Marie Hardwick first appeared on the cell death scene as a broad-scope scientist, interested in both mammalian cells and yeasts, the genetics of which offered means of asking different questions about cell death. In a sort of quirky way, she asked questions that either never occurred to those of us in the field too excited about the latest discoveries about apoptosis or that we did not dare to challenge: in the sequence for intrinsic (metabolic) apoptosis–[something happens] → Bax, Bak displace Bcl2 from mitochondrial membrane → mitochondrial membrane depolarization → leakage of cytochrome c and Apaf-1 → activation of apoptosome→caspase-driven degradation of cell, what is meant by [something happens]? What happens to the cytoplasm? Why are the cytoplasmic Bcl-2 family members in the cytoplasm in the first place? Do they possibly have any function other than to lay in wait for eventual apoptosis? Does Bcl-2 have a function other than helping to seal mitochondria against potential leakage? And is it possible that caspases, in active (proteolytic) or inactive form, do something other than act as executioners lurking in reserve? After all, organisms die in many ways, but it is rather uncommon to find situations in which organisms activate specific toxins or other specific means of destroying themselves. Even lysosomes, so named because they were seen to rupture in CCl4-induced hepatotoxicity, proved soon enough to be not suicide bags for cells but rather intracellular digestive and housekeeping organelles.
Among the observations that Marie has forcefully put forward and documented by yeast genetics and manipulation of mammalian cells, she and her laboratory have established that Bcl-2 family members influence metabolism, mitochondrial structure and therefore function, and neuronal growth and activity. She has demonstrated that the common means of studying function, by knockout or knockdown of specific genes, has an intrinsic flaw: As old-time biochemists or biologists might have suggested, but we rarely consider today, alteration of a central metabolic component generates complex feedbacks, so that the surviving altered cell is very different in many respects, with genome-wide up- or down-regulation of many other obviously-compensatory and not-so-obviously-compensatory genes. Therefore, at best, we have to be circumspect in our interpretation of the results. She has also, along with researchers such as Jean-Claude Ameisen, asked what caspases were before they were caspases–in other words, did they and do they serve other functions? Following this line of argument, she has generated models for the function of a programmed cell death even in unicellular organisms and its relationship to the earliest phases of tumorigenesis, and she has demonstrated that caspases can be active in cells that do not die. All of these studies provoke questions and ultimately lead to a more profound understanding of the meaning and purpose of organized cell death, rather than the more facile assumptions that tend to dominate discussions of apoptosis.
Marie is the first David Bodian Professor at Johns Hopkins. David Bodian, also a mid-westerner, was the first to establish that formaldehyde-killed polio virus could still immunize chimpanzees, an important step in the eventual development of polio vaccine. With her wide-ranging and catholic approach to biomedical questions, she is a worthy recipient of that post. She is modest and unassuming, yet witty and sharp. I was not at all surprised to learn that she has a twitter handle @JMHtweetsrarely. For all of her provocative contributions to our field, we are pleased to honor her with this award for her contributions.