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Clinician-scientist training A perspective from across the pond.

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Annals of Neurology Vol 68 No 1 July 2010
Rathelot JA, Strick PL. Muscle representation in the macaque
motor cortex: an anatomical perspective. Proc Natl Acad Sci U S
A 2006;103:8257-8262.
DOI: 10.1002/ana.22038
Neurodegenerative Brain Diseases Group, Department of
Molecular Genetics, VIB; Laboratory of Neurogenetics,
Institute Born-Bunge; and University of Antwerp, Antwerp,
Kristel Sleegers, MD, PhD, Nathalie Brouwers, PhD,
and Christine Van Broeckhoven, PhD, DSc
Kim HJ, Seong MW, Yun JY, et al. Predicted pathogenic missense mutation of PGRN found in a normal control. Ann Neurol
2010;67:415– 416.
We took notice with interest of the identification of a missense
mutation (p.Arg564Cys) in progranulin (GRN) in a Korean patient with progressive supranuclear palsy (PSP) and a healthy
Korean individual.1 We previously identified this mutation in a
Belgian Alzheimer disease patient (onset age, 70 years), whose
father was reported to have had late-onset dementia.2 We were
unable to examine segregation of p.Arg564Cys with disease, but
the mutation was absent from ⬎900 control chromosomes. The
mutation affects the protein domain encoding granulin E, a peptide with neuroprotective properties. Although conclusive proof
of a functional effect of p.Arg564Cys is not yet available, several
lines of evidence led us to hypothesize that it may act as a risk
factor for neurodegeneration. The mutation introduces an extra
cysteine residue in a highly conserved motif of cysteine residues,
required to stabilize the characteristic fold of the granulin domains through disulfide bridges between these residues. Mutations affecting the number of cysteines in other proteins containing comparable disulfide bond-rich domains (eg, NOTCH3,
FBN1, UMOD) lead to retention of the misfolded protein in
the endoplasmic reticulum (for review, see Sleegers et al3), forecasting that GRN p.Arg564Cys will lead to a reduction in secreted GRN protein. This is supported by an in silico prediction
of a possibly damaging effect on protein function (PolyPhen), in
vitro data on an identical substitution at a different residue of
GRN (p.Arg432Cys) that caused a 45% reduction in GRN secretion because of a less efficient transport through the secretory
pathway,4 and a marked reduction in serum GRN levels in the
patient carrying GRN p.Arg564Cys.5 Based on these findings,
GRN p.Arg564Cys could act as a low-penetrant risk factor for
neurodegeneration through a partial loss of functional protein,
and with that, of its neuroprotective properties. This implies
that not every mutation carrier unavoidably develops disease.
Even some carriers of pathogenic GRN null mutations are still
free of clinical symptoms at age 70 years. Therefore, the findings
of Kim and colleagues1 do not refute the possibility that
p.Arg564Cys is a risk factor for neurodegeneration. Their findings do re-emphasize that caution is warranted in predictive and
diagnostic testing, particularly in the absence of therapeutic consequences. The presence of this mutation in an Alzheimer patient and now also in a PSP patient underscores the need to
further explore a possible functional effect of this mutation.
Brouwers N, Sleegers K, Engelborghs S, et al. Genetic variability
in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 2008;71:656 – 664.
Sleegers K, Cruts M, Van Broeckhoven C. Molecular pathways of
frontotemporal lobar degeneration. Annu Rev Neurosci (published online ahead of print March 18, 2010).
Shankaran SS, Capell A, Hruscha AT, et al. Missense mutations in
the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin
production and secretion. J Biol Cell 2008;283:1744 –1753.
Sleegers K, Brouwers N, Van Damme P, et al. Serum biomarker
for progranulin-associated frontotemporal lobar degeneration.
Ann Neurol 2009;65:603– 609.
DOI: 10.1002/ana.22056
Clinician-Scientist Training:
A Perspective from across the Pond
James J. P. Alix, MBChB, PhD
As an aspiring clinician-scientist in the United Kingdom, I read
with intrigue the editorial concerning academic medical training
in the United States.1 Academic medicine in the United Kingdom has undergone a revolution, and I would like to draw attention to this.
Medical school in the United Kingdom is typically an undergraduate course lasting 5 to 6 years. Exposure to research is
part of such training, but time at the bench is very limited. A
small number of MB/PhD programs exist and do attempt to
fast-track entrants through BSc, MBChB, and PhD studies in
around 8 years. As a graduate of such a program, I can testify to
the hard work required; nonetheless, there were many positives
to be taken from the training, not least publication of my PhD
work in this very journal.2 However, it is our postgraduate training that has recently undergone transformation.
