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Obituary—Erminio Costa, M.D. (1924-2009), University of Illinois at Chicago

Editor’s note: The following obituary honors Erminio Costa, known in schizophrenia research circles in particular for his postmortem findings of GABA system disruption, as well as his more recent research on possible epigenetic etiology. He was Professor of Psychiatry at the University of Illinois at Chicago. This obituary was written by his colleagues Dennis Grayson and Alessandro Guidotti.

Erminio (Mimo) Costa, an expert in the field of neuropsychopharmacology, died Saturday, 28 November 2009, from complications of multiple myeloma. Dr. Costa is survived by his wife Ingeborg Hanbaur and sons Michael and Max. His son Robert passed away on 1 September 2006 from pancreatic cancer.

Dr. Erminio Costa

Dr. Costa was born in Cagliari, Italy, and obtained an M.D. from the University of Cagliari, graduating magna cum laude in 1947. This was the start of an enduring career in the fields of pharmacology and neuroscience. He continued his studies at the University, attaining the rank of Associate Professor (in 1948) and Professor of Pharmacology by 1954. In 1956, Dr. Costa joined the Thudichum Research Laboratory in Galesburg, Illinois, and studied under the direction of Drs. Harold Himwich and Murray Aprison in the neurochemistry laboratory. It was here that he was first exposed to clinical psychiatry at a time when chlorpromazine and its analogues became the standard of treatment for patients with schizophrenia. It was also during this period his passion for experimental neuropsychopharmacology was born. While presenting his work at a national meeting in 1958, Dr. Costa first met Dr. Bernard B. Brodie, considered by many to be the father of modern pharmacology. Dr. Brodie subsequently recruited Dr. Costa to the National Institutes of Health, where he became first a staff member and then Deputy Chief of the National Heart Institute's Laboratory of Chemical Pharmacology at the National Institutes of Health (NIH). In 1965, Dr. Costa joined Columbia University in New York as Director of Pharmacology of the W. Black Center for the study of Parkinson disease and three years later was asked to return to NIH, where he founded and for 17 years directed the prestigious Laboratory of Preclinical Pharmacology (LPP) of the National Institutes of Mental Health at St. Elizabeth's Hospital in Washington, D.C.

In 1985 at the age of 61, Dr. Costa founded and became Director of the Fidia-Georgetown Institute for the Neurosciences (FGIN) and Professor in the Departments of Anatomy and Cell Biology and Pharmacology at Georgetown University, Washington, D.C. (1985-1994). Here, he recruited a handful of scientists with their own expertise to create a program that was truly multidisciplinary. While each Lab Director was in charge of a research program, Dr. Costa oversaw the efforts and directed an often multifaceted approach to experimental neuroscience. At its height, FGIN employed 65 scientists from all over the world. Prior to the advent of the Internet, Dr. Costa and his colleagues implemented a Neuroscience Fax newsletter which was transmitted across the globe in an effort to reinvent how neuroscience findings might be communicated on a faster time scale.

During his career, Dr. Costa mentored numerous young scientists and made significant contributions to the field of neuropharmacology. Along with Dr. Brodie and numerous other eminent scientists, Dr. Costa was one of the founding members of the American College of Neuropsychopharmacology. Along with Professor Philip Bradley, University of Birmingham England, he shared the Chief Editor position for the Journal Neuropharmacology for some 27 years. In 1982, Dr. Costa was elected to the National Academy of Sciences (U.S.), and he maintained an active presence. Dr. Costa always considered scientific dialogue and rigorous analysis of scientific data to be integral to the training of junior scientists and the driving force for experimental design. During this time, the “Monday morning” scientific meeting, at which current research was presented by a member of the staff, became a tradition that would be carried into the next 20 years of his career. In 1988, together with Nobel Prize Laureates Rita Levi-Montalcini and Gerald Edelman, Dr. Costa founded and directed The International School of Neuroscience in Praglia Abbey, Padua, Italy. This school brought cutting-edge neuroscientists to a large audience of graduate students to expose them to the newest advances in the field. In addition to his accomplishments as a leader in the field of neuropharmacology, he championed the cause of neuroscience as a field second to none and without international boundaries. In 1991, Dr. Costa organized the Symposium on Molecular Neurobiology, sponsored by the National Academy of Sciences (U.S.) and the Academy of Sciences (USSR), held in Kiev, USSR. This effort allowed for the exchange of research data between scientists of the Soviet Union and the United States to foster international dialogue between researchers with similar interests. During his years at NIMH and later as Director of Fidia Georgetown Institute for the Neurosciences, Dr. Costa organized numerous world-renowned symposia and lecture series (the FIDIA Research Foundation Award Lectures in Neuroscience and Fidia Research Foundation Symposium Series). For many years, these were held as symposia satellites to the Annual Meeting of the Society for Neurosciences. From 1991 until 1996, Dr. Costa was a representative of the U.S. National Committee for IBRO. He was the driving force in organizing the "IBRO-SANS-USNC International Neuroscience Course on Neurotransmitter and Receptors" held at Rhodes University, Grahamstown, South Africa (1996).

