 1988 it amounts to 1.5% , in 1989 to 4.7%, and then
understanding complex systems requires a special mind it saturates at approximately 12%. Therefore, a lag of some

13
2-3 years is still required for the spread of a new method possible, which increases the number of applications, re-
from another discipline, in this case from biochemistry to quiring more reviewers who thus will not have time to do
physiology. research or read (other than proposals) or write or think or
While at first glance this rapid spread of new methods teach. This situation is sick. Why are we sustaining it?
appears encouraging, it may conceal a danger. It may indi- Shortage of funding has other negative effects. If an agency
cate that much of our present -day research is guided by the decides, as one possible policy, to distribute the available
techniques that become available rather than by the prob- money over more grants rather than to reduce the number
lems. Under the current competitive pressures ("publish or of approved grants, these will not be substantial enough to
perish"), researchers may be persuaded to exploit, as far as employ staff and students, which will reduce efficiency and
possible, a certain technique they have mastered without education. Or else, the applicant applies to other
regard to whether the results obtained are meaningful agencies ... The shortage also entails a lack of venture
within a wider context or theory (see above). However, capital, implying an immense pressure for immediate re-
tools are mere tools and should not primarily guide re- sults or, put another way, a lack of patience, which will
search. compromise long-term research projects at high risk. Just
Our own vision at this stage appears to be blurred inas- imagine: had Kant or Darwin been dependent on a three-
much as we accept the current situation, and even admire year grant from a modern funding institution, the Cri-
the beauty of new cellular messengers, channel and trans- tiques or Origin of Species would never have been written.
porter molecules, and forget to ask the more fundamental This shortness of breath also shifts research into easily
questions. Not only are we carried away by our enthu- doable directions, quenching strenuous experiments such
siasm, we also tend to forget to pay tribute to keep our as whole-animal experiments. Finally, this development is
own field in balance. This development is fostered by cur- accelerated by the requirement specified by funding agen-
rent funding policies; no wonder, because these are deter- cies that "modern and highest standards" be used, often
mined to a large degree by scientists on scientific advisory meaning the application oflatest methodology and foster-
committees. ing method- rather than problem-oriented reseach. One
request from our field to these institutions should be that
Funding. In a review and prefatory chapter, E.F. duBois for more independence and freedom.
has summarized the development of physiology during the DuBois' criticism probably also applies to all other
first half of the century in North America and complained sciences, but this is no excuse. It is no excuse at all for
that physiology in the United States has become " ... an physiology, because physiology has gained its strength
acromegalic giant ... ," that previously" ... the professor from the meticulous and careful examination of normal
spent the day making his own physical measurements and function (cf. above Magendie's and Ludwig's influence),
chemical analyses. Then he went home, and a maid cooked and even more so from carefully designed and conducted
the dinner and washed the dishes. Nowadays, it is the tech- experimentation.
nician who makes the scientific measurements, and the
professor washes the dishes after the dinner that has been Competition. The speed with which new achievements are
cooked by his wife" [12]. He continues to complain that the accomplished has increased, not only in our field. This has
professor now has to spend most of his/her time to raise led to a wrong type of competition. What in the last century
research money. "In old times his department was so small was called "friendly competition" [3] among ideas has now
that he could follow in detail the work of his assistants. turned into overt competition for material resources, i.e.,
Now he has less time for a larger staff." For which he has to for grant money and publication in prestigious journals,
obtain the funding, one may add. which is required to receive grant money. This situation is
This is the point of view of someone reflecting about physi- all the more destructive because the physiologist of today
ology in 1950. What would he say today? How much time spends most of his/her time in securing publication and
does today's average physiology professor spend in the grant support (see above). Rethinking and reversal of the
laboratory? How many critical experiments are performed situation are urgent. One trend apparent from the list of
by him- or herself? What prevents him from doing re- Nobel laureates (see above) was that teamwork has become
search in the lab? How much time do we spend in writing? indispensable. On a larger scale, science in general should
How much time in reading? How much is left for running be envisaged as one great cooperative effort. The wrong
experiments? type of competition is not only contrary to this spirit, but
One of the sobering experiences in editing this textbook counterproductive.
was that many of our colleagues who had agreed (by sign- As to publication, it would be fairly easy to escape from this
ing a contract!) to contribute a chapter never delivered it. vicious circle. Why not stay with traditional journals? Why
The reason most frequently given (if any was given at all) do we have to select the vehicle for our papers according to
was that they had to write grant proposals or papers to be the impact factor of the periodical? Are we really able to
submitted with these proposals or to sit on committees to judge which part of our work deserves such special atten-
peer-review others' grant proposals. The shortage of fund- tion? Will the paper be lost if it is published "only" in a
ing reduces the chance of a proposal being successful, traditional journal?
