Novartis Foundation Bulletin |
| Issue
6, July/August 2001
Welcome to the sixth edition of the Novartis Foundation's e-mail Bulletin. This issue features reports on:
The emerging truth about intersex conditions (Based
on presentations given at the Novartis Foundation symposium: The
genetics and biology of sex determination, held in London 1–3 May
2001) 'Is it a boy or a
girl?' parents ask at the sight of their newborn. In some circumstances
however, there will be no ready answer. Up to 1 in 3000 babies are
born intersexed--where it is impossible to tell if a child is male
or female. Traditionally, surgery has been employed to 'normalise'
ambiguous genitalia as early as possible. But an increasingly vocal
group of intersex people are now protesting that many of these techniques
can be mutilating and harmful. Intersex conditions
include a variety of genital anomalies, often an enlarged clitoris
or a very small penis, with an inadequate vagina or underdeveloped
testes. The most common disorder is Congenital Adrenal Hyperplasia
(CAH) owing to 21-hydroxylase deficiency. Girls with this enzymatic
defect are genetically female but produce an excess of androgens
starting in fetal life. This results in an unusually large clitoris
and fused labia. Thirty years ago,
it was common practice to remove the clitoris completely to feminize
genital appearance. Today clitorectomy is thankfully rare with surgeons
preferring to trim down the enlarged tissue to retain the nerve-rich
glans area and so preserve sensation. But a follow-up study of adult
intersex women by gynecologists at the University College London
Hospitals (UCLH), Catherine Minto and Sarah Creighton, has shown
that the more recent technique of clitoral recession, is not entirely
successful. '...Of those whose clitoris was operated on, one in
four would not be able to reach orgasm at all,' explains Creighton. Also under fire is
early vaginoplasty--in which a vagina is constructed with a portion
of the patient's gut or with skin flaps. Intervening in the first
12 months, surgeons claim, guarantees a better outcome, and avoids
further surgery. But new results from the UCLH team, examining 45
adolescent girls, showed 77 per cent still needed further major
surgery, prompting Creighton to ask: '..they don't need a vagina
as a baby. Why don't we leave that [surgery] until they are old
enough to be involved in the decision?' But is it ethical
to wait that long? Children left in a gender limbo will encounter
numerous obstacles in our sexually dimorphic society. Additionally,
anguished parents may struggle to accept an intersexed child and
opt for early corrective surgery. As INSERM researcher Nathalie
Josso (Montrouge, France) points out: 'We find that many parents
have strong opinions themselves, and this can influence clinical
decisions.' But where the debate
grows fierce is over the management of boys with a micropenis-a
rare disorder that affects 1 in 50,000 XY males. Because penile
reconstruction is technically more difficult than creating a vagina,
these boys are castrated and surgically reassigned as females, often
before they are a week old. Psychiatrist and
urologist William Reiner (Baltimore, USA) has followed infants with
cloacal exstrophy--born with normal testes but no penis. Despite
early feminizing surgery and being reared as girls, most exhibit
strong male behaviours and switch back to a male gender between
the ages of 5 and 16. 'If you have a Y chromosome, you have to be
very worried about raising this child as female,' he warns. Other long-term studies
are less condemning. 'Many patients are content with their own early
surgery,' concludes psychologist Heino Meyer-Bahlburg (New York,
USA). He finds that it is often the secrecy surrounding these conditions
that can have devastating psychological consequences. Ever-increasing knowledge
of the genetic and endocrine bases of intersex and data from follow-up
studies are shedding light on this controversial issue. As Eric
Vilain (California, USA) remarked at the Foundation's symposium
in May: 'Medical practice is now very cautious and does not use
surgery without at least a specialized team of people from various
disciplines...the problem is isolated surgeons making decisions
on their own without understanding what is going on.' To Melvin Grumbach
(California, USA) one consideration is paramount: 'Cosmetic appearance
is not the big thing, it's how they will function as an adult.' Lisa
Melton is Science Writer at the Novartis Foundation
The full version
of this article appeared in the June 2001 issue of The Lancet,
Vol. 357, No. 9274 ‘The genetics
and biology of sex determination’ will be published by Wiley in
February 2002 Hyperexciting
developments with voltage-gated sodium channels! (Based
on a presentation at the Novartis Foundation symposium: Sodium channels
and neuronal hyperexcitability, held in London, 14–16 November 2000) The majority of genes
encoding mammalian voltage-gated sodium channels have now been discovered.
