Research profile

Max Costa

I was born in Cagliari, Sardinia (Italy) on January 10th, 1952. I have 2 children: Michelle Costa (age 12) and Kevin Costa (age 11). I live in Hoboken, New Jersey, which is just across the Hudson River from Manhattan, New York. Although I was born in Cagliari, I came to America when I was about 5 years old and have lived here ever since. I grew up in Scarsdale, New York and Bethesda, Maryland.

Education and Employment

1974: Received my BS Degree from Georgetown University

1976: Received my PhD degree in Pharmacology from the University of Arizona Medical School

1977: Did one year of postdoctoral training at the University of Arizona in Radiation Oncology

1977: Assistant Professor of Laboratory Medicine, University of Connecticut Medical School

1979: Assistant Professor of Pharmacology, Texas A&M Medical School

1980–1985: Assistant, Associate and full Professor of Pharmacology, University of Texas School of Medicine

1986–1992: Professor of Environmental Medicine and Pharmacology, New York University School of Medicine

1993 to the present: Professor and Chairman, Department of Environmental Medicine; Professor of Pharmacology and Deputy Director of the NYU Cancer Institute

Research

My research career really started when I was in high school and had the opportunity to work during the summer with Dr. Floyd Bloom. Dr. Bloom was an electron-microscopist and I learned how to section and prepare tissue for electron microscopy. We were primarily searching for the Islets of Langerhahns in the pancreas. My next significant research experience occurred while I was an undergraduate student at Georgetown University. At that time I had a full-time job at the National Institutes of Health in Bethesda, Maryland and also attended college full-time. From 1970 to 1972, I worked in the laboratory of Dr. Seymour Kaufman, and from 1972 to 1974, I worked in the laboratory of Dr. Robert C. Gallo. In Dr. Kaufman's lab, I was able to do my own research project, which involved trying to understand and prevent hyperbaric oxygen tension induced seizures in humans and animals. While in Dr. Gallo's lab, I worked on a variety of projects related to the detection and presence of retro viruses as causes of human leukemia. In later years, Dr. Gallo became quite famous as one of the early discoverers of HIV.

It was quite challenging to go to college full-time and also work 40 h a week, but it taught me to become very organized and spend my time productively. In 1974, I moved to Tucson, Arizona to become a graduate student in the Department of Pharmacology at the University of Arizona School of Medicine. Since I had such an active research experience during college, I was quite familiar with many laboratory research techniques. This unique experience allowed me to be highly successful in my graduate research activities. Again, I was able to take classes and work full-time in the laboratory, modeling what I did in college. However, during graduate school, I recall, working 12 to 14 h a day, seven days a week. I was able to complete my PhD in two and a half years. I remained in Arizona for another year, before taking my first faculty position at the University of Connecticut School of Medicine. While a graduate student at the University of Arizona, I worked on cell signaling involving cyclic AMP, cyclic AMP dependent protein kinases, the induction of ornithine decarboxylase and the regulation of cell growth. While at the University of Arizona, I had the pleasure of working with a variety of outstanding scientists, including Dr Bernard B. Brodie, Dr Diane H. Russell, and Dr I.G. Sipes. In particular, Dr Brodie, who was a member of the US National Academy of Sciences, taught me how to write scientific papers.

In 1977, I became Assistant Professor of Laboratory Medicine at the University of Connecticut School of Medicine in Farmington, Connecticut. However, my laboratories were located at the Institute of Material Science in Storrs, Connecticut, the main campus of the University of Connecticut. The Chairman of the Department, was Dr F. William Sunderman, Jr., who followed in the footsteps of his father, working on nickel carcinogenesis. One of the stipulations of my employment there was that I was to collaborate with Dr Sunderman in the area of metal carcinogenesis. Specifically, I was using cell culture systems to study the molecular mechanisms of cell transformation by water insoluble nickel compounds, such as crystalline nickel subsulfide and crystalline nickel sulfide. My work with Dr Sunderman introduced me into the field of metal carcinogenesis, which is the area that I've worked in ever since. While I was at the University of Connecticut, I was able to obtain my first NIH grant on nickel carcinogenesis, which was funded under a special program called the Young Environmental Scientist Research Award.