In 1994, Dr. Costa became McDonnell Visiting Professor in Neurology at Washington University in St. Louis, Missouri, and Director of the Center for Neuropharmacology at the Nathan S. Kline Institute (NKI) for Psychiatric Research, Orangeburg, New York. In 1996, Dr. Costa was approached by Dr. Boris Astrachan to direct a research program in the Department of Psychiatry at the University of Illinois Chicago (UIC). At age 72, Dr. Costa rose to the challenge and recruited a team of top scientists including his long-time friend and co-worker, Dr. Alessandro Guidotti. Dr. Costa focused on research into the causes of schizophrenia. His efforts were the first to provide experimental evidence that the origins of schizophrenia might be epigenetic in nature. From 1996 until recently, Dr. Costa directed the Psychiatric Research Institute at UIC, and his contributions revealed important insights into our understanding of this insidious disease.

Dr. Costa's enthusiasm and ability to translate scientific hypotheses into successful experiments were contagious for all his collaborators—more than 300 in 60 years, from countries such as China, Japan, Russia, Afghanistan, Pakistan, India, and Nigeria, to a large number of European and Middle Eastern countries. His students always, even years after they had left his laboratories and been appointed to prestigious university positions, greatly valued his mentorship. Dr. Costa had an exceptional lifelong scientific career completely dedicated to discovery in neuroscience. His leadership and fostering of international scientific exchange has had a great impact in modern neuroscience for which he will long be remembered. During his recent retirement party (21 October 2009), well over 100 scientists representing nearly every continent attended to honor their mentor. During his long career, Dr. Costa authored over 1,000 manuscripts in prestigious scientific journals. He will be fondly remembered by his former students, collaborators, and peers.

Scientific Accomplishments
Dr. Costa’s scientific achievements, of unique breadth and depth, stem from his innovative and rigorous approach to tackling scientific issues. Dr. Costa was recognized with numerous awards over the years for his contributions, which have always been at the forefront of research in neuroscience and particularly in neuropsychopharmacology. His pioneering studies on serotonin in the human brain (1958) have been and are still followed by numerous other researchers. These scientists subsequently confirmed his initial reports on the multiplicity of serotonin receptors. His studies on serotonin established that this neurotransmitter was a target for the action of antidepressant and antipsychotic drugs. He introduced mass fragmentography as an innovative method that allowed the study of neurotransmitter steady-state levels and turnover rate in discrete rat brain nuclei, an index of specific neuronal system activation. This opened a new path to probe the mechanism of action of psychotropic drugs in vivo. In the early 1970s, Dr. Costa revealed the role of cyclic AMP in the trans-synaptic induction of tyrosine hydroxylase via a cascade of molecular cytosolic and nuclear events triggered by the activation and nuclear translocation of protein kinase A. These studies were among the first to show a regulatory action of cyclic AMP in the transcriptional activation of a specific gene, and currently this mechanism is considered to play an important role in the pathophysiology of depression and in the mechanism of dependence on drugs of abuse. He first proposed and discovered that the GABAA receptor is the target of anxiolytic benzodiazepines (1974). From these pioneering studies, he explored the mechanisms of GABAA receptor allosteric modulation and regulation that led to the discovery of the molecular mechanisms underlying benzodiazepine tolerance and dependence. As it applies to benzodiazepines, endogenous peptides, and neurosteroids acting on the GABAA receptors, his demonstration of drugs acting as allosteric modulators was fundamental to our appreciation of the structural heterogeneity of GABAA receptors. In addition, in the past few years, this discovery was expanded as a conceptual framework to probe the regulation and pharmacology of receptors for other neurotransmitters.

