# Benjamin Weiss (scientist)

Benjamin Weiss (January 26, 1937) is an American neuropharmacologist, Emeritus Professor of Pharmacology and Physiology at Drexel University College of Medicine. He is best known for his work with cyclic nucleotide phosphodiesterases. He was the first to propose, based on his experimental work, that selective inhibition of phosphodiesterases which are expressed differentially in all tissues, could be used as a target for drug development. His work is the basis for many marketed and developmental human drugs that selectively inhibit cyclic nucleotide phosphodiesterases.
His investigations on the modulation of adrenergic responses in the pineal gland have resulted in the formation of new concepts that may explain the phenomena of drug tolerance and drug hypersensitivity. He and his laboratory were also instrumental in the development of antisense oligonucleotides and antisense RNA as pharmacological tools to study calmodulin and dopamine receptors, and as pharmacological agents for antisense therapy in brain and other tissue.

## Early life and education

Weiss was born in The Bronx in 1937 and was raised on a chicken farm in New Jersey where his immigrant parents moved in 1946. Weiss went to Toms River High School, graduating in 1954. He received his undergraduate degree in Pharmacy in 1958 from the Philadelphia College of Pharmacy and Science (now, University of the Sciences), where he also earned a M.Sc. in 1960 and a Ph.D. in Pharmacology in 1963, under the tutelage of G. Victor Rossi. From 1963 to 1966 he had a Postdoctoral Fellowship and a Staff Fellowship at the National Heart Institute, National Institute of Health, where he studied under Bernard B. Brodie. He did further training as a research associate at Columbia University, College of Physicians and Surgeons, with Erminio Costa from 1966 to 1968.

## Personal life

In 1959 Weiss married Joyce Zelnick. They have three children and five grandchildren.

## Scientific career

From 1968 to 1972 Weiss worked at the National Institute of Mental Health at St Elizabeths Hospital, Washington, D.C., where he held the position of chief of the Section on Neuroendocrinology. In 1972 he accepted the position of professor of pharmacology at the Medical College of Pennsylvania (MCP), where he held the positions of professor of pharmacology and psychiatry, and chief of the Division of Neuropsychopharmacology. He was also a visiting scientist at the Mario Negri Institute for Pharmacological Researchin Milan, Italy, and a visiting scientist at the Weizmann Institute of Science in Rehovot, Israel. On retirement in 1999 he became an emeritus professor in the Department of Pharmacology and Psychiatry at MCP. In 2002, when Drexel University assumed leadership of MCP, he was given the position of professor emeritus in the Department of Pharmacology and Physiology at Drexel University College of Medicine, the position he now holds.

## Publications

Weiss is the editor of two books: (Weiss, Benjamin, ed., Cyclic Nucleotides in Disease$^{[1]}$), and Antisense Oligodeoxynucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents$^{[2)}$). He has also published over 300 scientific articles, reviews and abstracts on his research in molecular biology and molecular pharmacology.