In 1979, I took a position as Assistant Professor of Pharmacology at Texas A&M School of Medicine. Texas A&M had just started a new School of Medicine in collaboration with Baylor College of Medicine and I thought it would be a good opportunity to become involved with the Medical School at the time it was starting. At Texas A&M University, I collaborated with Dr H. H. Mollenhauer, who was an electron-microscopist. We discovered the phagocytosis and intracellular disposition of carcinogenic crystalline nickel subsulfide versus non-carcinogenic amorphous nickel sulfide particles. We published our work in Science. The study was important because it helped to explain why these water insoluble nickel compounds may be such potent carcinogens to humans (M. Costa and H. H. Mollenhauer, Carcinogenic activity of particulate metal compounds is proportional to their cellular uptake, Science, 1980, 209, 515–517). Our research showed that the carcinogenic forms of nickel were phagocytized by cancer target cells and their dissolution inside the cell by the acidic pH of the endocytic vacuoles caused soluble nickel ions to enter cells and reach the nucleus at very high levels. This phagocytosis and dissolution process resulted in very high levels of nickel inside the cell, and considerably higher than could be achieved with soluble nickel salts and also allowed nickel to reach very high levels in the nucleus.

My teaching responsibilities were tremendous at Texas A&M University, and while I was able to do some research, I decided in 1980 to move to the Department of Pharmacology at the University of Texas Medical School. Dr Sheldon Murphy, who had just moved to the University of Texas Medical School at Houston from Harvard University, recruited me there. The University of Texas was starting a premier Division of Toxicology program within the Department of Pharmacology at the University of Texas. Dr Murphy convinced me to go to the Society of Toxicology meetings, and I became involved with this relatively new discipline. While at the University of Texas Medical School at Houston, I continued my studies of nickel carcinogenesis, studying the effects of nickel on chromatin, and studying the phagocytosis and dissolution process of the nickel sulfide particles. In collaboration with Dr Peter Davies, we studied, with video intensification microscopy, the uptake and intracellular movement of the nickel sulfide particles. At the University of Texas Medical School in Houston, I was able to obtain a number of research grants and trained a large number of graduate students and postdoctoral fellows. Dr G. Allen Robison was the Chairman of the Pharmacology Department at the University of Texas Medical School at Houston and he was very supportive of my research during my tenure there. However, Dr Sheldon D. Murphy decided to move from the University of Texas to become Chairman of the Department of Environmental Health at the University of Washington School of Public Health in Seattle, Washington.

By 1985, I was practically the only toxicologist left in the Department at the University of Texas and I, therefore, decided to move on to New York University and became Professor of Environmental Medicine and Pharmacology. While I am Professor at New York University School of Medicine in New York City, my laboratories are located at the Institute of Environmental Medicine near Tuxedo, New York. It was at New York University that I made many advances in the genetic and epigenetic effects of nickel carcinogens. In particular, we discovered carcinogenic nickel compounds could inactivate senescence and other tumor suppressor genes by inducing de novo DNA methylation. This work was also published in Science (C. B. Klein, K. Conway, X. W. Wang, R. K. Bhamra, X. Lin, M. D. Cohen, L. Annab, J. C. Barrett and M. Costa, Senescence of nickel-transformed cells by a mammalian X chromosome: Possible epigenetic control, Science, 1991, 251, 796–799). Subsequent studies, helped us understand how carcinogenic nickel compounds could inactivate cancer-related genes. We discovered that tumor suppressor and senescence genes that are located near heterochromatin were susceptible to gene activation by carcinogenic nickel compounds. In fact, when we used transgenic cell lines, we were able to find that when the same gene was placed near heterochromatin versus another position, the position of the gene near heterochromatin was essential for targeting nickel induced gene inactivation (Y-W. Lee, C. B. Klein, B. Kargacin, K. Salnikow, J. Kitahara, K. Dowjat, A. Zhitkovich, N. T. Christie and M. Costa, Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: A new model for epigenetic carcinogens, Mol. Cell. Biol, 1995, 15(5), 2547–2557). The work on nickel phagocytosis and intracellular dissolution represented a substantial breakthrough in the area of nickel carcinogenesis at the time the work was done. Additionally, in the late eighties and early nineties, the discovery that nickel-induced DNA methylation to silence genes was also novel work for the time, when DNA methylation was not a popular area, and most people thought that DNA hypo-methylation was the mechanism involved in activating oncogenes in carcinogenesis.