Given the poor results and numerous side effects associated with current neuroleptics, during the last 15 years Dr. Costa dedicated his efforts to finding better pharmacological treatments for schizophrenia. Typical for him, he took an innovative path. He and his colleagues established that reelin, an extracellular matrix protein that controls the correct positioning of neurons in laminated structures of the brain, continues to be expressed in the telencephalon and hippocampus of adult mammals, where it is synthesized and secreted by GABAergic interneurons. Reelin binds to integrin receptors expressed in dendritic spine post-synaptic densities and as a result of this binding, increases protein synthesis locally in dendritic spines, thus implying that reelin plays a fundamental role in synaptic plasticity. In 1998, Dr. Costa and his collaborators discovered that reelin and the enzyme that makes GABA (GAD67) were downregulated in the brains of schizophrenia patients, a finding in line with the observed neuropil hypoplasticity and decrease in dendritic spine density in the cortex and hippocampus of these patients. Interestingly, those GABAergic neurons that show reduced expression of reelin and GAD67 also show an increased expression of a DNA-methylating enzyme (DNMT1). These findings suggest that the reelin and GAD67 downregulation in the brains of schizophrenia patients is associated with hypermethylation of the corresponding promoters of these genes, and furthermore, these studies point to the possibility that an epigenetic mechanism underlies schizophrenia morbidity. Indeed, animal experiments with valproate, an inhibitor of histone deacetylases that indirectly increases DNA demethylase activity, led Costa and colleagues to suggest that histone deacetylase inhibitors be tested in the treatment of schizophrenia, and further, that they might mitigate schizophrenia vulnerability in individuals at high risk by decreasing reelin and GAD67 promoter hypermethylation and restoring reelin and GAD67 expression.

Dr. Costa’s exceptional scientific career will have a great impact in modern neuroscience for years to come as he continues to be quoted in scientific journals and his investigations provide the basis for much current experimentation.—Dennis Grayson and Alessandro Guidotti, Department of Psychiatry, University of Illinois Chicago.

Donations for the Erminio Costa Memorial Lecture should be made payable to:
University of Illinois—Department of Psychiatry
Note: In memory of Dr. Erminio Costa

Mailing Instructions:
Carla R. Ross
Room 551, M/C 912
University of Illinois at Chicago
Department of Psychiatry
1601 W. Taylor
Chicago, IL 60612

Comments on News and Primary Papers
Comment by:  Artyom Tikhomirov
Submitted 2 December 2009
Posted 3 December 2009

My condolences. May he rest in peace. Let his outstanding work be furthered by his pupils and thus let the memory of him live on.

View all comments by Artyom TikhomirovComment by:  Lorna Role
Submitted 22 December 2009
Posted 23 December 2009

Erminio will be missed by many, including me. My first encounter with Erminio was as a graduate student attending my first scientific meeting— a Catecholamine Gordon conference at Asilomar. His enthusiasm, firey disposition and commitment to science was an inspiration! My condolences to his family and special thoughts to Sandro ...

View all comments by Lorna Role

Comments on Related News

Related News: Mental Health Community Mourns Passing of Wayne Fenton

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 8 September 2006
Posted 8 September 2006

The following was circulated in the American College of Neuropsychopharmacology:

Sunday afternoon, September 3, 2006, we lost an outstanding leader of psychiatric research and a wonderful person. Wayne Fenton, M.D. was found dead in his office, the victim of a homicide while providing an urgent consultation to a 19-year-old psychotic patient. During his tenure at Chestnut Lodge, Dr. Fenton and Dr. Tom McGlashan conducted the influential long-term follow-up study of Lodge patients which clarified the limitations of therapeutics for schizophrenia. In his role as Director and CEO of Chestnut Lodge Hospital he transformed that institution from a long stay hospital with a focus on intensive psychotherapy for schizophrenia into a modern facility providing integrated psychosocial and pharmacotherapy for severely ill persons.

He joined NIMH in 1999, and during the past two years he has served as both Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs. He provided the leadership that enabled NIMH to define the unmet treatment needs in schizophrenia and create the MATRICS and TURNS process focused on drug discovery for cognition impairments in schizophrenia. He also initiated the process that defined negative symptoms as a priority for drug discovery, emphasizing the poor functional outcomes associated with these two pathologies. He successfully brought academic scientists, NIMH leadership, pharmaceutical industry scientists, and FDA leaders together in an effort to accelerate drug discovery for schizophrenia. These accomplishments are central to the interest of the ACNP, and many of our members have participated in these programs with Dr. Fenton’s leadership.

Wayne was not a member of the ACNP, but he has set a scientific agenda and process in place that is central to the ACNP mission. He was a terrific person. His death is a tremendous loss to the field, and a deep personal loss to all of us who have known him.