## Research

Cyclic Nucleotide Phosphodiesterases:
Weiss and co-workers developed rapid phosphodiesterease assays $^{[3,4]}$, separated different isozymes of phosphodiesterase in various tissues by electrophoretic methods $^{[5,6]}$and showed that drugs could selectively inhibit the several isozymes of phosphodiesterase (link) isozymes. He showed that a single cell type may contain more than one form of phosphodiesterase $^{[6,7]and}$ that different forms of phosphodiesterase could be induced or activated by certain neurohormones(e.g. norepinephrine) $^{[7]}$and intracellular proteins (e.g. calmodulin) $^{[8,9]}$. He demonstrated that there are different forms of phosphodiesterase in different tissues including the mammalian brain $^{[5,6]}$and lung $^{[10]}$.
Weiss was the first to show that phosphodiesterase activity is altered in certain disease states $^{[11,13,14,15,16]}$and to propose that selective inhibition of phosphodiesterase could be the basis of drug selectivity $^{[17,18,19,20]}$. Weiss and co-workers did extensive work which demonstrated that certain neuropeptides $^{[21,22]}$, alpha adrenergic antagonists $^{[23]}$and phenothiazineantipsychotic drugs were potent inhibitors of calmodulin activated enzymes $^{[24,25,26,27,28]}$.
Modulation of Adrenergic Receptor-Linked Adenylate Cyclase System: Using the pineal gland as a model, Weiss and his colleagues were the first to show that the beta-adrenergic receptor-linked adenylate cyclasesystem is modified chronically by a variety of physiological factors and pharmacological perturbations [reviewed in $^{29}$]. His laboratory demonstrated that this system is influenced by sympathetic neuronal input, in that a long-term decrease in sympathetic input results in an increased responsiveness to adrenergic stimuli $^{[30,31]}$; by environmental lighting, in that darkness, which increased sympathetic input to the pineal gland decreases the response to adrenergic input$^{[32]}$; by hormonal status, in that low estrogen levels increase the responsiveness to norepinephrine$^{[33]}$and by the age of the animal, in that older animals evidence a decrease in beta-adrenergic receptors and a reduced response to adrenergic stimuli $^{[34,35,36]}$.
Weiss showed additionally that the responses to adrenergic stimuli are also altered by a variety of pharmacological agents that chronically change adrenergic input. For example, long-term treatment with agents that reduce sympathetic input, like reserpine$^{[37]}$, 6-hydroxydopamine$^{[38]}$, guanethidine$^{[39]}$, and certain phenothiazine antipsychotic drugs $^{[40]}$all increase the density of beta-adrenergic receptors and increase the responsiveness to adenylate cyclase. By contrast, treatment with drugs such as the anti-depressant desmethyimipramine, which increases adrenergic input, reduces the adrenergic receptors $^{[41]}$.These studies show that long-term changes following physiological or pharmacological alterations in adrenergic input may be explained by a common biological principle: the degree to which an adrenergically innervated structure can be stimulated is inversely related to the degree to which it had been previously stimulated. This hypothesis may provide a biochemical basis for explaining the altered responsiveness of the adrenergic system seen in aging and in males vs. females, and may explain the mechanism for drug supersensitivity and drug tolerance.
Antisense Oligonucleotidesand Antisense RNA:Weiss’ laboratory made discoveries on: 1) The role of calmodulin in neuronal differentiation and proliferation; 2) Behavioral and biochemical correlates of dopamineresponses in brain; 3) Development of antisense oligonucleotides and antisense RNA as pharmacological tools to study calmodulin and dopamine receptors, and as pharmacological agents for gene therapy in brain; and 4) Reversal of dopaminergic supersensitivity: preclinical mechanisms and clinical applications. 6) The studies laid the foundation for the therapeutic use of antisense oligonucleotides and antisense RNA in a variety of disease states. A number of drugs are currently on the market and many others are in clinical development using the concept of antisense therapy, including in cancer, Huntington's Disease, and other neurological diseases.
Weiss and his group, assisted by Genoveva Uzunova (Davidkova), who carried out a significant part of the antisense RNA studies in his group, used molecular biological, biochemical, pharmacological, cell biological techniques (cell cultures, fluorescence microscopy), and mouse models, to develop antisense oligonucleotides to the D1 and D2 dopamine receptors. They showed for the first time that intracerebroventricular (i.c.v.) and intrastriatal injection oligonucleotides targeted to the D1 or D2 dopamine receptor in mouse brain can block the biological effects of the targeted receptor with very high specificity and, importantly, without inducing receptor supersensitivity, which is a significant drawback to the conventional neuroleptic drugs such as haloperidol$^{[42,43,44]}$. Therefore, these novel pharmacological agents would not likely induce the debilitating motor side effects resulting from conventional pharmacological agents..
Since the effects of the oligonucleotides are relatively short-lasting (up to 2–3 days) and it is necessary to inject them repeatedly in mouse brain in order to achieve a long-term reduction in the D2 dopamine receptor mRNA and the dopamine receptor protein, and the concomitant long-term blockade of the behaviors modulated by these receptors, Weiss’ group developed a second approach – expression of D2 dopamine antisense RNA in brain by a non-viral plasmid vector. This approach was the first to show that a single intrastriatal injection of D2dopamine receptor antisense RNA (targeted to the long isoform of the murine D2 dopamine receptor) can effectively block D2 dopamine-mediated behaviors for up to one month $^{[45]}$. Moreover, this did not induce D2 receptor supersensitivity, unlike the conventional neuroleptic haloperidol, which blocks D2 dopamine receptors and several other subtypes of dopamine receptors $^{[46]}$. These studies opened up the possibility to develop a new gene therapeutic approachto treat neurologic and psychiatric conditions associated with D2 receptor hyperactivity such as chorea and addiction to alcohol $^{[47]}$. In a broader perspective, a similar gene therapeutic approach targeting other central nervous system (CNS) neuroreceptors and proteins may prove useful for treating other disorders of the CNS . The antisense RNA approach is an alternative to the RNA interference approach. RNA interference.
During this period, the studies of Weiss and his group were also focused on the use of antisense oligonucleotides $^{[48]}$and antisense RNA expression vectors to calmodulin $^{[49]}$ ,which is a ubiquitous calcium binding protein in brain encoded by three different genes that give rise to several transcripts. These studies helped to elucidate the essential role of calmodulin in the proliferation and differentiation of nerve cells and suggest a novel approach with the potential for gene therapy of tumors that express high levels of calmodulin, such as gliomas and certain forms of breast cancer. $^{[50,51]}$.

## Honors and awards

In 2001, Drexel University College of Medicine established a Graduate Student Fellowship in his name. He was named as one of the Top One Thousand Most Quoted Contemporary Scientists in the World. He has received awards from the Numismatic Literary Guild and a medal issued jointly by the Token and Medal Society and the American Israel Numismatic Association.