Dr Roi Gazit – Novel Inroads From Hematopoietic Stem Cells to the Treatment of Leukemia
Dr. Roi Gazit is a biomedical scientist interested in improving the success rate of current treatments of leukemia. His research has focused on understanding Hematopoietic Stem Cells, the precursors of all blood cells. This understanding will create patient-compatible cell grafts for transplantation.
Can you discuss how your research background led to your interest in Hematopoietic Stem Cell Research?
My interest in Biology started early on childhood, and grew during high school. I have always been interested in how living organisms develop and regenerate. This natural curiosity led me to pursue a B.Sc. degree in life sciences, which developed into studying brain development for my M.Sc. I then turned to Immunology, focusing on the study of Natural- Killer (NK) cells for my PhD. Hematopoietic Stem Cells (HSCs) have attracted me by their unique combination of being the continuous source for all blood and immune cells. The rapidly developing field of adult stem cells presents amazing opportunities for young scientists, and combine multidisciplinary methods to advance understanding and develop novel therapies.
Your research interests are focused on exploring the role and functioning of Hematopoietic Stem Cells. Why these cells and why now? Where does this research fit in the larger context of current biomedical research?
Hematopoietic Stem Cells (HSCs) are saving tens of thousands of lives every year, thanks to bone-marrow transplant. However, this requires an adequate match-donor that is not always available. As the stem cell field is rapidly developing, HSCs are leading both basic understanding and translational studies. Understanding fundamental principles of adult stem cells has major implications for regenerative medicine as well as for cancer biology.
Have you experienced any obstacles doing your research and how did you overcome them?
Cutting-edge research is the unpaved road towards the unknowns, so you better enjoy overcoming obstacles if you are to pave this road for others. I have encountered, and keep encountering, both technical and conceptual obstacles; some of which I have overcame by hard work, some by working together with good colleagues. It is most helpful to foresee the road ahead to overcome obstacles, no matter what technical, conceptual or personal troubles you run into, you always get ahead easier if you know what you aim for.
Has your work revealed any significant findings to date?
Some of my major findings include (1) finding role of NKp46 against influenza virus in-vivo, by generating the first NK cell specific knockout and knock-in. (2) Molecular understanding of Hematopoietic Stem Cells (HSCs) transcriptome (3) Reprogramming of committed blood cells directly into HSCs (4) Novel HSC-reporter mouse (5) Leukemia-models.
Your investigation of Hematopoietic Stem Cells is motivated in part by its role in providing a cure for leukaemia. Do they play any other roles in the organism? Have you worked with any other researchers for this study? If so, how did they contribute?
HSCs are needed throughout normal healthy life, their role being to generate the blood and immune cells required for homeostasis. A healthy human generate about one million new blood cells every second, which translates into an astronomic number of cells every day! HSCs are further essential for regeneration from insults, especially in leukemia that severely impairs the normal blood system.
Do you envision any type of Hematopoietic Stem Cells-based treatments and how they might be implemented?
HSCs are the functional unit of bone-marrow transplant. Dr. Donnall Thomas’ pioneering studies of bone-marrow transplant are now applied worldwide, and constitute the leading clinical utilisation of stem-cells.
What implications might this study have on future work and potentially on healthcare, society and policy?
Once the ability to reprogramme blood cells directly into HSCs would be translated into humans, and robustly validated for safety, we will have a novel source of perfectly matched own cells for transplantation. This might actually be a very rapid implication, as bone-marrow transplant is well established. Nevertheless, we must take all caution and carefully ensure safety first. A major advantage of working with adult stem cells, such as HSCs, is the potential rapid implication for healthcare on the one hand, and the avoidance of any ethical issues that other embryonic stem cells may encounter.
Are you planning to extend this research further? Where might you focus your attention and why?
I will keep working on reprogramming of HSCs. We made the first discovery of specific factorsand I want to understand how they work. This will help progress in this field, and might suggest ways to increase the efficiency of this novel reprogramming. At the same time, we are also using our system for the generation of novel leukemia-models that can be tailor-made and propagate in immune-competent mice.
Hematopoietic Stem Cells and Leukemia
Leukemia is a disease of the white blood cells, which leads to hematopoietic and immune system dysfunction. Current leukemia treatment research, such as Dr. Roi Gazit’s work on Hematopoietic Stem cells offers new perspectives on curing leukemia and furthering understanding of the relevant fundamental biology.
STEM CELLS: WHAT THEY ARE, AND WHY THEY ARE IMPORTANT
Stem cell research has received a great deal interest in the last decade. Stem cell research is currently at the forefront of biomedical research, and holds great promise towards the development of new treatments for some of the deadliest diseases. Stem cells are undifferentiated cells that can divide to produce more stem cells and can differentiate into specialised cells. The focus of Dr. Roi Gazit’s research interests is hematopoietic stem cells (HSCs). They are a class of somatic, adult stem cells that can differentiate into any of the blood and immune cells (including red blood cells, and various types of white blood cells). HSCs are located in the bone marrow, and they are the functional unit enabling bone-marrow transplant. Since HSCs have the potential to develop into healthy blood cells, they have been used in the treatment of leukemia.
