RECENTLY TENURED

Luigi Ferrucci

Luigi Ferrucci received his M.D. and Ph.D. in biology and the pathophysiology of aging at the University of Florence, Italy, in 1980 and 1983, respectively. He completed his training in geriatric medicine in 1984 and started working at the Italian National Institute on Aging, where he established a continuous collaboration with the NIA Laboratory of Epidemiology, Demography, and Biometry. During the past 15 years, he has spent an average of three months a year at NIA as a visiting scientist. In September 2002, he joined the NIA Clinical Research Branch and is now the director of the Baltimore Longitudinal Study on Aging.

I have always been interested in older people and in aging as a biological process. Only through understanding the multifaceted secrets of aging may we be able to meet the challenges that the demographic transition is posing to the stability of the health-care system in industrialized and developing countries.

My primary research activity focuses on risk factors for physical and cognitive disability in older people, and on the interactive role played by chronological aging, multiple morbidity, and frailty in the disablement process. From my experience as a geriatrician, I am particularly interested in disability that develops progressively and is not explained by any acute event or progressive disease that can be clinically detected.

Scientific questions concerning this type of disablement can only be explored in longitudinal studies with follow-up visits repeated over an extended period of time.

In particular, we are interested in studying subjects with an accelerated decline of muscle mass and strength, changes in body composition, and loss of weight and appetite—a combination of symptoms called the "frailty syndrome." My current work is aimed at understanding the main causes of frailty in older persons in the attempt to find strategies that can be used to reduce disability in the elderly and to prolong active life expectancy.

I have approached the frailty syndrome from different perspectives. Particularly promising is the study of inflammation and its effect on the anatomical integrity and functionality of the different physiological systems. Another puzzling aspect is the ability of humans to compensate for the effect of physical impairments. Compensation may develop at many levels, from specific metabolic pathways to changes in behavior. Understanding compensation may reveal new strategies for delaying and preventing disability in older persons.

I am convinced that good science develops from collaboration and discussion, and I invite scientists at NIH with an interest in the field of aging to contact me. (See also "BLSA To Reassess Assessment Protocols.")

Eliot Gardner

Eliot Gardner received his undergraduate training at Harvard University in Cambridge, Mass., where he was introduced to psychopharmacology working directly under the mentorship of two of the field’s pioneers, Gerald Klerman and Alberto DiMascio. He received his Ph.D. in neuroscience and physiological psychology from McGill University in Montreal, Quebec, in 1966 and served as a medical research officer in the U.S. Air Force at the Aeromedical Research Laboratories (U.S. Air Force School of Aerospace Medicine) at White Sands, N.M. He did postdoctoral work in neurology and pharmacology at Albert Einstein College of Medicine in New York City and joined the faculty there in 1972, rising in rank to professor of psychiatry and behavioral sciences, professor of neuroscience, director of basic research in psychiatry, director (and founder) of the Research Residency Training Program in Psychiatry, and co-director (and co-founder) of the Addiction Medicine Fellowship Program. In 2000, he joined NIDA’s Intramural Research Program as a senior investigator.

My interests are in the area of the brain mechanisms of reward and reinforcement and their relation to drug addiction. Early in my career, I was one of the first to map the neuroanatomy of reward circuits in the nonhuman primate brain, and one of the first to suggest that dopamine was the crucial reward-related neurotransmitter in the meso-accumbens reward circuit. I was also one of the first to demonstrate that deep temporal lobe structures, such as the hippocampus and amygdala, modulate reward functions within the meso-accumbens reward circuit.

About 15 years ago, I turned my attention to the psychoactive and addictive constituent of marijuana and hashish: D⁹-tetrahydrocannabinol (THC). At the time, THC was considered an "anomalous" addictive substance that did not derive its addictive potential from interaction with the brain’s reward circuitry.

In a lengthy series of studies, my lab demonstrated that THC is not anomalous at all, but interacts with the brain’s reward circuits in a manner strikingly similar to that of other addictive drugs (Pharmacol Biochem Behav 40:571–580, 1991; Neurobiol Dis 5:502–533, 1998).

In the course of our work with THC, we also demonstrated clear genetic differences in vulnerability to the rewarding effects of addictive drugs. My work with THC and other cannabinoids continues. (Chem Phys Lipids 121:267–290, 2002).

For quite some time, my work on brain reward mechanisms has had a strong medication discovery and development theme (Am J Addict 9:285–313, 2000). I believe that our understanding of the neurobiological substrates of addiction has reached a point such that the quest for anti-addiction medications is now reasonable.

