Head, Geoffrey A.

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Geoffrey A Head

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Frontiers in Physiology

Exciting Challenges Ahead For Integrative And Regulatory Physiology

Geoffrey A. Head

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www.frontiersin.org September 2010 | Volume 1 | Article 127 | 1
SPECIALITY GRAND CHALLENGE ARTICLE
published: 01 September 2010
doi: 10.3389/fphys.2010.00127
Exciting challenges ahead for integrative physiology
Geoffrey A Head*
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
*Correspondence: geoff.head@baker.edu.au
The genetic and “omics” revolution which 
has so gripped biomedical research in the 
last decade, particularly in terms of invest-
ment in large scale infrastructure has at the 
same time challenged traditional areas of 
endeavor such as physiology. Driven by the 
pharmaceutical and biotech industry, high 
throughput “omics” platforms (genomics, 
proteomics, metabolomics, transcrip-
tomics, nutrigenomics) have blossomed, 
providing vast arrays of information the 
complexity of which is requiring its own 
“bioinformatics” specialty area. However, 
each new discovery must be placed in its 
physiological context. From the various 
arrays, potential targets can be further 
examined with high throughput in vitro 
studies which provide the first cast of 
potentially relevant and important infor-
mation as to the cellular context including 
receptor signaling and second messengers. 
However, realization of whether such dis-
coveries are important as novel therapies 
has been problematic in the translation 
of these findings possibly due to insuf-
ficient or absent preclinical animal stud-
ies. This is often due to the unforeseen 
complexity of multicelled/organ/whole 
animal systems which are orders of mag-
nitude greater than in vitro assays. The 
contribution of particular modulators 
thought to be important may in fact be 
minimal due to inbuilt redundancy or 
if effective, off target effects which were 
not predicted by the narrow focus of in 
vitro testing, precluding development of 
the agent further. The drivers to skip the 
preclinical stages of development are time 
and cost. However, the downside is missed 
opportunities and costly but ineffective 
clinical trials. Integrative physiologists 
have a critical role in both the preclinical 
and clinical phases of discovery but are 
often overlooked. Our challenge will be 
to make a strong case for our involvement 
in this process of discovery, designing and 
implementing appropriate experiments to 
truly understand the function in context.
The opportunities arising from the omic 
revolution are enormous and the strides in 
transgenics in particular have been truly 
remarkable. Physiologists have been rein-
vigorated by the arrival of an overwhelm-
ing number of new single double and triple 
knockout combinations of their favorite 
entity. The effort involved in cataloging 
each new and novel phenotype is actually 
an enormous task and perhaps beyond our 
current capacity. In the last few years novel 
tissue specific over expression, constitutively 
active and dominant negative variants have 
emerged which have given us unprecedented 
variety of new tools and disease models. The 
cre–lox system for example has opened up 
the possibility of eliminating specific genes 
in tissues by injecting the cre-recombinase. 
The exciting “grand” challenge for integra-
tive physiologist will be to incorporate this 
new information into an expanding, ever 
more complex view of physiological systems. 
The difficulty is  twofold. Firstly, choosing 
what to investigate is not at all simple given 
the complexity, the specialized nature and 
narrowing of focus required to extract the 
nuances of biological function. It can take 
many years of investigation to properly phe-
notype a mice with a single gene knockout. 
Resources are not limitless and qualified, 
trained and experienced physiologists are 
becoming a rare species. Secondly, the com-
plexity within each area is not conducive 
to a generalist’s approach in which a vast 
array of information needs to be expertly 
constructed into an “integrated” picture of 
physiological function. Can any one person 
realistically be expected to understand the 
intricacies of detail at the molecular, cellu-