which forces the researcher to apply to as many agencies as With regard to grants, much depends on how society

14
judges the value of science as part of its culture. As long as using the terms "cellular physiology," "membrane physiol-
sport and entertainment stars are most highly valued and ogy" and, especially, "molecular physiology" because we
therefore paid indecently high incomes, science does not wish to emphasize that they all belong under the roof of
stand a good chance of receiving a fair share, unless for physiology. They are ultramicroscopic and microscopic
reasons of prestige. As science lives on from education, it views of organic and organismic function.
should spend part of this effort to entrench its influence on Physiology always has been [2] and will continue to be
societal development. attractive, but it must not become fashionable. This obvi-
ously does not mean that we propose to stay with the tech-
Animal Rights. In the rich Western societies, whole-ani- niques of past decades, but that we should use all new
mal experiments have increasingly met with strong, mostly techniques available without losing our identity. The game
emotional opposition, heated up by often demagogic of physiology is the same, whether played on the organism,
anti vivisectionists. If we experiment on an animal, say a cat organ, cell, or the molecular level. Molecular biology offers
or a dog, or kill a rat to understand how an organ works, we new methods. They are available for every discipline in-
are publicly incriminated. This generally irrational attitude cluding physiology.
has had a large impact on legislation, which has become We can learn from a similar situation that prevailed many
ever more restrictive. In general, little help has come from years or decades ago in morphology. The use of the micro-
our politicians who, irrespective of their political orienta- scope and the electron microscope opened up new worlds,
tion, have not shown much understanding for biomedical yet the microscopic view alone blurs clear vision. Many
research. At the same time, exactly the same societies con- scientists in the eighteenth and nineteenth centuries there-
sume meat of industrially produced animals on a large fore bluntly refused to use the microscope at all [40]. Their
scale, dispose of stray animals at large, kill animals in huge attitude was proven wrong by further developments.
numbers by traffic and other environmentally damaging Hence, we would be ill advised if we succumbed to an
impacts of modern life, take it for granted that medical analogous pitfall in physiology. However, the success of
care and medication be top standard, and enjoy the ben- morphology has been built up on the consistent combina-
efits of this standard which secures a much longer life in tion of available techniques at several levels and the inte-
good health (cf. Chap. 119). This high standard is made gration of all available information.
possible precisely by animal experiments. Thus, the atti- Many new tools are now available and many more will yet
tude against animal experiments is grossly imbalanced, appear and spread rapidly into physiology laboratories.
hypocritical, and cynical. We shall list just a few:
Physiologists, on the other side, have tried to circumvent
these societal pressures by escaping to experiments in cell • Optical techniques (enhanced video microscopy) to
cultures. If it progresses, this development is potentially monitor cell volume and shape.
dangerous, because it will again impede the integration of • Atomic force microscopy to monitor cell shape and
low-level knowledge into understanding of the intact or- membrane shape changes with good time and with
ganism. We have to spend some of our time and efforts to superb spatial resolution.
make it clear to the public that we are neither vivisection- • Fluorescence methods to monitor cellular ion activity.
ists in the old sense nor Frankensteins and that animal • Laser scan microscopy to enhance spatial resolution of
experiments are necessary as long as this public wants to (for example) fluorescence changes while still allowing
cherish its privileges of a good life. reasonable time resolution.
We have referred in this section to physiology'S "mid-life • In situ hybridization of defined nucleic acids.
crisis" because we can identify several behavioral patterns • Antibody labelling of proteins in the cell and on the cell.
in today's physiology that correspond to that phase in hu- • Quantitative studies at the mRNA, DNA (peR), and
man life. It is characterized by a certain degree of satura- protein levels.
tion, ignorance of individual history, and dissatisfaction • Laser activation of caged compounds within the cell.
with the current situation. Is there a way out? • Microelectrodes inserted into cells to monitor voltage
and cellular ion activities.
• Patch clamp methods to monitor single channel events
8 Perspectives on the cell and in excised membrane patches.
• Whole-cell patch clamp methods for monitoring cell
When at last we venture into extrapolating from current surface areas (membrane capacitance measurements),
trends into the future of our science, we are obviously in of cell voltage, and of whole cell currents.
the same notoriously and inevitably poor situation of a • Cellular fractionation techniques, and purification of
weather forecaster; our projections are bound to be tainted membrane vesicles of defined origin. Transport meas-
by much wishful thinking. urements in vesicles.
There is little doubt that physiology will continue to • Purification techniques for cellular proteins.
flourish at the levels of individual cells, cell membranes, • Reconstitution techniques of cellular proteins in artifi-
cellular transduction mechanisms, cellular homeostasis, ciallipid bilayers.
and membrane transport proteins. Intentionally we avoid • Primary cell cultures from well-defined sources.

