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J. Marie

David Bodian Professorship

J. Marie Hardwick, PhD, studies why neurons die prematurely and how to activate cell death programs in pathogenic microorganisms.

Contact Info

615 N. Wolfe Street, Room E5140

Research Interests

Programmed cell death; Neurodegeneration; Fungal cell death mechanisms; Genome evolution; Cell stress; Epilepsy; Apoptosis; Autophagy; Viral pathogensis
Experiences & Accomplishments
University of Kansas
Research topic: Molecular mechanisms leading to programmed cell death

Our research focuses on how cells sense their status and activate programmed cell death. We study molecules that switch from normal physiological functions to cell suicide functions relevant to neurodegeneration, host-pathogen interactions, and tumorigenesis. While a great deal is known about how apoptosis factors kill mammalian cells, little is known about their alternative physiological functions in healthy cells, or how these alternative functions impact subsequent cell death. Conversely, pro-death functions of yeast proteins are essentially unknown despite their many well-studied physiological functions. Ongoing projects apply a range of technologies and diverse model systems to discover and characterize these novel functions. Many life-death molecular switches affect membranes of subcellular organelles such as mitochondria, endoplasmic reticulum and autophagosomes/lysosomes. Our yeast discovery tools have uncovered cancer-like genome evolution as well as neurodegenerative disease mechanisms now being pursued in mouse models. Our studies in flies have advanced our studies of cell death in the mammalian brain. Also ongoing is the pursuit of evolutionarily conserved as well as unique cell death mechanisms potentially useful for controlling fungal pathogens.
Honors & Awards
Host cell death responses to virus infections of the brain and of yeast determine disease pathogenesis. An underlying theme in our lab is the investigation of host cell death machinery in disease pathogenesis, which started with these early studies of viral persistence, pathogenesis and toxicity.

Levine B, Huang Q, Isaacs JT, Reed JC, Griffin DE, Hardwick JM, 1993. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature 361, 739-42. Citations: 519
Lewis J, Oyler GA, Ueno K, Fannjiang YR, Chau BN, Vornov J, Korsmeyer SJ, Zou S, Hardwick JM, 1999. Inhibition of virus-induced neuronal apoptosis by Bax. Nat Med 5, 832-5. Cited by 103
Ivanovska I, Hardwick JM, 2005. Viruses activate a genetically conserved cell death pathway in a unicellular organism. J Cell Biol 170, 391-9. Cited by 80. Featured in Editor’s Choice (same issue); Reviewed in AAAS Science STKE 296: p287

Caspase proteases convert Bcl-2 family members and IAP proteins, but not their viral homologs, into potent cell death factors – in infection and ischemic brain injury. Ongoing studies focus on how this conversion to killer mode is regulated.

Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM, 1997. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278, 1966-8. Cited by 1297
Clem RJ, Cheng EH, Karp CL, Kirsch DG, Ueno K, Takahashi A, Kastan MB, Griffin DE, Earnshaw WC, Veliuona MA, Hardwick JM, 1998. Modulation of cell death by Bcl-XL through caspase interaction. Proc Natl Acad Sci U S A 95, 554-9. Cited by 532
Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC, Hansford R, Kastan MB, Lazebnik YA, Hardwick JM, 1999. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J Biol Chem 274, 21155-61. Cited by 487
Bellows DS, Chau BN, Lee P, Lazebnik Y, Burns WH, Hardwick JM, 2000. Antiapoptotic herpesvirus Bcl-2 homologs escape caspase-mediated conversion to proapoptotic proteins. J Virol 74, 5024-31. Cited by 147
Clem RJ, Sheu TT, Richter BW, He WW, Thornberry NA, Duckett CS, Hardwick JM, 2001. c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment. J Biol Chem 276, 7602-8. Cited by 123
Seo SY, Chen YB, Ivanovska I, Ranger AM, Hong SJ, Dawson VL, Korsmeyer SJ, Bellows DS, Fannjiang Y, Hardwick JM, 2004. BAD is a pro-survival factor prior to activation of its pro-apoptotic function. J Biol Chem 279, 42240-9. Cited by 54
Ofengeim D, Chen YB, Miyawaki T, Li H, Sacchetti S, Flannery RJ, Alavian KN, Pontarelli F, Roelofs BA, Hickman JA, Hardwick* JM, Zukin* RS, Jonas* EA, 2012. N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death. Nat Neurosci 15, 574-80. Featured in the Scientist, and Neurosci News & Views: Chemo for stroke (same issue); Cited by 38

Non-apoptotic functions of cell death factors in healthy cells. Before Bcl-2 family proteins engage the apoptosis pathway, they have novel non-apoptotic roles in healthy cells (e.g. regulating neuronal activity, mitochondrial energetics, and more). This concept was also advanced through our studies of other cell death regulators using molecular and cellular biology, biochemistry, microscopy, genetics and systems biology applied to the analysis of experiments with cultured cells, mice, flies, mosquitos and yeast.