lar, tissue organ and whole animal/human 
sufficiently to be able to integrate all of the 
contributions of the system being studied.
An excellent example of this phenom-
enon is the renin–angiotensin aldosterone 
(RAAS) system for regulation of blood pres-
sure and fluid (blood) volume homeosta-
sis. A Medline search of angiotensin (Ang) 
yields a staggering 92000, renin 47000 and 
aldosterone 32000 references. Components 
of the system include a cascade of bioac-
tive peptides starting from the precursor 
angiotensinogen (1-14) and include Ang 
I (1-10), Ang II (1-8), Ang III (2-8), Ang 
(1-7), Ang IV ( 3-8) (Moeller et al., 1998). 
Enzymes involved include renin, proren-
nin, aminopeptidase A and N, neutral 
endopeptidase 24.11, prolyl endopeptidase, 
angiotensin converting enzyme (I and II). 
At the gene level there is can be important 
regulatory steps which for renin include 
promoter and enhancer sequences (Adams 
et al., 2006). Receptors include angiotensin 
receptor 1 (AT
1
) which has a and b isoforms 
as well as AT2 receptors. The receptor for 
Ang IV appears to be an enzyme, insulin reg-
ulated aminopeptidase (IRAP) (Lew et al., 
2003). Evolution has fashioned this system 
of enzymes, protein signaling molecules 
and receptors into performing a myriad of 
actions, not only the regulation of blood 
pressure. There are indeed many different 
tissue renin–angiotensin systems in addition 
to the kidney. A separate RAS is present in 
the central nervous system where in addi-
tion to regulating thirst and the sympathetic 
outflow and therefore blood pressure, it is 
involved in processing sensory informa-
tion, memory, learning, pain (Raghavendra 
et al., 1999) mood and emotional behavior 
(von Bohlen und Halbach and Albrecht, 
2006). RAAS may also influence the loco-
motor system since renin enhancer knock-
out mice have lower locomotor activity 
and angiotensin has been shown to alter 
the release of dopamine in the forebrain 
(Raghavendra et al., 1998). Interestingly, 
mice lacking angiotensinogen have lower 
spontaneous locomotor activity (Okuyama 
et al., 1999). Circulating angiotensin does 
appear to signal centrally through activa-
tion of AT
1
-receptors in circumventricular 
organs which do not have a blood brain 
barrier (Davern and Head, 2007). Moreover, 
the areas within this barrier that are acti-
vated are also rich in AT
1
-receptors. There 
are also many other tissues within the body 
Frontiers in Physiology | Integrative Physiology  September 2010 | Volume 1 | Article 27 | 2
Head Grand challenge for integrative physiology
Davern, P. J., and Head, G. A. (2007). Fos-related anti-
gen immunoreactivity after acute and chronic angi-
otensin II-induced hypertension in the rabbit brain. 
Hypertension 49, 1170–1177.
Leung, P. S., and Sernia, C. (2003). The renin-angiotensin 
system and male reproduction: new functions for old 
hormones. J. Mol. Endocrinol. 30, 263–270.
Lew, R. A., Mustafa, T., Ye, S., McDowall, S. G., Chai, S. Y., 
and Albiston, A. L. (2003). Angiotensin AT4 ligands 
are potent, competitive inhibitors of insulin regulated 
aminopeptidase (IRAP). J. Neurochem. 86, 344–350.
Moeller, I., Allen, A. M., Chai, S. Y., Zhuo, J., and 
Mendelsohn, F. A. (1998). Bioactive angiotensin 
peptides. J. Hum. Hypertens 12, 289–293.
Nishimura, H. (1978). Physiological evolution of the 
renin-angiotensin system. Jpn. Heart J. 19, 806–822.
Nishimura, H. (2001). Angiotensin receptors-- evolutionary 
overview and perspectives. Comp. Biochem. Physiol., 
Part A Mol. Integr. Physiol. 128, 11–30.
Okuyama, S., Sakagawa, T., Sugiyama, F., Fukamizu, A., 
and Murakami, K. (1999). Reduction of depressive-
like behavior in mice lacking angiotensinogen. 
Neurosci. Lett. 261, 167–170.
Raghavendra, V., Chopra, K., and Kulkarni, S. K. (1998). 
Modulation of motor functions involving the 
dopaminergic system by AT1 receptor antagonist, 
losartan. Neuropeptides 32, 275–280.
Raghavendra, V., Chopra, K., and Kulkarni, S. K. (1999). Brain 
renin angiotensin system (RAS) in stress-induced anal-
gesia and impaired retention. Peptides 20, 335–342.
Takei, Y., Joss, J. M., Kloas, W., and Rankin, J. C. (2004). 
Identification of angiotensin I in several vertebrate 
species: its structural and functional evolution. Gen. 
Comp. Endocrinol. 135, 286–292.
von Bohlen und Halbach, O., and Albrecht, D. (2006). 