The functional diversity of channels, their patterns of expression,
interaction with regulatory subunits, and association with disease
states, or 'channelopathies', were reviewed at the Novartis Foundation
meeting in November last year. Voltage-gated sodium
channels comprise a family of proteins whose conservation of structure
is contradicted by a bewildering, but thankfully recently streamlined,
nomenclature. The functional channels are single large proteins,
comprising four repeated domains of six transmembrane segments folded
into sodium selective pores, and activated by changes in membrane
potential. Two of the channels are primarily expressed in muscle,
and others in complex patterns in central and peripheral neurons
and glia. A family of 10 channel genes exist in mammals, organized
within four paralogous chromosome segments adjacent to the HOX gene
clusters. As human and mouse
genome sequencing comes close to completion it seems unlikely that
additional functional alpha-subunits, which comprise the channel
pore-forming regions and voltage sensors, will be uncovered. However,
two novel beta-subunits, responsible for regulating channel expression
and kinetics and sub-cellular localisation, have recently been identified.
Lori Isom (Ann Arbor, USA) and Bill Catterall (Seattle, USA) highlighted
interactions of sodium channels with many proteins including extracellular
and cytoskeletal elements and tyrosine phosphatases and synaptotagmin,
suggesting that other accessory subunits may well exist. But what are all
these sodium channels for? Interpretations of their pattern of expression
in different neuronal subsets and in vitro expression and
analysis can identify differences in pharmacology and kinetics.
The association of channel dysfunction with various pathological
states gives clues to the normal physiological role of channel isoforms. Hyperexcitability,
as exemplified by epileptic activity, may be intimately associated
with sodium channel dysregulation. The dramatic effects of dysregulation,
leading to epilepsy and other subtler disorders, are now emerging.
Michael Segal (Harvard, USA) demonstrated the persistent sodium
channel activity that leads to epileptiform activity, in hippocampal
neurons, thus aiding in identification of potential anticonvulsants.
Louis Ptacek (Utah, USA) discussed mutants of Nav1.4 that give rise
to familial periodic paralyses characterised by episodes of muscle
weakness induced by stress or fatigue. Various channelopathies
involve mutant subunits. Miriam Meisler (Ann Arbor, USA) noted that
mutations in Nav1.1 result in type II epilepsy with febrile seizures,
whereas beta-1 subunit mutations cause the type I syndrome. Jeff
Noebels (Baylor, USA) suggested the recent discovery of the co-expression
of the cardiac channel Nav1.5 in the limbic system may explain why
mutations in this channel lead not only to LQT syndrome but also
to epilepsy. Indirect effects
on channel expression can also have deleterious effects. Steve Waxman
(Yale, USA) discussed the aberrant sodium channel expression within
the CNS in various demyelinating diseases. He also considered the
pattern and plasticity of sodium channel gene expression in sensory
neurons in various pain pathologies, and correlated altered channel
expression with changes in excitability. Expanding on this, Stuart
Bevan and John Wood (London, UK) emphasised the increasing interest
in sodium channels as potential analgesic drug targets, particularly
in neuropathic pain. This meeting underscored
advances in the past decade in appreciating the role of sodium channels
in the function of excitable tissues. Identification of new mutant
or polymorphic channel or regulatory genes may identify therapeutic
targets for additional pathologies. These are indeed exciting times
in sodium channel studies. John
Wood is Professor of Molecular Neurobiology at University College,
London
The full version
of this article can be found in Trends in Neuroscience, Vol. 24,
No. 4, John Wood, Hyper-exciting developments in Sodium channels,
p 197-198, 2001, http://www.elsevier.com/locate/tins
‘Sodium channels
and neuronal hyperexcitability’ will be published by Wiley in November
2001 (A
Report from the bursar of the Novartis Foundation symposium: Causes
and consequences of acidic pH in tumours, held in London 10-12 October
2000) ***The symposium
bursary scheme enables young scientists from any country to attend
symposia as active discussants and then spend up to 12 weeks in
the laboratory of one of the participants. This scheme has attracted
over 1500 applications from 20 countries. In all, more than 100