My anti-addiction discovery and development work currently focuses on several neurobiological and psychopharmacological strategies: 1) slow-onset, long-acting inhibitors of the dopamine transporter (DAT), specifically acting within the nucleus accumbens; 2) slow-onset, long-acting enhancers of the neurotransmitter g-aminobutyric acid (GABA), specifically acting via the GABA-B receptor; and 3) antagonists of the dopamine D3 receptor.

Working with drug-design chemists, my lab has examined a variety of slow-onset, long-acting DAT inhibitors (J Med Chem 43:4981–4992, 2000). We find that several have promising in vivo profiles in animal model systems—elevating nucleus accumbens dopamine (DA) as assessed by in vivo brain microdialysis, lowering electrical brain-stimulation reward thresholds, and dose-dependently inhibiting intravenous cocaine self-administration.

Working with colleagues at the Brookhaven National Laboratory, we have shown that g-vinyl-GABA, an irreversible inhibitor of GABA-transaminase, dose-dependently blocks the effects of cocaine, nicotine, heroin, and several other addictive drugs on nucleus accumbens DA as assessed by in vivo brain microdialysis.

It also blocks the effects of cocaine on electrical brain-stimulation reward thresholds, inhibits intravenous cocaine self-administration, dose-dependently blocks both the acquisition and expression of cocaine- and nicotine-induced conditioned cue preferences, and inhibits the acquisition and expression of cocaine-induced neuronal sensitization, a cellular mechanism believed to underlie certain aspects of the addictive disease process (Synapse 30:119–129, 1998; Synapse 31:76–86, 1999; Eur J Pharmacol 414:205–209, 2001; Synapse 41:219–220, 2001; Synapse 46:240–250, 2002).

These preclinical profiles are promising as predictors of anti-addiction clinical utility.

Working with colleagues at Saint John’s University in New York and the GlaxoSmithKline Psychiatry Centre of Excellence for Drug Discovery in the United Kingdom, we have shown that selective D3 receptor antagonism blocks cocaine’s enhancement of electrical brain-stimulation reward, blocks the acquisition and expression of cocaine-induced conditioned cue preferences, and blocks cocaine-triggered reinstatement of cocaine-seeking behavior in an in vivo animal model of drug-taking relapse (J Neurosci 22:9595–9603, 2002).

From such preclinical studies, we may be close to finding effective pharmacotherapies for addiction in humans.

Most recently, my students and I have shown that reinstatement of cocaine-seeking behavior in lab animals can be triggered by low-intensity, anatomically precise electrical stimulation of two deep brain loci—the ventral subiculum of the hippocampus and the basolateral complex of the amygdala (Science 292:1175–178, 2001; Psychopharmacology 167:in press, 2003). This result is extremely exciting, as these brain loci are selectively activated during drug craving in humans (as determined by neuroimaging techniques such as positron emission tomography) and as this approach allows us to anatomically map the relapse circuits in the brain for the first time.

Mapping the brain’s relapse circuits and determining their neurochemical substrates may permit the design and development of specific anti-craving and anti-relapse medications (Neurobiology of Mental Illness, 2nd edition, London: Oxford University Press).

These are exciting days in the field of addiction medicine.

Matthew Longnecker

Matthew Longnecker received an M.D. from Dartmouth Medical School in Hanover, N.H., in 1981 and completed a residency in internal medicine at Temple University Hospital in Philadelphia. He earned a Sc.D. in epidemiology from Harvard School of Public Health in 1989 and was an assistant professor of epidemiology at the UCLA School of Public Health in Boston before joining the Epidemiology Branch at NIEHS in 1995. He is now a senior investigator.

At NIEHS, my research has focused on the health effects of persistent organic pollutants. Through diet, we all are exposed to small amounts of toxic agents that were either manufactured or created inadvertently. These agents are widely dispersed in the environment and bioaccumulate in the food chain. Among the more widely known persistent organic pollutants are dioxins, polychlorinated biphenyls, and dichlorodiphenyldichloroethylene, or DDE, a metabolite of the insecticide DDT.

At higher levels of exposure, dioxin is known to be a human carcinogen, and it causes an acnelike skin condition, chloracne. Children who were inadvertently exposed before birth to large doses of a mixture of dioxinlike compounds and polychlorinated biphenyls have several abnormalities, including a persistent deficit on cognitive examinations.

Studies show that poisonings with DDT have temporary neurologic effects, but they do not establish long-term toxic effects, although links with selected cancers have been suggested. The questions that I have addressed focus on potential effects of lower levels of exposure experienced by the general population or—in the case of DDT—by populations exposed to moderate-to-high levels resulting from use in controlling disease vectors (such as mosquitoes).

My interest in the health effects of persistent organic pollutants began with a study of breast cancer in the early 1990s, when cancer epidemiologists devoted much attention to this issue.

