1
ITMAT
July 27, 2011
J. Larry Jameson, M.D., Ph.D.
Dean, Perelman School of Medicine
Career Pathways for Physician-Scientists
2
Residency University Clinical
Fellowship
Mid
Career
First faculty Appt
Late
Career
Retirement
Medical
School
4y 8y 3y
2y
Enthusiastic,
talented but nervous
Entitled
and
invincible
Humble but
quick
learners
Confident
and
Reflexive
Top of game &
Perplexed about
Career
Post-tenure
bliss
Wise but few
new tricks;
Accelerate or
wind down
$ Business of running a
research team $
10y
10y10y
Other end of
stethoscope
22 30 33
35
4555
65
Life Cycle of a Physician Scientist
3
Overview
• Research context for physician-scientists
• Nationally
• At Penn
• An analysis of one person‟s career path
• A little science with a few pearls
• Discussion
4
The Pipeline Is Narrow
Copyright restrictions may apply.
Ley, T. J. et al. JAMA 2005;294:1343-1351.
Composition of the Physician Workforce in the United States, 1980-2003
5
MSTP Enrollment Is Growing… Slowly
Copyright restrictions may apply.
Ley, T. J. et al. JAMA 2005;294:1343-1351.
Numbers of Matriculating MD-PhD Students in the United States, 1990-2004
6
Medicine, 29%
Surgery, 11%
Pediatrics, 10%Pathology, 8%
Neurology, 8%
Radiology, 7%
Psychiatry, 6%
Dermatology, 5%
Radiation oncology, 3%
Postdoc, 5%
Ophthamology, 4% Anesthesiology, 2%
OB/Gyn, 1%
Emergency Medicine, 1%
MD-PhD program graduates
Brass et al., Academic Medicine, April 2010
95% do residencies
7
Re
sid
en
cy c
ho
ice
0%
10%
20%
30%
40%
50%
60%
70%
80%
1965-1978 1979-1988 1989-1998 1999-2007
Medicine/Neurology/Pathology/Pediatrics
Dermatology/Ophthalmology/RadiationOncology/Surgery
Graduation year
Trends in residency choices
MD-PhD program graduates: residency
8
Academia, 68%
Research Institute, 5%
Industry, 8%
Private Practice, 16%
Other, 3%
MD-PhD program graduates: Long term outcomes
Brass et al., Academic Medicine, April 2010
9
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Yes No No data
82%
13%5%A
re y
ou
do
ing
rese
arch
?
Research by MD-PhD program graduates
Are you doing research?
0%
10%
20%
30%
40%
50%
60%
70%
Yes No No data
61%
14%
25%R
es
ea
rch
fu
nd
ing
Do you have research grants?
0
100
200
300
400
500417
304 314
11
Typ
es
of
rese
arch
What kinds of research are you doing?
Brass et al., Academic Medicine, April 2010
10
An “Objective” Analysis of One
Person‟s Path — Mine
11
Harrison’s
Editor
President
Endo SocDean
NorthwesternChair, DoM
Northwestern
1980 1985 1990 1995 2005
ASCI
MGH
Endo Fellowship
MGH
Residency
AAP AAAS
MSTP
UNC
IOM
DeGroot
Editor
Chief, Endo
Northwestern
Van Meter Award
ATA
Oppenheimer
Endo Soc
PMM
Editor
Chief, Thyroid
Unit MGH
HHMI
MAB
ABIM
30 40 50
Dean
Penn
Career Path
Koch Award
Endo
Training &
Leadership
Recognition
Editorial
12
ENU
Mutagenesis
Transgenic
miceGene
Knockout
1980 1985 1990 1995 2005
Cloning
PCR
Transfection
CAT/Luc Assays
DNA
Sequencing
ChIP
Assays
Human Mutation
Analyses
In situ
Automated
DNA SequencingMac
Computer
Gel shift
Assays
„Omics
Impact of Disruptive Technologies
13
0
50
100
150
200
250
0
5
10
15
20
25
30
85-8
6
87-8
8
89-9
0
91-9
2
93-9
4
95-9
6
97-9
8
99-0
0
01-0
2
03-0
4
05-0
6
To
tal Im
pa
ct
Nu
mb
er
of
Art
icle
s/A
ve
rag
e I
mp
act
Years
Number of Articles Average Impact Total Impact
Instructor
Independent
Lab at MGH
Move to
NW
Harrison‟s
Chair, Medicine
R29R01-CG R01-CG
R01-GR
U54
R01-TSH
U54
R01-TSH
PO1 PO1U01-ENU
R01-DAX1SPOREDOD
Balancing Science and Leadership
14
Reflections on the Data
• Grants should be staggered
• Collaborative grants stimulate new research areas
• New technologies drive laboratory science
But, are not sufficient … novel ideas are necessary
• Clinical relevance engenders interest
• A high impact paper is usually no more work
• The quality of the team & its chemistry are key ingredients
