NOT-OD-04-006: FINDINGS OF SCIENTIFIC MISCONDUCT

Department of Health
and Human Services (HHS)
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FINDINGS OF SCIENTIFIC MISCONDUCT

RELEASE DATE:  November 13, 2003

NOTICE:  NOT-OD-04-006	

Department of Health and Human Services (DHHS)

Notice is hereby given that the Office of Research Integrity (ORI) and the 
Assistant Secretary for Health have taken final action in the following case:

Timothy R. Smith, Ph.D., Michigan State University:  Based on the findings of 
Michigan State University, the respondent’s admission, and analysis conducted 
by ORI in its oversight review, the U.S. Public Health Service (PHS) found 
that Timothy R. Smith, Ph.D., former Postdoctoral Fellow, Department of 
Biochemistry and Molecular Biology at Michigan State University, engaged in 
scientific misconduct in research supported by National Institute of General 
Medical Sciences (NIGMS), National Institutes of Health (NIH) grant P01 
GM57323, entitled  Oxygen utilizing membrane heme proteins. 

Specifically, PHS found that Dr. Smith falsified and fabricated data 
involving research into the physical interaction of prostaglandin 
endoperoxide synthetase-2 (PGHS-2) with cell membranes, and the effects of 
arachidonate and nonsteroidal anti-inflammatory drugs (NSAIDs) on PGHS-2 
structure.

Dr. Smith committed scientific misconduct by falsifying and fabricating data 
for the following tables and figures in his 2000 doctoral dissertation and in 
a paper in the Journal of Biological Chemistry (275:40407-40415, 2000) 
entitled  Arachidonic Acid and Nonsteroidal Anti-inflammatory Drugs Induce 
Conformational Changes in the Human Prostaglandin Endoperoxide H2 Synthase-2 
(Cyclooxygenase-2)  (JBC paper):

I.  JBC paper Table II, entitled  Comparison of inter-residue distances as 
determined by EPR spectroscopy and as calculated from the x-ray crystal 
structures  (and corresponding Dissertation Table 6 entitled  EPR determined 
and X-ray crystal modeled inter-nitroxide distances of PGHS-2 MBD mutants );

II.  JBC paper Table III entitled  Changes in inter-nitroxide differences 
between PGHS-2 holoenzyme and the apoenzyme, and the arachidonate, 
flurbiprofen, and SC58125 complexes  (and corresponding Dissertation Table 
7), entitled  Relative changes in inter-nitroxide distances for NSAID and 
arachidonate complexes compared to the unliganded enzyme );

III.  JBC paper Figure 4 (binding curves) (and corresponding Dissertation 
Figure 20 entitled  Binding curves for the association of heme, flurbiprofen 
and arachidonic acid with PGHS-2 double mutants );

IV.  Dissertation Table 8 entitled  EPR determined inter-nitroxide distances 
for NSAID and arachidonate complexes of PGHS-2 MBD mutants; 

V.  Dissertation Table 9 entitled  Relative changes in inter-nitroxide 
distances for NSAID and arachidonate complexes compared to the unliganded 
enzyme; 

VI.  Dissertation Table 10 entitled  Kinetic properties and NSAID 
sensitivities of PGHS-2 active site mutants; 

VII.  Dissertation Table 11 entitled  EPR determined inter-nitroxide 
distances for NSAID and arachidonate complexes of PGH-2 MBD mutants; 

VIII.  Dissertation Table 12 entitled  Relative PGHS-2 protein incorporation 
of PGHS-2 into lipsomes of varying composition; 

IX.  Dissertation Table 13 entitled  EPR determined inter-nitroxide distances 
for detergent solubilized and lipsome reconstituted PGHS-2 mutants;  and

X.  Dissertation Figure 27 entitled  Lipid and activity profile of sucrose 
gradient fractions. 

The research misconduct was significant for several reasons.  First, the JBC 
paper was novel in that it reported that binding of arachidonate and NSAIDs 
induced structural changes in PHS-2.  For the naturally occurring fatty acid 
arachidonate, this had not previously been shown.  These results could be 
interpreted as having important implications for understanding the catalytic 
mechanism of this enzyme.  In addition, a considerable expenditure of other 
researchers  time and resources was prompted by using results generated from 
the falsified and fabricated data in the JBC paper.

Dr. Smith has entered into a Voluntary Exclusion Agreement (Agreement ) 
in which he has voluntarily agreed:

(1)  to exclude himself from serving in any advisory capacity to PHS 
including but not limited to service on any PHS advisory committee, 
board, and/or peer review committee, or as a consultant for a period of 
three (3) years, beginning on October 27, 2003;

(2)  to exclude himself voluntarily from any contracting or 
subcontracting with any agency of the United States Government and from 
eligibility or involvement in nonprocurement programs of the United 
States Government defined as  covered transactions  in the debarment 
regulations at 45 C.F.R. Part 76 for a period of three (3) years, 
beginning on October 27, 2003.  During the three (3) year period of 
voluntary exclusion, PHS grant funds may be used to pay for page 
charges for any written work currently being prepared for submission 
and/or publication on which Dr. Smith is listed as an author only if 
(I) such written work is unrelated to the misconduct findings described 
in the Agreement, (ii) Dr. Smith is not listed as first author, and 
(iii) the publication does not state that Dr. Smith was supported by a 
PHS grant.  Dr. Smith must certify that all data supporting such 
written work is true and accurate to the best of his knowledge; and

(3)  to submit a letter within 30 days of notification of this action 
to JBC requesting retraction of the following paper:  Smith, T., 
McCracken, J., Shin, Y.K., & DeWitt, D.   Arachidonic Acid and 
Nonsteroidal Anti-inflammatory Drugs Induce Conformational Changes in 
the Human Prostaglandin Endoperoxide H2 Synthase-2 (Cyclooxygenase-3).   
J. Biol. Chem. 275:40407-40415, 2000.  Dr. Smith agreed that the 
retraction will state that he alone was responsible for the 
falsification and fabrication of the results and will specifically list 
the falsified figures delineated on page 1 of the Agreement (Findings 
I, II, and III).  Dr. Smith must submit a draft of the retraction 
letter for ORI approval prior to sending it to JBC.  This requirement 
for retraction will be noted on the ALERT System until Dr. Smith sends 
a copy of the retraction letter to ORI.

INQUIRIES

For further information contact:

Director
Division of Investigative Oversight
Office of Research Integrity
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