With the greatest sadness,

William T. Carpenter Jr., M.D.
American College of Neuropsychopharmacology

View all comments by William Carpenter

Related News: Mental Health Community Mourns Passing of Wayne Fenton

Comment by:  Thomas McGlashan
Submitted 14 September 2006
Posted 14 September 2006

This eulogy was given at a memorial service for Wayne Fenton on September 7, 2006.

My name is Tom McGlashan, a friend and colleague of Wayne Fenton’s. I also speak for my wife Patricia.

Wayne has touched all of us in many ways—so many ways it is hard to condense in a few words. I will focus on the parts around which he and I interacted the most—his work.

Wayne Fenton entered my life when he came to Chestnut Lodge Hospital in the mid-1980s. His arrival was one of the best things that ever happened to me. He came to Chestnut Lodge in part drawn by a research follow-up study I had begun there. I was excited because his arrival doubled the size of our research department. But I was also nervous, never having been a mentor, never having had a mentee. But I didn’t have to worry for long. He was a natural. He didn’t need much guidance. Before I knew it, the research department was producing more than double its prior output. In what seemed like no time, a dozen papers emerged from the department and floated forth with almost uncontested peer-review blessings—a collection referred to occasionally as the Fenton series of the Chestnut Lodge Follow-up Study, each paper a solid contribution to our knowledge about the diagnosis and the course of schizophrenia and its manifestations over long periods of time.

Wayne repeated such bursts of creative research many times and across several domains such as developing psychosocial treatments for schizophrenia, introducing psychoactive drugs and drug research to Chestnut Lodge, including the first use of clozapine in Maryland. He became an expert in institutional care such that when Dexter Bullard Jr. passed on, it was natural for Wayne to assume leadership of Chestnut Lodge. While running the hospital he was also—sort of on the side—collaborating with Montgomery County in a research project testing alternatives to institutional treatment. Such was the scope of his pluralistic vision. The way he saw it, one thing never worked for everyone. For some, an institution was therapeutic; for others it was toxic. The answers about what “works” were not clear or simple, but Wayne always tried his best to answer them, to try out new ideas, to try.

I left Chestnut Lodge in 1990 to run the Yale Psychiatric Institute, and I tried several times to get Wayne to New Haven to continue our collaboration. He had received his training in psychiatry at Yale and was always nostalgic about the place. But every time I called in earnest, his phone was off the hook, and I realized he would never leave Montgomery County. When Chestnut Lodge closed in the late 1990s, how fortunate it was for NIMH that it was located in Montgomery County! Wayne only had to move from West Montgomery Avenue to Executive Boulevard—to the good fortune of Steve Hyman and Tom Insel and company, and to the good fortune of American psychiatry. Another of his sustained bursts of creativity ensued. This time it was of orchestral magnitude and complexity, weaving together his well-honed talents in research, clinical care, and administration. I cannot detail his many initiatives because I was not there, but I do know that his impact on the extramural research field has been substantial because I live and work in that field, and the number of times I heard colleagues utter Wayne’s name in awe, and occasionally in vain, assured me that he was still in Montgomery County and still larger than Montgomery County.

An abiding legacy of Chestnut Lodge was that Wayne loved seeing patients who were seriously ill. He was tenaciously dedicated to schizophrenia, from unraveling the mystery of its origins to treating people with the disorder. It was this dedication which unfortunately is at the root of our gathering here in shock and mourning. This time, Wayne encountered the disorder at its typical debut in the brain and mind of a youth. This time, however, the disorder took two lives, not one. Wayne’s name is now inscribed on the vertiginous wall of doctors who died at the hands of the disorder they were trying to treat. The patient’s name is not likely to achieve the same outcome. He is alive, but what he has lost to the disorder may well be the subject of a lifetime of mourning. I know Wayne would regard this as the antithesis of everything he was trying to achieve, because we know that he never gave up the effort to understand and treat the sickest among us.

Nor should we ever give up. To finish, I would like to read a note Wayne’s family received two days ago from one of Wayne’s former patients. It shows what he showed many times—good things can happen, too.

To Doctor Fenton
Who helped me in my time of need and led me to the way of a happier life. To his loving wife and children whom he loved dearly and to his love for the better of others. His memory will never be forgotten! To those who knew him, you know how great a man he was. To those who didn’t, may you try to understand that this man was a hero to many.
Love, a patient

View all comments by Thomas McGlashan