15
• Establishment of immortalized cell cultures with defined The spectrum of new methods is remarkable. It is obvious
origin. that many of these techniques have their origin in
• Cloning techniques for DNAs of certain proteins. anatomy, biochemistry, and genetics, but also in com-
• Antisense RNA to inhibit endogenous mRNA expres- pletely different fields. Furthermore, the types of question
sion. that will be asked and answered are closely related to those
• Site-directed mutagenesis of cloned proteins. investigated by other sciences. It is thus tempting to leave
• Transgenic animals. behind any "classic" classification of sciences and create a
• "Knock out" animals with well-defined genetic defects. new broad discipline of "life sciences." However, such a
• Alarge number of pharmacological "tools," which can fusion does not appear justified from our viewpoint. The
be used to interfere with certain proteins and other techniques may be identical, the questions may be similar,
molecules. and collaboration is certainly wise. Nonetheless, the anato-
• Computers. Last, but not least, the dizzying develop- mist asks questions in a different way from the biochemist,
ment of computer technology will yield unforeseen ca- and the latter's approach in turn is different from that of a
pabilities of modelling and simulation. These will be the physiologist. The biochemist is interested in the chemical
true tools that are indispensable for real integration. constituents and their interaction, the physiologist wants
Understanding of dynamically complex networks, be to understand their function. The anatomist, e.g. the
they biochemical pathways at cellular level or neuronal neuroanatomist, wishes to understand the wiring and con-
circuits in our brains, cannot be achieved by making use nection of neurons. The neurophysiologist invests his/her
simply of our linear thinking, but requires compara- efforts in understanding the operation and regulation of
tively sophisticated tools. this wiring.
What then about systems physiology? Is it still of perti-
The areas of whole-cell experimentation have profited nence and does it have a perspective? The reasons why
from improved recording techniques and the availability systems physiology has lost ground during the last two
of chronically instrumented animals. In addition, this area decades have been detailed above. But this should not be
gains new momentum as new techniques become avail- taken as a sign of its senescence and ultimate extinction.
able, such as magnetic resonance imaging, positron emis- On the contrary, we believe there will be a resurgence and
sion spectroscopy, and new recording and monitoring prosperous future for systems physiology, which has al-
techniques of brain function. These developments hold ready begun (see above). To foster this development, it
vast promise. appears essential that physiology find and keep its identity
Whole-animal studies are also of specific relevance for amongst the other sciences. And to promote this process, it
pathophysiology. Several genetically defective strains of will be necessary for education to include profound knowl-
animals mimic the symptomatology of diseases in man, edge of general physiology, as was elaborated in the past.
e.g., spontaneously hypertensive rats, diabetes insipidus This is a difficult task, since there is a strong temptation to
rats. The availability of transgenic animals (mostly mice) become expert as soon as possible in a highly specialized
also makes whole-animal experimentation very attractive. area, maybe just the application of a special method. The
A specific type of transgenic animals are those in which one danger is even aggravated by the fact that, especially in the
specific gene is suppressed or knocked out. One most re- United States, teaching and teachers are highly specialized.
cent example is the knock out mouse, which is a conven- The future of physiology will depend on our ability to
ient model to study the pathophysiology and the course of provide and maintain a general background for the entire
cystic fibrosis, for example [8]. field. Besides consolidation of the subject's identity, which
Several of the above techniques can be combined within includes an awareness of its present state and history, a
one experiment, so that a variety of parameters can be sound education is necessary to provide a basis for the
obtained synchronously. Unfortunately, many of these integration of newly explored facts. Only from such a per-
techniques require expensive equipment, which was not spective can one ask further questions which relate to
typically available in physiology departments of former broader contexts than the very detail which has been inves-
times. Also, the expertise of many other disciplines is tigated.
needed. Again, there is some danger that the investment All this implies that physiology, including patho-
required to establish such new techniques leads to a physiological aspects, should retain and possibly streng-
method- rather than question-oriented type of research. then its classic and prominent position in medical schools
We must be on our guard against this. and faculties, as a fundamental basis for medical educa-
There is little doubt that whole-animal studies and tion. After all, physiology is concerned as much now as two
studies on isolated organs will continue to provide a wealth and a half millennia ago with the logic of life and is thus
of knowledge in the field of physiology. We have em- one of the cornerstones of medicine.
phasized throughout this chapter that all physiologists
have to be concerned about the integrative as well as the
analytical aspects in their field. If they neglect this concern
the field will split. If they succeed, the "progressive tri-
umph of physiology over molecular biology" [2] will come
about.

16
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