When I moved to NIEHS, I wrote a comprehensive review of human data on health effects of persistent organic pollutants. From this, I realized that there were many potential health effects other than cancer for which the mechanistic data were much more suggestive of human effects.

For example, in 1995, investigators showed that DDE—the metabolite of DDT that is ubiquitous in human blood—blocks androgen action. Androgen action is required in the male embryo for normal development of the genitalia. At that time, rates of male birth defects were increasing, yet there were few data to address whether this pollutant might be responsible.

To pursue the hypothesis that in utero androgen blocking would cause male birth defects, I designed a study that simultaneously addressed other questions regarding the health effects of persistent organic pollutants.

Compared with other studies of the health effects of persistent organic pollutants, my study was huge. It has proven to be a valuable resource for investigating a number of relationships—though the findings regarding DDE and male birth defects were inconclusive.

One of the relationships that was clearly apparent in this study, however, was that women with higher levels of DDE in their blood during pregnancy were more likely to deliver preterm babies (before 37 completed weeks of gestation).

If DDT does lead to an increase in pre-term births, it would also be expected to increase infant mortality. DDT is still in use in 25 countries today where users believe it has no adverse effects on humans. Thus, new findings about DDT toxicity could have a significant effect on choice of vector control strategies.

I am following up on potential health effects of DDT exposure through ongoing field work in Mexico, where the pesticide has been used for malaria control.

In conjunction with Mauricio Hernandez at Mexico’s National Institute of Public Health, we are studying pregnant women and their offspring, examining a number of health outcomes.

Jeffery Miller

Jeffery Miller received his M.D. from Stanford University in 1985 and completed his internal medicine and chief medical residencies at the University of Colorado at Denver. In 1991, he joined the Molecular Biology Section of the Clinical Hematology Branch of NHLBI and received further laboratory and clinical training in the subspecialty of hematology before beginning his tenure track in the Laboratory of Chemical Biology of NIDDK in 1995. He is now a senior investigator in the Laboratory of Chemical Biology.

My interests are broadly aimed toward the advancement of basic and clinical knowledge involving erythroid cells. Erythroid diseases affect millions of people worldwide and include all forms of anemia, malaria, and hemoglobinopathies.

One of the most fascinating aspects of some hemoglobin-related disorders is that they become clinically important only after birth, when erythroid cells undergo a developmental switch in hemoglobin production from fetal to adult forms.

For this reason, I have pursued several routes toward the clinical goal of increasing fetal hemoglobin in erythroid cells to prevent or treat sickle cell diseases and beta thalassemias, which result from abnormal adult forms of hemoglobin.

My group has focused on understanding the expression of fetal hemoglobin using genome-based information. We began by obtaining highly purified populations of primary human erythroblasts at defined stages of development and maturation. These cells were used to create gene libraries and a comprehensive database of gene activity.

To date, we have entered into public databases more than 14,000 expressed sequence tags from these libraries. Our eventual goal is the complete description of gene activity associated with the development of erythroid cells. We will make the erythroid genome widely available to the scientific community through the Internet.

On the basis of our profiles of erythroid gene activity, we were able to define the pattern of fetal globin expression as stem cells commit to erythroid development and subsequently accumulate hemoglobin. We determined that fetal and adult genes are expressed with similar patterns during erythropoiesis, albeit at quite different levels, and we are attempting to develop a new model of this process.

In addition, we have determined that signal transduction from growth-related cytokines may be useful for increasing the expression of fetal hemoglobin—even among fully committed populations of adult erythroid cells. We are now using the gene profiles to explore novel signaling networks in erythroblasts in the context of fetal hemoglobin expression.

We hope that this genomic approach will lead to the development of fundamentally new therapies aimed at increasing postnatal production of fetal hemoglobin.

In addition to hemoglobin-related projects, we have applied this genomic approach to the identification of genes encoding novel growth-related or membrane-localized molecules. One project involved the search for the Dombrock blood group carrier molecule. Dombrock is one of the primary antigen groups associated with hemolysis after blood transfusion, but the identity of the Dombrock molecule itself had remained a mystery for more than 35 years.

By mapping the genomic location of the erythroid transcripts in our database, we were able to identify the gene encoding the Dombrock carrier molecule. This knowledge led us to define the single nucleotide polymorphisms responsible for Dombrock-related hemolysis. Through collaboration, we then used this information to develop a molecular assay designed to match donor and recipient blood to prevent hemolysis.

In the future, we plan to continue to use genome-based studies to advance the understanding of basic biological themes manifest during erythropoiesis. We hope this approach will permit us and others to improve the clinical outlook for patients afflicted with erythroid diseases.

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