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

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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

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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)

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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

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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

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Cluster 2

DBD

Cluster 1Cluster 3

RTH Mutants Cluster

TR

Dimerization

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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

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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

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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

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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

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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

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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

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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

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SF-1 Drives Differentiation of ES Cells

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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

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"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

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