The CNS renin-angiotensin system. Cell Tissue Res. 
326, 599–616.
Received: 06 August 2010; accepted: 06 August 2010; pub-
lished online: 01 September 2010.
Citation: Head GA (2010) Exciting challenges ahead for 
integrative and regulatory physiology. Front. Physio. 1:127. 
doi: 10.3389/fphys.2010.00127
This article was submitted to Frontiers in Integrative 
Physiology, a specialty of Frontiers in Physiology.
Copyright © 2010 Head. This is an open-access article subject 
to an exclusive license agreement between the authors and the 
Frontiers Research Foundation, which permits unrestricted 
use, distribution, and reproduction in any medium, provided 
the original authors and source are credited.
with Ang I being present in birds, axol-
otl and sea lamprey (Takei et al., 2004). 
The latter is a 500 million year old spe-
cies jawless eel like fish. Homologues of 
the AT
1
-receptor are present in amphib-
ians and birds but low homology with AT 
receptors from teleosts (ray-finned fishes) 
suggests there was a prototype AT receptor 
(Nishimura, 2001). An interesting question 
is whether the evolution of the RAAS which 
paralleled the emergence of amphibians 
was a major factor in dealing with salt and 
water balance thus enabling the transition 
(Nishimura, 1978).
The grand challenge therefore for 
integrative physiologists is to integrate 
the spatial and temporal components of 
regulatory functions at all biological levels 
ranging from the molecular, cellular, tissue 
and organs to clinical studies. “Frontiers in 
Integrative Physiology” will be an excellent 
vehicle to bring new insights into physi-
ological processes and regulatory systems 
as well as their perturbation during path-
ological processes. Submissions which 
include multidisciplinary techniques and 
approaches and that focus on mechanisms 
and regulatory functions are therefore 
strongly encouraged.
RefeRences
Adams, D. J., Head, (equal first author) G. A., Markus, 
M. A., Lovicu, F. J., van der Weyden, L., Köntgen, F., 
Arends, M. J., Thiru, S., Mayorov, D. N., and Morris, 
B. J. (2006). Renin enhancer is critical for regulation 
of renin gene expression and control of cardiovascular 
function. J. Biol. Chem. 281, 31753–31761.
Bernstein, K. E. (2006). Views of the renin-angiotensin 
system: brilling, mimsy, and slithy tove. Hypertension 
47, 509–514.
Boehr, D. D., McElheny, D., Dyson, H. J., and Wright, P. 
E. (2006). The dynamic energy landscape of dihydro-
folate reductase catalysis. Science 313, 1638–1642.
that  utilize a local version of the renin– 
angiotensin system for example in the testes 
where it is involved in regulating male repro-
duction (Leung and Sernia, 2003). Kenneth 
Bernstein wrote recently “One of the great 
challenges scientists face is to develop a com-
fort level viewing biological systems and, in 
particular, the RAS, as part of multifacto-
rial parallel processing.” (Bernstein, 2006) 
This is indeed a challenge which is music to 
the ears of integrative physiologists who are 
most comfortable with multifactorial sys-
tems. The challenge is to engage and partner 
the transgenic specialists in productive col-
laborations to bring together and “integrate” 
new discoveries into the perspective of such 
parallel physiological processes and regula-
tory systems.
There is yet another aspect to the chal-
lenge and that relates to the fourth dimen-
sion “time”. Physiological processes can be 
extremely fast for example protein rota-
tional and conformational changes as well 
as protein–protein interactions have been 
measured in the nanosecond range (Boehr 
et al., 2006). Physiologists are well familiar 
with time frames of seconds, minutes and 
hours while ultradian and circadian proc-
esses have largely been the realm of spe-
cialists in chronobiology and biological 
clocks (Rhythmologists). However, physi-
ological process are as much about devel-
opment, reaching adulthood, successful 
reproduction, aging and transgeneration 
communication (genetic and epigenetic) 
phenomenon and finally evolution. Once 
again the RAAS is a noteworthy example of 
this dimension with for example expression 
of AT
1
-receptor and AT
2
-receptors chang-
ing between development and  adulthood. 
RAAS is teleologically an ancient system 


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