Innovative research in genetics has produced a way to correct a rare syndrome called ICF or (or Immunodeficiency, Centromere instability and Facial anomalies syndrome). This is an immune disorder which can seriously endanger babies and children. The method was published in the journal eLIFE and includes the research of doctoral student Shir Toubiana and her supervisor Prof. Sara Selig at the Molecular Medicine Laboratory at the Rappaport Faculty of Medicine at the Technion; as well as their colleague Dr. Maria Matarazzo of the Institute of Genetics and Biophysics ABT CNR, Italy.
ICF syndrome is a rare and dangerous disease that causes immunodeficiency and mortality in the majority of patients during the first two decades of their lives. Additionally, the chromosomes – the molecules containing the genetic material – are characterized by instability in the patient cells.
From the genetic point of view, in about half of the patients, the syndrome is caused by mutations in the DNMT3B gene that is responsible for adding a chemical group of methyl to certain regions of the DNA. The main role of DNA methylation is to control gene expression and maintain chromosome stability – a biological process that protects, among other things, telomeres, the ends of chromosomes. As such, malfunctions in the methylation process lead to a disruption of telomere regulation and premature aging of patients’ cells. The disorder in ICF syndrome patients most likely starts early in their embryonic development.
Shir Toubiana, an outstanding doctoral student and a future physician, was diagnosed as hearing impaired since birth. Since then, she has been wearing hearing aids in both ears, but to her, that not a disadvantage but a challenge. She studied within the regular education system and did her military service as an instructor and mentor in the IDF Junior Command Preparatory School near the Reali School in Haifa.
A few months after being discharged, Toubiana was already studying at the Rappaport Faculty of Medicine, and by the end of her third year in Medical school, she was accepted into the prestigious MD/PhD program, that combines medicine with research and prepares its participants to become physician-researchers. Graduates of the program earn a dual degree: Doctor of Medicine (MD) and a Doctor of Life Sciences (PhD). As a research doctoral student, Toubiana was accepted into the Baroness Ariane de Rothschild Women’s Doctoral scholarship Program for outstanding doctoral students, that empowers doctoral students from diverse backgrounds to reach their goals in academia and in Israeli society.
Toubiana’s contributions to the field of medicine are already having an impact. From the genetic point of view, in about half of the patients with ICF, the syndrome is caused by mutations in the DNMT3B gene that is responsible for adding a chemical group of methyl to certain regions of the DNA. The main role of DNA methylation is to control gene expression and maintain chromosome stability – a biological process that protects, among other things, telomeres, the ends of chromosomes. As such, malfunctions in the methylation process lead to a disruption of telomere regulation and premature aging of patients’ cells. The disorder in ICF syndrome patients most likely starts early in their embryonic development.
The study published in eLIFE describes the successful correction of mutations in the DNMT3B gene in cells of ICF patients. Following the correction, performed on stem cells derived from the skin cells of those patients, the modified protein performed methylation of the DNA in different regions of the genome.
We have restored the functional capacity of DNMT3B and so we have been able to rescue the methylation in centromeres – the areas in the centers of chromosomes – but not in most telomeres,” says Toubiana. “We have found that the failure is due to certain molecular barriers that are part of the ‘epigenetic memory’ of patients’ original skin cells. Through chemical manipulation, we were successful in lowering some of these barriers, and indeed, the level of methylation in the telomere environment has increased.” She clarifies that although this is an important stage, “there is still a lot of work to be done on the way to treating these patients. Among other things, to find a way to allow DNMT3B to re-methylate at all its targets. Such a step will bring us closer to effective treatment, not only for ICF syndrome but also for other epigenetic diseases.”
The present study incorporated two innovative and important technologies in repairing mutations in patients’ cells: induced pluripotent stem cells (iPS) and the CRISPR-Cas9 genome editing system. In the first stage, adult cells taken from the patient undergo reprogramming using molecular means that transform them from skin cells into pluripotent stem cells – iPS, that is, cells that have the potential to become body cells of different types. The stem cells obtained in this way are genetically modified using the novel CRISPR-Cas9 method. It is worth noting that the development of iPS technology led to the 2012 Nobel Prize in Medicine and that CRISPR-Cas9 technology was at the center of the Technion’s Harvey Prize awarded at the end of 2019.
“In the future, I aspire to combine clinical work as a physician with basic scientific research,” says Toubiana. “I believe that the two disciplines are intertwined and grant the physician a broader view of their patients and the possibility of researching the mechanism underlying their disease in depth.”
Alongside the intense academic and research activities, Toubiana still finds time to develop her leadership skills. This is the second year that she is a member of the Steering Committee of the Ariane de Rothschild program, founded by the Edmond de Rothschild Foundation. “This is a great opportunity to reflect our needs as doctoral students, to initiate and bring up new professional training ideas that will help us in the future and that will be implemented in collaboration with the foundation. Planning these activities requires a lot of investment, but the reward is a sense of self-fulfillment in giving to the community that I have become a part of.”
For the full study in eLIFE click here.