• Build relationships with colleagues and mentors
• Leadership roles consume time & energy but have impact too
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Perelman School of Medicine
• Collaboration and collegiality are hallmarks of this institution
• Long standing tradition of scientific excellence
• Attract faculty of the highest caliber from across the country
• A rich environment for faculty professional development
• Institutional commitment to mentoring
16
17
18
$262$304
$360 $371$426
$477$508 $509
$541 $539 $533$575
$690
$0
$100
$200
$300
$400
$500
$600
$700
$800
FY 98 FY 99 FY 00 FY 01 FY 02 FY 03 FY 04 FY 05 FY 06 FY 07 FY 08 FY 09 FY 10
PENN PSOM Funding Trends: Total
FY98 - FY10
PENN NIH Rank
#2 #2#2 #2#3 #2#2 #3#3
Growth in Total Research FundingD
oll
ars
in
milli
on
s
Total Research Funding
ARRA Funding
#3 #3 #3*
$4.7
$106
#3*
* Estimated based on preliminary data
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Number of
Articles
Source: PubMed Search Engine; CSC Analysis
Penn SOM Publications in Top Tier Journals
Number of Penn Articles per Journal
Top 13 Journals by “Impact”CY03 (77)
CY06 (97)
CY09 (145)
57
12
4
6
10
54
3
7
4
7
3
65
11 11
1
10
45
13 13
75
6
12 12
18
4
21
16
9
5
12
18
87
3
0
10
20
30
Cel
lN
ature
Genetics
NEJM
Nat
ure
Medic
ine
Nat
ure
Sci
ence
Imm
unity
Gen
es
& D
eve
lopm
ent
Mole
cula
r C
ell
JA
MA
J. E
xp. M
ed
Neu
ron
EM
BO
J
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Major SOM Facilities
Clinical Research
Building
204,211 GSF
Biomedical
Research Building
385,000 GSF
Blockely Hall
166,425 GSF
21
School of Medicine Facilities
Translational Research Center
Dedication May 3, 2011
531,373 GSF (400k GSF SOM)
22
A Few Vignettes
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MW presented at age 15 months with developmental delay
and growth retardation. Her pulse was 140 bpm.
TFT‟s included: T4 = 33 g/dL
TSH = 3.2 mIU/mL
RTH was diagnosed. By age 7, she
developed chest pain, shortness of breath,
and experienced tachycardia (>200 bpm)
with exertion. ADHD was severe. She was
treated with -blockers and methimazole,
resulting in clinical improvement but
worsening goiter.
Analysis of the TR gene revealed an
Leu 454 Ser mutation.
RTH: A Dominant Negative Mechanism
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Free T4, T3
Inappropriately normal TSH
TRTachycardia
Hyperactivity
-
-
T4 & T3
TR
+
+
TSH
T4
Hypothalamus
T3
TRH
Peripheral Actions
25
WT+
TR Mut
DN
Activ.
+T3
WT+
TR Mut
DN
Activ. +T3
Positive Regulation: TREtk
Basal WT
Lucifera
se A
ctivity
+T3
+T3
Negative Regulation: TSH
Basal WT
+T3+T3
Chatterjee VKK et al., J Clin Invest 1991; 87:1977
RTH Mutants: Dominant Negative Effects
26
Cluster 2
DBD
Cluster 1Cluster 3
RTH Mutants Cluster
TR
Dimerization
27
DBD
P214R
NCoR-
L428R
Dimer-
C127S
DBD-P453H
RTH
TR
DBDRTH / DBD-
DBDRTH / NCoR-
DBDRTH / Dimer-
Luciferase Activity
DBDWT
DBDRTHWT +
WT +
WT +
WT +
Nagaya T et al., J Biol Chem 1993; 268:15766
Mechanism: 2nd
Site Mutations
28
Normal
TRMutant
TRRXRs
T3 T3
Normal
TR
M
Mutant Thyroid Hormone Receptors:
• Retain DNA binding
• Retain dimerization
• Retain transcriptional repression
• Lack transactivation
• Block wild type receptor action
TRE
T3 T3 T3
M
T3
CoR
Role of Mutant Receptors in RTH
M
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Gonads
Pituitary
LH
FSH
GnRH
LH pulses
GnRH pulses
KAL1
FGFR1
GPR54
SF1**
DAX1 **
LEP
LEPR
GNRHR
SF1
DAX1
LHB
FSHB
WT1
SF1
SRY
SOX9
DAX1
FOXL2
RSPO1
ATRX
DHH
FSHR
LHR
AMH
AMHR
WNT4
INSL3
AR
ER
Genetic Disorders of HPG Axis
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An Exception to a Venerable Rule
17 year old presents with pubertal delay. Treated with testosterone for 2
years; no evidence of spontaneous puberty after hormone withdrawal.
