Batsheva Kerem

Last updated
Batsheva Kerem
BornMarch 16, 1955
Tel-Aviv, Israel
NationalityIsraeli
Known fordiscovery of mutations causing cystic fibrosis
SpouseEitan Kerem
Scientific career
Fieldsmolecular genetics
InstitutionsHebrew University, Hospital for Sick Children, Israel National Center for CF Genetic Research
Thesis  (1986)
Academic advisors Lap-Chee Tsui

Batsheva Kerem (born 1955) is an Israeli geneticist who was on the research team that identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later established the Israel National Center for CF Genetic Research. [1] She discovered the most prevalent cystic fibrosis-causing mutations among the Israeli population, allowing for the establishment of nationwide genetic screening programs to identify carriers of these mutations and enabling prenatal diagnoses. [2] She researches how some CF mutations prevent CFTR protein production by causing nonsense-mediated decay and abnormal mRNA splicing, and how therapies might be able to counteract those problems. [3] She also studies the role of genetic instability in cancer. [3] She is currently a professor at the Hebrew University. [3]

Contents

Early life and education

Batsheva Kerem was born in Tel-Aviv in 1955 and raised in Israel. She served as an IDF officer in the military. She received a B.Sc. with distinction in biology from the Hebrew University in 1979, followed by a Ph.D. from the direct doctoral program of Hebrew University's Department of Genetics in 1986. [1] Her Ph.D work was supervised by Menashe Marcus and Howard Cedar. [4] She did a brief post doctoral fellowship with Tamar Schaap in the Department of Genetics at Jerusalem's Hadassah Medical School, from 1986 to 1987. [4] She then moved to Canada for further postdoctoral training at the Hospital for Sick Children in Toronto, Canada (commonly known as SickKids), where she worked in the laboratory of Lap-Chee Tsui from 1987 to 1990. [4]

Career

Kerem has spent her career at the Hebrew University. She was hired as a senior lecturer in 1990, at which time she established the Israel National Center for CF Genetic Research. [1] She was promoted to associate professor in 1998 and Full Professor in 2003. [5] She established the National Genomic Knowledge Center at Hebrew University's Institute of Life Sciences and served as its chair from 2000-2014. [5] She served as the Head of Authority for research students from 2007-2011. [5] She was appointed President Advisor for Promotion of Women in Science in 2013. [5] She is a member of the European Research Council (ERC) for advanced scientists and has served on the editorial board of the European Journal of Human Genetics and EMBO Reports. [5] She was appointed President of the Genetic Society of Israel in 2007. [1]

Research

Kerem helped identify the gene behind cystic fibrosis, the CFTR gene (short for cystic fibrosis transmembrane conductance regulator), which was found to be an ion channel. This work was carried out when she was a postdoctoral fellow in the lab of Lap-Chee Tsui at the Hospital for Sick Children (SickKids) in Toronto, Canada, and was a collaboration between Tsui's lab, including fellow postdoctoral researcher Johanna Rommens, and a team of researchers led by Francis Collins at the University of Michigan. [6] The CFTR gene was discovered through genetic linkage analysis involving looking for genetic markers that were present in patients with cystic fibrosis but not present in their non-affected relatives. Due to the phenomenon of recombination, whereby parts of chromosomes swap homologous segments during germ cell development, each chromosome a child inherits is a mix of the both of that parent's copies of that chromosome. Markers would only be consistently co-inherited with the gene behind cystic fibrosis if they were close together on the chromosome, so Kerem and other researchers used markers to find the approximate location of the gene. [2] They then used a combination of chromosome walking and chromosome hopping or jumping to locate the CF gene, which they named cystic fibrosis transmembrane conductance regulator (CFTR). [6] Kerem helped identify the globally most common CFTR mutation, F508del, a deletion of the 508th amino acid (protein letter) in the CFTR protein, which is normally a phenylalanine (abbreviated F). [2]

Part of her work at SickKids involved examining blood samples sent from around the world and, when looking at the CFTR gene in samples sent from Israeli patients, she found that they didn't carry any of the previously-identified mutations. [2] She became intrigued so, when she moved back to Israel in September 1990, she collected blood from most Israeli CF patients and searched their CFTR genes for mutations. She discovered that about 60% of Israel's Ashkenazi Jewish CF patients had a nonsense mutation abbreviated as W1282X (signifying that the genetic instructions for 1282rd amino acid in the protein, which is normally a tryptophan (W), has been mutated to a stop signal (X)). [7] This early stop signal, a premature termination codon (PTC), caused the production of truncated, dysfunctional CFTR protein. She published this finding in 1992 and in 1997, Israel's government introduced population carrier screening for it. [2]

