Genomic responses in mouse models poorly mimic human inflammatory diseases
- Junhee Seoka,1,
- H. Shaw Warrenb,1,
- Alex G. Cuencac,1,
- Michael N. Mindrinosa,
- Henry V. Bakerc,
- Weihong Xua,
- Daniel R. Richardsd,
- Grace P. McDonald-Smithe,
- Hong Gaoa,
- Laura Hennessyf,
- Celeste C. Finnertyg,
- Cecilia M. Lópezc,
- Shari Honarif,
- Ernest E. Mooreh,
- Joseph P. Mineii,
- Joseph Cuschierij,
- Paul E. Bankeyk,
- Jeffrey L. Johnsonh,
- Jason Sperryl,
- Avery B. Nathensm,
- Timothy R. Billiarl,
- Michael A. Westn,
- Marc G. Jeschkeo,
- Matthew B. Kleinj,
- Richard L. Gamellip,
- Nicole S. Gibranj,
- Bernard H. Brownsteinq,
- Carol Miller-Grazianok,
- Steve E. Calvanor,
- Philip H. Masone,
- J. Perren Cobbs,
- Laurence G. Rahmet,
- Stephen F. Lowryr,2,
- Ronald V. Maierj,
- Lyle L. Moldawerc,
- David N. Herndong,
- Ronald W. Davisa,3,
- Wenzhong Xiaoa,t,3,
- Ronald G. Tompkinst,3,
- the Inflammation and Host Response to Injury, Large Scale Collaborative Research Program4
- aStanford Genome Technology Center, Stanford University, Palo Alto, CA 94305;
- Departments of bPediatrics and Medicine,
- sAnesthesiology and Critical Care Medicine, and
- tSurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
- cDepartment of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
- dIngenuity Inc., Redwood City, CA 94063;
- eDepartment of Surgery, Massachusetts General Hospital, Boston, MA 02114;
- fDepartment of Surgery, Harborview Medical Center, Seattle, WA 98195;
- gShriners Hospitals for Children and Department of Surgery, University of Texas Medical Branch, Galveston, TX 77550-1220;
- hDepartment of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO 80045;
- iDepartment of Surgery, Parkland Memorial Hospital, University of Texas, Southwestern Medical Center, Dallas, TX 75390;
- jDepartment of Surgery, Harborview Medical Center, University of Washington School of Medicine, Seattle, WA 98195;
- kDepartment of Surgery, University of Rochester School of Medicine, Rochester, NY 14642;
- lDepartment of Surgery, University of Pittsburgh Medical Center Presbyterian University Hospital, University of Pittsburgh, PA 15213;
- mDepartment of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada M5B 1W8;
- nDepartment of Surgery, San Francisco General Hospital, University of California, San Francisco, CA 94143;
- oDivision of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada M4N 3M5;
- pDepartment of Surgery, Stritch School of Medicine, Loyola University, Chicago, IL 60153;
- qDepartment of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110; and
- rDepartment of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903
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Contributed by Ronald W. Davis, January 7, 2013 (sent for review December 6, 2012)
Abstract
A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
Footnotes
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↵1J. Seok, H.S.W., and A.G.C. contributed equally to this work.
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↵2Deceased June 4, 2011.
- ↵3To whom correspondence may be addressed. E-mail: dbowe{at}stanford.edu, wxiao1{at}partners.org, or rtompkins{at}partners.org.
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↵4A complete list of the Inflammation and Host Response to Injury, Large Scale Collaborative Research Program can be found in SI Appendix.
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Author contributions: M.N.M., S.F.L., R.V.M., L.L.M., D.N.H., R.W.D., W. Xiao, R.G.T., and I.H.R.I.,L.S.C.R.P. designed research; J. Seok, H.S.W., A.G.C., M.N.M., H.V.B., W. Xu, H.G., L.H., C.C.F., C.M.L., S.H., E.E.M., J.P.M., J.C., P.E.B., J.L.J., J. Sperry, A.B.N., T.R.B., M.A.W., M.G.J., M.B.K., R.L.G., N.S.G., B.H.B., C.M.-G., S.E.C., P.H.M., J.P.C., L.G.R., R.V.M., L.L.M., D.N.H., W. Xiao, and R.G.T. performed research; J. Seok, W. Xu, D.R.R., H.G., R.W.D., and W. Xiao contributed new reagents/analytic tools; J. Seok, A.G.C., H.V.B., W. Xu, D.R.R., H.G., C.C.F., C.M.L., and W. Xiao analyzed data; and J. Seok, H.S.W., A.G.C., M.N.M., H.V.B., W. Xu, G.P.M.-S., L.L.M., W. Xiao, and R.G.T. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1222878110/-/DCSupplemental.
Freely available online through the PNAS open access option.
