Israel Hanukoglu

Education

Israel Hanukoglu received his undergraduate degree cum laude with double majors in biology and psychology and a minor in political science from the Hebrew University of Jerusalem. He then went to the University of Wisconsin-Madison for graduate studies and received his M.Sc. degree in 1976 in an inter-disciplinary Endocrinology-Reproductive physiology program. His Ph.D. thesis was on the "Mechanism of electron transport to cytochrome P-450 in adrenal cortex mitochondrial steroid monooxygenase systems" carried out under the supervision of Prof. Colin R. Jefcoate.

Contributions to science

Prof. Hanukoglu's scientific work concentrated in three different areas outlined below.

Structures of keratins

Hanukoglu's career in molecular biology started at the Department of Biochemistry of the University of Chicago (1980-1983 with Elaine Fuchs), where he cloned and sequenced cDNAs coding for cytoskeletal proteins, actin and alpha keratins. He elucidated the first structures of cytoskeletal keratin families, and predicted the long helical domains of these proteins. By computerized analysis of amino acid sequences he predicted that the central rod domain of intermediate filament proteins is composed of four helical segments separated by three short linker sequences. Later crystallographic studies have confirmed this as a general model for intermediate filament protein structure.

Steroid hormone synthesis

During his Ph.D. thesis research, Israel isolated the mitochondrial enzymes that catalyze the first step in the synthesis of steroid hormones in all steroidogenic tissues, including the adrenal cortex, and the reproductive organs. The first step of steroidogenesis is dependent on the transfer of electrons from NADPH to a P450 type enzyme (P450scc) via an electron-transfer chain that includes two additional proteins. These proteins are located on the inner mitochondrial membrane. Israel reconstituted this system using proteins he purified, characterized the process of electron transfer between the proteins, and built a kinetic model that simulated precisely the dynamic behavior of this complex system.

In his first academic position at the Department of Biology at the Technion-Israel Institute of Technology, he first determined the molar stoichiometry of the mitochondrial P450 system proteins using specific antibodies that he generated. He then set out to clone the cDNAs and the genes that code for these enzymes. His lab was the first to clone the cDNAs and the gene coding for adrenodoxin reductase - the first enzyme in the electron transfer chain of the mitochondrial P450 system.

By sequence and structural analyses of adrenodoxin reductase, Israel identified its binding sites for the electron donor and acceptor coenzymes, NADPH and FAD. By sequence analyses of the large oxidoreductase type of enzyme families, he noted that the FAD binding site is a classical Rossmann fold, but the NADPH binding site has a different consensus sequence that could be responsible for NAD vs. NADP coenzyme specificity. The importance of the motifs he identified was confirmed by re-engineering of coenzyme specificities of different enzymes. Elucidation of the crystal structure of adrenodoxin reductase further verified Israel's identification of the coenzyme binding sites.

As the steroidogenic tissues have very high levels of antioxidants, Israel suspected that the P450 systems may leak electrons producing oxygen radicals. He examined this issue and showed that indeed, electrons that leak during the action mitochondrial P450 systems generate reactive oxygen species. His studies also showed that in bovine ovary, levels of antioxidants are coordinately regulated with steroidogenesis.

His other work in this field includes elucidation of the mechanism of action of corticotropin (ACTH) in regulating steroid hormone synthesis in the adrenal cortex, regulation of adrenal steroidogenic capacity in disease states, and the cloning and elucidation of the structure of ACTH receptor.

In this field, Israel organized the first International Symposium in Molecular Steroidogenesis in Jerusalem in 1991 which served as the cornerstone for a continuing series of international symposia for scientists who specialize in this field.

Epithelial sodium channel (ENaC)

In his clinical work as an endocrinologist, Israel's senior brother, Prof. Aaron Hanukoglu (Tel Aviv University, Sackler Medical School and E. Wolfson Medical Center), identified that a hereditary disease named pseudohypoaldosteronism (PHA) type I encompasses two independent syndromes. Following this discovery the two brothers continued their collaboration to understand the molecular basis of the severe form of PHA.

By their collaborative work that also included additional labs, the Hanukoglu brothers discovered that the severe forms of pseudohypoaldosteronism type I result from mutations in three genes (SCNN1A, SCNN1B, and SCNN1B) that encode for protein subunits of the Epithelial sodium (Na⁺) channel (ENaC). These studies also helped establish that ENaC is the principal channel involved in blood volume and blood pressure regulation in humans.

Following these studies, the Hanukoglu brothers directed their attention to understand the structure and function of ENaC assembled from normal and mutated subunits. Their analyses showed that the phenotypic variations in the severity of pseudohypoaldosteronism are associated with the types of genetic mutations. Their work on the structure of ENaC subunits led to the identification of charged residues and regions responsible for transport of the protein to membrane and for regulation of extracellular Na⁺ ions.

In an extensive review of studies on ASIC and ENaC, Prof. Hanukoglu has summarized the major similarities between ASIC and ENaC type channels.

To define the sites of localization of ENaC in tissues and within cells, Hanukoglu's laboratory generated polyclonal antibodies against extracellular ENaC subunits. These antibodies for the first time permitted visualization of intracellular localization of ENaC at high resolution and led to the discovery that in all cells with motile cilia ENaC is located on cilia. These studies establish that ENaC is an important regulator of fluid level in the luminal side of cells with motile cilia in the reproductive and respiratory tract.

Systemic pseudohypoaldosteronism patients with mutated ENaC subunits may lose significant amount salt in sweat especially at hot climates. To identify the sites of salt loss, Hanukoglu brothers examined the localization of ENaC in the human skin. In a comprehensive study examining all the layers of skin and epidermal appendages, they found a widespread distribution of ENaC in keratinocytes in the epidermal layers. Yet, in the eccrine sweat glands, ENaC was localized on the apical cell membrane exposed to the duct of these sweat glands. Based on additional observations, they concluded that the ENaC located on the eccrine gland sweat ducts is responsible for the uptake of Na⁺ ions from sweat secretions. This recycling of Na⁺ reduces the concentration of salt in perspiration and prevents the loss of salt at hot climates via perspiration.

Awards

In addition to the personal prizes above, the research presentations from the laboratory of Prof. Hanukoglu received four awards at national and international meetings.

Academic and Civic activities

Besides a scientific career Hanukoglu has maintained an active academic and civic leadership role. In 2003, Hanukoglu founded Israel's first Molecular Biology B.Sc. degree program in the Ariel University Center of Samaria and served as the Chairman of the Molecular Biology Department there from 2003 to 2008.

Prof. Hanukoglu is currently on the editorial board of three journals. He is one of the top reviewers of scientific articles in the life sciences (ranked to be in the top 98 percentile according to the Publons registry).

In 1995 Prof. Hanukoglu was elected as the Chairman of the Professors for a Strong Israel, a self-described "non-partisan organization of academics united by a shared concern for the security and the Jewish character of the State of Israel." From 1996 to 1999 he served as the Science Adviser to the Prime Minister of Israel Benjamin Netanyahu. Hanukoglu was placed as an honorary candidate on the Herut – The National Movement list.

In 2003 he was appointed as the scientific adviser to the Mayor of Rishon-Lezion for establishing the Jewish Nobel Prize Laureate Boulevard Outdoor Museum. Since 1996 he has served as a founding member of the Ariel Center for Policy Research executive board.

Obama Birth Certificate Controversy

Hanukoglu's website, the Israel Science and Technology Homepage, includes the page, "Long-Form Birth Certificate of Obama is a Forged Document." The analyses presented assert that "without a doubt that the Long-Form Birth Certificate of Mr. Obama is a fabricated, fake and forged document."