Much of Kerem's later contributions to cystic fibrosis research involves studying defects in the production of CFTR caused by premature termination and improper RNA splicing. In order to make a protein, a cell first makes RNA copies of the DNA gene for that protein. These RNA copies contain regulatory regions called introns which are removed in a process called RNA splicing in order to produce mature messenger RNAs (mRNAs) which are used by the cell's protein-making machinery (ribosomes and helpers) to make the corresponding protein in a process called translation. Certain CF-causing mutations, instead of affecting the CFTR protein's shape and functioning, affect how the messenger RNA (mRNA) copies of the genetic recipe for CFTR are processed, thus preventing CFTR protein from being made. [8]

In addition to identifying and classifying the wide spectrum of CFTR mutations, Kerem studies how therapies might be able to counteract the problems present among the various classes. For example, Kerem researches how pharmaceutical compounds that promote read-through of these stop codons might be able to counteract problems caused by premature termination codon (PTC) mutations such as the W1282X she discovered was common among Ashkenazi Jewish patients. [8] Additionally, she invented a discovery platform which serves as the basis of the biotechnology company SpliSense, which is working to develop antisense oligonucleotides (ASOs) to counteract mRNA splicing mutations by using small segments of DNA complementary to specific regions of the RNA in order to hide improper splice sites and promote proper splicing. [9] [10]

In the late 1990s she began studying chromosome structure and function. [1] She has investigated genome instability and made significant contributions to knowledge of the involvement of frequent fragile sites in cancer. [1]

Personal life

Batsheva Kerem is married to Dr. Eitan Kerem, head of the Division of Paediatrics at the Hadassah Medical Organization, who also researches cystic fibrosis. [11] They have carried out collaborative research together, including the development of potential therapeutics. [12] The reason Batsheva chose a postdoctoral fellowship in Tsui's lab at SickKids was in part because she and Eitan were looking for job opportunities where they would be able to work nearby one another. [2] She carried out her groundbreaking CF research in Tsui's lab while a mother to two children. [2] Batsheva has spoken out about gender inequality in science and, when she was one of the few women to receive an EMET Prize, she used the opportunity to advocate for better representation of women among prize recipients. [13]

Honors

Key publications

Related Research Articles

<span class="mw-page-title-main">Cystic fibrosis</span> Autosomal recessive disease mostly affecting the lungs

Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutation is not always harmful, the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a particular phenotype or trait of interest.

<span class="mw-page-title-main">Synonymous substitution</span>

A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.

<span class="mw-page-title-main">Gene mapping</span> Process of locating specific genes

Gene mapping or genome mapping describes the methods used to identify the location of a gene on a chromosome and the distances between genes. Gene mapping can also describe the distances between different sites within a gene.

Congenital absence of the vas deferens (CAVD) is a condition in which the vasa deferentia reproductive organs fail to form properly prior to birth. It may either be unilateral (CUAVD) or bilateral (CBAVD).

An exonic splicing silencer (ESS) is a short region of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing effect, ESSs recruit proteins that will negatively affect the core splicing machinery.

<span class="mw-page-title-main">MT-ND4</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.

<span class="mw-page-title-main">Shwachman–Diamond syndrome</span> Medical condition

Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal and cardiac abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. It is associated with the SBDS gene and has autosomal recessive inheritance.

<span class="mw-page-title-main">Ivacaftor</span> Pharmaceutical medication used to treat cystic fibrosis

Ivacaftor is a medication used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis. It is also included in combination medications, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor which are used to treat people with cystic fibrosis.

The history of genetics can be represented on a timeline of events from the earliest work in the 1850s, to the DNA era starting in the 1940s, and the genomics era beginning in the 1970s.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

Robert Williamson is a retired British-Australian molecular biologist who specialised in the mapping, gene identification, and diagnosis of human genetic disorders.

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

Johanna Rommens is a Canadian geneticist who was on the research team which identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later discovered the gene responsible for Shwachman-Diamond syndrome, a rare genetic disorder that causes pancreatic and hematologic problems. She is a Senior Scientist Emeritus at SickKids Research Institute and a professor in the Department of Molecular Genetics at the University of Toronto.