In 1993, following a national search, I became Chairman of the Department of Environmental Medicine and Director of the Institute of Environmental Medicine at New York University School of Medicine. I have also continued my research in nickel and chromium carcinogenesis. In the area of nickel carcinogenesis, we have further studied the mechanism of nickel-induced gene silencing by examining histone H3 and H4 covalent modifications. We find that nickel causes these and other histones to be deacetylated in their lysines located at their N-terminal tails and also causes the methylation of lysine 9 on histone H3. The loss of acetylation causes the histones to assume positive charges on their lysines, while the methylation of the lysines (mono, di and trimethylation) prevents the acetylation and neutralization of the positive charges. One remarkable fact about DNA methylation and histone methylation is that there is currently no known enzyme that can reverse this process (i.e., a demethylase) and the cell goes to great expense to activate genes by replacing histone H3 with lysine 9 methylation with a histone variant that does not have lysine 9 methylation. DNA methylation may also be reversed by a DNA repair process, whereby the 5-methylcytosine is excised from the DNA. Our recent work on nickel carcinogenesis has found that soluble, as well as insoluble nickel compounds, activate hypoxia signaling in cells. We believe that this is occurring by the ability of nickel to inhibit Fe uptake, and we have found that nickel depletes about 40% of the total cellular stores of Fe (Chen, Davidson and Costa unpublished). One way that nickel does this is by inhibiting DMT-1, the Fe transporter (Davidson, Garrick and Costa). Because of the depletion of cellular Fe and perhaps also because nickel can displace Fe from a HIF-1α proline hydroxylase (the Fe is coordinated to histidines, which are favored binding sites of nickel), this results in the inhibition of the hydroxylation of HIF-1α in the oxygen dependent domain (ODD), which will now stabilize the protein and prevent its degradation. When HIF-1α is hydroxylated in the ODD, it will be targeted for degradation by VHL. The stabilization of HIF-1α results in its partnering with ARNT and activation of hypoxia-inducible genes, such as vascular endothelial growth factor, induction of a number of glycolytic enzymes etc. This process signals the cell that it needs to survive hypoxia but the cell is at normal oxygen tension. This process may be important for nickel carcinogenesis because cells that have a pre-existing mutation for cancer are now given the opportunity to grow and metastasize under low oxygen tension.

In addition to nickel, we have also studied other metals such as chromium. We have studied the interaction and binding of Cr(III) with DNA and nuclear proteins. In particular, we have characterized the nature of DNA–protein crosslinks induced by hexavalent Cr when it is converted to trivalent Cr inside the cell. We have also studied the mutagenic activity of various Cr–DNA adducts. Most recently, we have found that hexavalent Cr in the drinking water can greatly enhance the incidence of skin cancers induced by UV in a hairless mouse model. This is the first study to show that hexavalent Cr is carcinogenic (albeit enhancing since Cr alone did not cause skin cancers) following drinking water exposure. These studies are important because humans are not exposed to a single carcinogen, and we get exposure to UV from sunlight, cigarette smoke etc. Perhaps metal carcinogens pose the highest risk when there is combined exposure to other carcinogens.

Future directions

We are continuing our work on nickel carcinogenesis by studying histone modifications as it relates to nickel-induced gene silencing. For these studies we may utilize yeast systems since they are simpler than mammalian cells. We are continuing to study the effect of nickel on Fe depletion from cells and how this impacts Fe homeostasis. We are also interested in how nickel is delivered to the nucleus from particles versus soluble nickel ions and are using fluorescent nickel chelators to study this process in intact cells. We are also studying the effects of nickel on histone modifications and Fe homeostasis in vivo using mice since we are concerned that there may be differences in tissue culture compared to animals. We will also continue with the skin cancers induced by Cr in hairless mice with UV to study other metals and to understand the mechanism involved.

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