Karyotype XY FSH normalLH increased, low testosterone ? 1o gonadal failure
Testicular biopsy: Leydig cell hypoplasiaArrest of spermatogenesisLH stimulation normal testosterone !!
Serum LH bioactivity reduced when tested in vitro
Family history: ConsanguinityInfertility in 3 maternal uncles
Hypothesis: Mutation in LH gene
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33
I
II
III
IV
V
Proband
• LH = 64.2 IU/L
• FSH = 113 IU/L
• Testosterone = 51 ng/dL
2
Weiss et al; N Engl J Med 1992; 326:179
1st Gonadotropin Gene Mutation
32
1 41 42 121
Gln 54 Arg
RIA
Bioactivity
LH
IU
/L
0
10
20
30
40
50
Wild type Gln 54 Arg
LH Gene Mutation Eliminates Bioactivity
33
1 461
Zinc A
fingers box AF-2
DAX1 GKD DMD Xp21
1 Nuclear Receptor-like
DAX-1: Dosage sensitive sex-reversal,
Adrenal hypoplasia congenita, X-chromosome
Honda S et al: J Biol Chem 268:7494, 1993
Zanaria E et al: Nature 372:635, 1994
470
Nuclear Receptors SF-1 and DAX-1
SF-1: Steroidogenic Factor-1
34
Abnormal VMH
GnRH deficiency
Gonadotropin deficiency
Adrenal agenesis
Gonadal agenesis
XY sex reversal
Mullerian structures present
Decreased Dax-1
Luo X et al: Cell 77:481, 1994
SF-1 Knockout Mouse
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1 cm
MDYSYDEDLDE FFKRTVQNNKHY FQKCLTVGMRLEAVR
GY
Y
S
DKV
G H
GC
VPC
L
LL
CT
SE
C
G
Zn
K
K
K
RKR
CS
QSE
CCRT
Zn
C
TF
P
DI
TQ
E
“P” box
“D” box
Zinc finger I Zinc finger II
P box
Achermann JC et al. Nat Genet 22:125, 1999
Heterozygous G35E Mutation in SF-1
36
SF1
Mutation
Genotype Karyotype-
Phenotypic
sex
Adrenal
Function
Gonad Uterus Year
Published
G35E heterozygous XY-female Failure Dysgenetic Present 1999
R255L heterozygous XX-female Failure Ovary Present 2000
R92Q homozygous XY-female Failure Dysgenetic Present 2002
Deletion heterozygous XY-female Normal Agenesis Absent 2004
C19X heterozygous XY-female Normal Dysgenetic Present 2004
18delC heterozygous XY-female Normal Dysgenetic Absent 2004
C19X
R255L
18delC
SF1 mutations account for ~10% of XY gonadal dysgenesis
Human SF-1 Mutations
37
cholesterol
pregnenolone
progesterone
deoxycorticosterone
corticosterone
18-OH B
aldosterone
17α-OH P5
17α-OH P4
11-deoxycortisol
cortisol
DHEA
estrone
androstendiol
testosterone
17β-estradiol
Δ4-androstenedione
StARCYP11A1
3β-HSD
CYP21A1
CYP11B1CYP11B2
CYP11B2
CYP11B2
CYP17
CYP19
17β-HSD
Steroidogenic Pathways
38
SF-1 Drives Differentiation of ES Cells
39
Summary Points
• Identify and leverage your unique strengths
• Recognize and adopt disruptive technologies
• Surround yourself with high quality people
• Aspire to high impact research
• When in doubt….adapt to changes
• Make your research clinically relevant
40
"Be inspired by the knowledge that exists at the time you
train, but be irreverent toward this knowledge...for this is
the road to true understanding” -Charles Janeway, M.D.-
Eaton’s Portrait of Agnew
Science Evolves Continuously
41