<span class="mw-page-title-main">Cystic fibrosis and race</span>

Underrepresented populations, especially black and hispanic populations with cystic fibrosis are often not successfully diagnosed. This is in part due to the minimal dissemination of existing data on patients from these underrepresented groups. While white populations do appear to experience a higher frequency of cystic fibrosis, other ethnicities are also affected and not always by the same biological mechanisms. Thus, many healthcare and treatment options are less reliable or unavailable to underrepresented populations. This issue affects the level at which public health needs are being met across the world.

Michael James Welsh is an American pulmonologist. He is the current Roy J. Carver Chair in Biomedical Research, the Professor of Internal Medicine in Pulmonary, Critical Care and Occupational Medicine at the Department of Internal Medicine, and the Director of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa. He is also a professor at the Department of Neurosurgery, Department of Neurology, and Department of Molecular Physiology and Biophysics. He received the 2022 Shaw Prize in Life science and Medicine, together with Paul A. Negulescu, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.

<span class="mw-page-title-main">Isolated hyperchlorhidrosis</span> Medical condition

Isolated hyperchlorhidrosis, also known as Carbonic anhydrase XII deficiency, is a rare autosomal recessive genetic condition characterized by a lifelong tendency to lose massive amounts of sodium and chloride through sweat which leads to various symptoms.

References

  1. 1 2 3 4 5 6 "Professor Batsheva Kerem". The Israel Cancer Association. Retrieved 2021-01-09.
  2. 1 2 3 4 5 6 7 Trivedi, Bijal P., 1970- (2020). Breath from salt : a deadly genetic disease, a new era in science, and the patients and families who changed medicine forever. Dallas, TX. ISBN   978-1-948836-37-1. OCLC   1083824294.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  3. 1 2 3 4 5 6 7 staff, Author IsraCast (2008-10-11). "Prof. Batsheva Kerem". IsraCast. Retrieved 2021-01-09.{{cite web}}: |first= has generic name (help)
  4. 1 2 3 "Team". scholars.huji.ac.il. Retrieved 2021-01-09.
  5. 1 2 3 4 5 6 "Batsheva Kerem". exonskipping.eu. Retrieved 2021-01-09.
  6. 1 2 Marx, J. L. (1989-09-01). "The cystic fibrosis gene is found". Science. 245 (4921): 923–925. Bibcode:1989Sci...245..923M. doi:10.1126/science.2772644. ISSN   0036-8075. PMID   2772644.
  7. ↑ Shoshani, Tzipora; Augarten, Arie; Gazit, Ephraim; Bashan, Nurit; Yahav, Yaakov; Rivlin, Yosef; Tal, Asher; Seret, Hagit; Yaar, Liora; Kerem, Eitan; Kerem, Bat-sheva (January 1992). "Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease". American Journal of Human Genetics. 50 (1): 222–228. ISSN   0002-9297. PMC   1682509 . PMID   1370365.
  8. 1 2 Nissim-Rafinia, Malka; Linde, Liat; Kerem, Batsheva (2005), Bush, A.; Alton, E.W.F.W.; Davies, J.C.; Griesenbach, U. (eds.), "The CFTR Gene: Structure, Mutations and Specific Therapeutic Approaches", Progress in Respiratory Research, Basel: KARGER, pp. 1–10, doi:10.1159/000088467, ISBN   978-3-8055-7960-5 , retrieved 2021-01-16
  9. ↑ Leichman, Abigail Klein (2018-05-14). "5 Israeli startups seeking cures for rare genetic diseases". ISRAEL21c. Retrieved 2021-01-09.
  10. ↑ netbiz. "SPLISENSE". Integra Holdings. Retrieved 2021-01-09.
  11. ↑ "Hadassah's Prof. Eitan Kerem Brings New Hope to Cystic Fibrosis Patients". Hadassah UK. 2017-10-30. Retrieved 2021-01-09.
  12. ↑ "The Past, Present and Future of Cystic Fibrosis". Hadassah Magazine. 2016-09-27. Retrieved 2021-01-16.
  13. ↑ "Perfecting the art of having it all". The Jerusalem Post | JPost.com. Retrieved 2021-01-16.
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