LEUKEMIA: A STEM CELL APPROACH
Leukemia is the first diseases to be treated with stem cells, by performing bone marrow transplants. Leukemia is a cancer of the blood and of the bone marrow; the white blood cells of a patient suffering from leukemia are accumulating abnormally. Since the hematopoietic and immune systems’ role in the organism is to protect the body against infection and disease, the symptoms of the disease are bleeding problems, feeling tired, fever, and an increase risk of infections. The excess of white blood cells in leukemia patients perturbs the blood system, and supress normal red blood cells that are needed to supply oxygen, and platelets that prevents bleeding. Leukemia can also come to a lethal conclusion in those patients who contract illnesses such as pneumonia, as one is unable to fight the infection. Being a form of cancer, leukemia is caused by a series of mutations. These mutations may also be genetically inherited, which makes predisposition to leukemia an inherited factor. Alternatively, exposure to radiation, certain types of chemotherapy, and accumulation of acquired mutations are all possible causes of leukemia. Many types of leukemia originate in the HSCs, before they have had a chance to differentiate into a specific type of blood cell. Treatment with stem cells involves first treating leukemia with chemotherapy, which often is successful in killing leukemic cells, but it also severely damages the normal HSCs in the blood marrow. These can then be replaced by HSC transplantation from a healthy donor, whose immune system type must match the patient’s. The procedure is risky because it can have a range of unwanted side effects: infections and graft-versus-host disease (occurring when the donor’s blood cells attack the patient’s tissue). There is a great deal of work in the field of stem cell research aiming to “reprogram” cells so as to make them compatible with the host’s immune system, which would possibly eliminate the risk of rejection.
ADULT STEM CELL REPROGRAMMING
Dr. Gazit is using a multi-pronged approach to studying HSCs. Thanks to the ImmGen consortium Dr. Gazit gained unprecedented data of gene expression across the hematopoietic- and immune-system. This allowed identification of HSC-specific genes and prediction of key regulators, some of which are being validated and explored. During his postdoctoral studies at Derrick Rossi Lab, Dr. Gazit took part in the identification of HSC’s transcription factors and established an experimental system for functional demonstration of reprogramming in-vivo. This allowed to define six core factors and two facilitators that can turn blood cells into “induced-HSCs,” which transplant and reconstitute all types of blood and immune cells. This discovery pave the way for making the stem cells that are needed for bone-marrow transplant out of own blood cells, which is being extensively researched. Dr. Gazit has additionally developed a new model which express a fluorescent reporter gene in HSCs specifically, allowing direct identification of these cells. This model further allow to follow and study HSCs upon stimulation- when other markers are losing specificity this novel model seems to provide a stable reliable track of the cells. Finally, continuing the reprogramming study, Dr. Gazit found robust ability to generate leukemia-models using defined oncogenicdrivers in immune-competent mouse. These novel models allow examination of new treatments in-vivo against various leukemia types. At the same time they may shed new light on basic biology of cancer, and on the presumable identity of “Leukemia-Initiating- Cells”. Dr. Gazit is also interested in the immunology aspect of HSCs. The hematopoietic cells are the source of virtually all the body’s immune cells as well as the blood cells, and there is mutual dependence between the two, Gazit explains. “Somehow there’s feedback between the stem cells and immune cells–it makes sense that the body has a regulator mechanism to tell the stem cell that more immune cells are needed, or that there are too many. One great interest is to uncover the activity and relationship of the stem cells with the whole immune system, which will affect the treatment of any infection. That’s a long term dream—we are having amazing discoveries already, and hope to keep busy with this broad field for many years.
“We dream of reprogramming hematopoietic stem cells (HSCs) to make them stronger and more capable of transplant, and maybe even generating them from a patient’s own cells,” Dr. Gazit says. “If you can reprogram blood cells back to the HSC state, you have an unlimited resource for adult stem cells ready for clinical utilisation. That’s a big dream–and we have reason to believe we can do it!” Dr. Gazit wishes to understand the basic biology behind adult stem cells. Understanding the differences between adult stem cells and other adult cells at a molecular level may then aid the researcher to turn adult blood cells into HSCs, which can then be used for transplants. Since the stem cells thus reprogrammed come from the patient who will receive the transplant, there is presumably no risk for rejection. Somatic cell reprogramming back into the stem state is not new. Somatic cells have been reprogrammed before into a pluripotent state by defined transcription factors (TFs), and Dr. Gazit believes that the expression of a minimal set of factors can induce blood cells back into their proximal adult stem cell state of HSC. “My goal is to understand how specific genes regulate adult stem-cells, and use this understanding to help patients as soon as possible” says Dr. Roi Gazit. “We have succeeded already in turning blood-cells directly into such stem-cells that may cure multiple diseases, including leukemia, lymphoma, anaemia and more. Our results from animal studies require translation into humans and expand our basic understanding of both normal and malignant stem-cells”.
The Shraga Segal Department of Microbiology
Immunology and Genetics
Faculty of Health Sciences, Ben-Gurion
University of the Negev
Dr. Roi Gazit is a Senior Lecturer (Assistant Professor) at the University of the Negev, Be’er-Sheva, Israel. He is an Ilze Katz Career Development Chair in Health Sciences Research and a member of the National Institute for Biotechnology in the Negev (NIBN) and of the Centre for Regenerative Medicine and Stem Cells at the Ben-Gurion University. He has completed a post-doctoral research at the Immune Disease Institute, Harvard Medical School University with Derrick J. Rossi and also collaborated extensively with the ImmGen Consortium. He received his B.Sc. and M.Sc. in Life Science from the Hebrew University of Jerusalem, and did PhD studies at the laboratory of Ofer Mandelboim, Hebrew University Haddasah Ein-Kerem.
T: +972 8 647 7268
W: http://in.bgu.ac.il/en/nibn/Pages/staff/ Dr_Roi_Gazit.aspx
EU FP7 (CiG)