Cheng EH, Levine B, Boise LH, Thompson CB, Hardwick JM, 1996. Bax-independent inhibition of apoptosis by Bcl-XL. Nature 379, 554-6. Cited by 510
Fannjiang Y, Kim CH, Huganir RL, Zou S, Lindsten T, Thompson CB, Mito T, Traystman RJ, Larsen T, Griffin DE, Mandir AS, Dawson TM, Dike S, Sappington AL, Kerr DA, Jonas EA, Kaczmarek LK, Hardwick JM, 2003. BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. Dev Cell 4, 575-85. Cited by 92
Jonas EA, Hoit D, Hickman JA, Brandt TA, Polster BM, Fannjiang Y, McCarthy E, Montanez MK, Hardwick JM, Kaczmarek LK, 2003. Modulation of synaptic transmission by the BCL-2 family protein BCL-xL. J Neurosci 23, 8423-31. Featured in: This Week in the Journal (same issue); Cited by 91
Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA, 2008. Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission. J Neurophysiol 99, 1515-22. Cited by 35.
Berman SB, Chen YB, Qi B, McCaffery JM, Rucker EB, 3rd, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM, 2009. Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184, 707-19.; Featured on issue cover; Cited by 150
Alavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA, 2011. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat Cell Biol 13, 1224-33. Cited by 134
Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O'Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM, 2011. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195, 263-76. Cited by 100
Aouacheria A, Combet C, Tompa P, Hardwick JM, 2015. Redefining the BH3 Death Domain as a 'Short Linear Motif'. Trends Biochem Sci 40, 736-48. Cited by 12
White K, Arama E, Hardwick JM, 2017. Controlling caspase activity in life and death. PLoS Genet 13, e1006545.

Cell death model system for yeast uncovers prevalence of non-random genome plasticity – one mutation leads to two mutations, and the same pairs of mutant genes co-occur in human tumors.
Using new tools to study gene-dependent cell death in Saccharomyces cerevisiae, we uncovered many surprises, including a widespread phenomenon of gene mutation-drive genome evolution. The evidence strongly indicates that simply the loss of nearly any single gene is sufficient to drive the selection for a new compensatory mutation in a specific direction or same second gene. Is this phenomenon important for the earliest events towards tumorigenesis?

Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G, Hardwick JM, 2004. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 18, 2785-97. Cited by 265.
Teng X, Cheng WC, Qi B, Yu TX, Ramachandran K, Boersma MD, Hattier T, Lehmann PV, Pineda FJ, Hardwick JM, 2011. Gene-dependent cell death in yeast. Cell Death Dis 2, e188. Cited by 25
Teng X, Dayhoff-Brannigan M, Cheng WC, Gilbert CE, Sing CN, Diny NL, Wheelan SJ, Dunham MJ, Boeke JD, Pineda FJ, Hardwick JM, 2013. Genome-wide consequences of deleting any single gene. Mol Cell 52, 485-94. Cited by 53. Featured in The Scientist, “One gene, two mutations”; SGD New & Noteworthy, “Gene knockouts may not be so clean after all”; NIH/ NIGMS Biomedical Beat blog

Yeast cell death genetics – a path to understanding brain function and neurodegeneration
The top hit in our genome-wide yeast screens was a previously unrecognized homolog of newly identified but uncharacterized disease genes. Yeast studies also uncovered nutrient-sensing pathways that led to the testing of the role of ketogenesis and amino acid-sensing in mouse epilepsy models.

Cheng WC, Teng X, Park HK, Tucker CM, Dunham MJ, Hardwick JM, 2008. Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects. Cell Death Differ 15, 1838-46. Cited by 38
Hartman AL, Zheng X, Bergbower E, Kennedy M, Hardwick JM, 2010. Seizure tests distinguish intermittent fasting from the ketogenic diet. Epilepsia 51, 1395-402. Cited by 28
Hartman AL, Santos P, Dolce A, Hardwick JM, 2012. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice. PLoS One 7, e45156. Cited by 33
Hartman AL, Santos P, O'Riordan KJ, Stafstrom CE, Hardwick JM, 2015. Potent anti-seizure effects of D-leucine. Neurobiol Dis 82, 46-53. Cited by 7.

Widespread basal (day-job) caspase activity in healthy cells. Our early work on caspases in regulating viral pathogenesis uncovered clues that caspases have additional non-apoptotic roles in healthy cells prior to activation of cell death. An ultrasensitive caspase biosensor for Drosophila engineered by Hogan Tang, designated CaspaseTracker to study “anastasis”, provided the first clear evidence of widespread caspase activity in healthy long-lived cells of many fly tissues, including neurons in the brain. Now we seek the functions of these “healthy” caspases.

Nava VE, Rosen A, Veliuona MA, Clem RJ, Levine B, Hardwick JM, 1998. Sindbis virus induces apoptosis through a caspase-dependent, CrmA-sensitive pathway. J Virol 72, 452-9. Cited by 126
Tang HL, Tang HM, Fung MC, Hardwick JM, 2015. In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Rep 5, 9015. Cited by 16.
Tang HL, Tang HM, Fung MC, Hardwick JM, 2016. In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila. JoVE

Joint Appointments:
Department of Pharmacology and Molecular Biology, Johns Hopkins School of Medicine
Department of Neurology, Johns Hopkins School of Medicine
Oncology Center, Johns Hopkins School of Medicine
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health

List of Publications:
Select Publications
An underlying theme in our lab is the investigation of host cell death machinery in disease pathogenesis, including cell stress, neurodegeneration, epilepsy, viral pathogenesis, fungal cell death mechanisms, genome evolution, tumorigenesis, nutrient-sensing and more. [see overview]