bursaries have been awarded*** Acidity is a common feature of most tumour tissues. Over eighty years ago, Warburg originally reported this to be mainly due to the high rates of aerobic lactate production. More recent work by Ian Tannock's group (Toronto, Canada) demonstrated that cells engineered to lack this capacity to produce lactate are still able to generate tumours with an acidic environment. Uncertainty about the real causes of tumour acidity and its potential role in tumour development has prompted increased research efforts during the last decade. The 'Acidic pH in tumours' symposium, held in London last year, was a unique opportunity to gather internationally recognised specialists in this topic. Attending this symposium was an exciting and useful experience, especially whilst completing my PhD dissertation: 'Alterations in pH regulation in animal tumour models'. The meeting gave me a deeper insight into this subject, provided directly by the most relevant investigators in this field. My subsequent bursary period was spent in Professor Gillies's laboratory, at the Cancer Center in Arizona University, where I worked in the improvement of high-resolution magnetic resonance spectroscopic imaging (1H MRSI) approaches for extracellular pH (pHe) measurement in vivo. An obvious consequence of extracellular acidification is the inverse pH gradient across the plasma membrane in cancer cells as compared to normal cells. This is important since most chemotherapeutic agents are weak bases or weak acids, and their distribution between intracellular and extracellular compartments depends on transmembrane pH gradient. Hence, the non-invasive measurement of pHe in tumours has, in principle, great potential to assess the most adequate cancer therapy. Recent collaboration between my laboratory in Spain, led by Sebastián Cerdán and Paloma Ballesteros, and Robert Gillies and Zaver Bhujwalla's groups in the US, has developed a novel 1H NRM indicator, 2-imidazol-1-yl-3-etoxycarbonylpropionic acid, for pHe measurements by 1H MRSI. This imaging also offers the attractive possibility of studying correlations between pHe and the distribution of important metabolites, such as lactate, since they can be simultaneously measured. Over the last two years I have been investigating this feature, jointly with Michel Decorps and colleagues in Grenoble, in a model of rat glioblastoma. We found an extracellular pH that was lower than the intracellular one, and supposedly lower than pHe in normal brain, although this has not so far been measured. This was one aspect that I addressed with Dr. Shornack, during my stay in Arizona. We received promising results supporting the feasibility of obtaining pHe maps even in the normal brain. Nevertheless, a principal problem with these experimental approaches is the still poor spatial resolution provided by MRSI. Tumours are known to exhibit a disorganised vascular system, giving rise to heterogeneous supply of oxygen and nutrients. Since pHe and hypoxia are intimately related, pHe is also heterogeneous. This heterogeneity occurs in the range of microns, which is still far from the current spatial resolution available to most MRSI machines. Improvements in resolution may be achieved in the near future from new generations of high field magnets (up to 17.6 T), which are increasingly available. Next January I will be joining Professor Gillies's laboratory as a postdoctoral student and continue working in this increasingly exciting field. I am grateful to
the Novartis Foundation for giving me the opportunity to attend
the symposium and for providing the funds for my bursary period
in Arizona. I enjoyed both activities enormously. I am also grateful
to Professor Gillies for his advice during my stay in his laboratory. María-Luisa
García-Martín is currently based at the Instituto
de Investigaciones Biomédicas "Alberto Sols" CSIC/UAM,
Madrid, Spain
‘The tumour microenvironment: causes and consequences of hypoxia and acidity' will be published Wiley in September 2001 For abstracts from
the symposium see http://www.novartisfound.org.uk/fp240.htm For details the bursary scheme and forthcoming bursaries see http://www.novartisfound.org.uk/bursary.htm The
Novartis Foundation bursary scheme
The aim of the bursary scheme is to enable young scientists to attend Novartis Foundation symposia and, immediately following the meeting, spend up to 12 weeks in the department of one of the symposium participants. Applicants (of any nationality) must be aged between 23-35 years on the closing date for application. It is essential that they be actively engaged in research on the topic covered by the symposium. They should not already have accepted an invitation to participate in that symposium. The
award includes: For
more details see http://www.novartisfound.org.uk/bursary.htm Meetings Other forthcoming
open meetings include: To book your place
at these meetings please contact the open meetings organizer Symposia: Discussion meetings: Publications Complexity
in biological information For
details of this, and other recently published books and how to order
see: http://www.novartisfound.org.uk/nbook.htm Book
Sale 2001
Publicity Reports: Hospitality Personalia
On the 11th July we were pleased to welcome Trustees, members of the Executive Council and UK Scientific Advisors to join staff at the Annual Dinner, following the Executive Council annual general meeting. As announced in issue 4, the new year heralded the appointment of two new members to the Executive council: Sir Paul Nurse Professor John Westwick Full details of personalia and activities
at the Novartis Foundation can also be |