After years of decline, there is now a clear academic career
pathway in place.3 Academic posts exist at all grades to provide
exposure to research environments throughout post–medical
school training (Fig), which in the United Kingdom involves 4
Medical School
5-8 years
Intercalated BSc
Academic Foundation
2 years
Includes protected
research time
Core and Specialist Academic Training
Approx. 8-10 years
ACF-3 years
Clinical lectureship
4 years
Senior lecturer
Senior fellowship
Training fellowship 3 years
Potential Conflicts of Interest
Nothing to report.
July, 2010
FIGURE: Example of combined clinical and academic training
pathway in the United Kingdom. Academic training can begin
at medical school with further opportunities throughout postgraduate training. ACF ⴝ academic clinical fellowship.
Adapted from Recommendations for Training the Researchers
and Educators of the Future, with permission.3
of Neurology
years of general medical training before entering speciality training. A key feature is that trainees, if they so wish, can experience
research in different specialties during an early part of their career before deciding on specialization. Although it is too early to
say whether the initiative has made a significant difference to
medical academia, many entrants to these new posts achieve
training fellowships to complete PhDs and begin in earnest a
clinical academic career.
In keeping with your editorial, there is some truncation of
our general professional training; however, the targets for exit
remain the same. Similarly, criteria for completion of specialist
training remain unchanged, but this period is not shortened.
Those in the fast lane of training might expect therefore to take
a postdoctoral fellowship in their early 30s. With principal investigator status still some time away, it appears that we are no
closer to unshackling youth than our American counterparts.
With this new framework in place, the United Kingdom
has risen to the challenge of training the next generation of
clinician-scientists, but it is not speed that has driven change. I
would propose that, rather than concentrate on fast tracking a
minority of trainees, there are 3 key concepts to foster research
excellence among medical graduates: (1) opportunities to engage
in research of interest should be open to all medical graduates;
(2) there should be support and mentorship for trainees wishing
to move off-piste should the right opportunities arise; and (3) a
clear career pathway needs to be in place to provide an attractive
alternative to a purely clinical career. It is through an open and
flexible training system that both precocious talents can be nurtured and late bloomers given opportunity. Is it worth all the
effort? Of course, for we all stand to benefit from their hard
DOI: 10.1002/ana.22040
Flexible Residency Program
William J. Weiner, MD
Hauser, Lowenstein, and Johnston addressed the important issue
of prolonged training in neurology and neuroscience.1 The proposed solution is to adopt the “flexible residency program,”
which creates an “intensive research experience” during the neurology residency while “assuring” compliance with Accreditation
Council for Graduate Medical Education regulations regarding
training.2 This proposal, now being widely embraced, fails to
explain exactly how in the same time period (residency) during
which the trainee is developing clinical neurologic expertise, the
time for an “intensive research experience” is to be carved out.
One possible outcome of this program is graduate residents who
are not fully trained in neurology. Will these be the individuals
who come to a clinic 1 half-day a week to diagnose and manage
patients with complicated neurological problems? Is the clinical
practice of neurology a lesser art and science than laboratory
investigation? Or, to put it another way, why does neuroscience
require more training and clinical neurology less?
Department of Neurology, University of Maryland School of
Medicine, Baltimore, MD
Potential Conflicts of Interest
Nothing to report.
Potential Conflicts of Interest
Hauser SL, Lowenstein DH, Johnston SC. Getting youth in the
game: can we accelerate training for clinician-scientists? Ann
Neurol 2010;67:A5–A6.
Hauser SL, McArthur JC. Saving the clinician-scientist: report of
the ANA long range planning committee. Ann Neurol 2005;60:
Nothing to report.
Centre for Neuroscience, Division of Experimental Medicine,
Imperial College, London, UK
DOI: 10.1002/ana.22064
Hauser SL, Lowenstein DH, Johnston SC. Getting youth in the
game: can we accelerate training for clinician-scientists? Ann
Neurol 2010;67:A5–A6.
Alix JJ, Fern R. Glutamate receptor-mediated ischemic injury of
premyelinated central axons. Ann Neurol 2009;66:682– 693.
Report of the Academic Careers Sub-Committee of Modernising
Medical Careers and the UK Clinical Research Collaboration,
2005. Medically and dentally qualified staff: recommendations for
training the researchers and educators of the future. Available at:
http// Accessed 19 March 2010.
Comment from the Editors
We recognize that there are compromises inherent in any
plan that reduces—even modestly—the aggregate clinical
experience acquired during residency. The flexible residency program is designed to satisfy the needs of residents
with deep research interests and career plans that will
combine research and clinical care. It is not intended for
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clinicians, acros, training, scientists, perspectives, pond
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