Annual Scientific Meeting
Make Plans for Vancouver!
Early Bird Registration until 24 June
40th Annual Scientific Meeting
25-28 August, Westin Bayshore Hotel, Vancouver, Canada
You have until 24 June to register for the Vancouver meeting and obtain the early bird discount. Why not take a moment right now to scan the program and submit your registration?
The program begins Thursday afternoon with opening remarks followed by the Don Metcalf lecture by this year's winner – Hal Broxmeyer, Ph.D. See the profile of Dr. Broxmeyer in this issue. Then, reprogramming and epigenetics topics are covered before the evening Welcome Reception.
On Friday, young investigators begin their day with the ever-popular Meet the Professors Breakfast. That ends in time for the morning's sessions on progenitor cell biology, leukemia, microenvironment and ageing. Following lunch, talks are on transplantation/gene therapy/regenerative medicine before moving to the poster sessions. An evening young investigator event also is planned.
Saturday is day two of the Meet the Professors Breakfast for young investigators, followed by the session on lymphoma. Next up is Iannis Aifantis, this year's McCulloch and Till Award winner. See the profile of Dr. Aifantis in this issue. A triple session on leukemia follows and then developmental biology and genomics are covered.
As would be expected from this international society, speakers represent eight countries.
24 June – Early Bird Registration Deadline
Save up to $175 – register today.
Be sure to also make your hotel reservations at the Westin Bayshore Vancouver at the ISEH rate of CAD $199.
10 June-8 July – Late Breaking Abstract Submission
You have one last opportunity to present your latest work. Read more
25-28 August – Annual Scientific Meeting
Full details on the ISEH website.
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Take a quick tour of the May and June issues and get a feel for the great scientific content. Read the full issues.
In this Issue – May 2011
A compendium of genome-wide hematopoietic transcription factor maps
Hannah et al
Report a new valuable resource called the Hemo-ChIP Compendium, in which they integrated data from 53 ChIP-Seq experiments, covering 13 different haematopoietic cell types and 30 different factors relevant to transcriptional control of mouse haematopoiesis. They generated very comprehensive and user friendly data files which will ensure broad utility in the haematopoiesis research community, as they will allow the average experimental biologist to easily gain access to a genome-wide map of haematopoietic transcription factor binding. They give examples of how this compendium highlights known hematopoietic regulatory elements with multiple transcription factors bound and identified a new regulatory element within the Mastermind-like 3 locus, a transcriptional cofactor that cooperates with Notch genes. The availability of this ChIP-Seq compendium will accelerate the discovery of transcriptional mechanisms operating in the hematopoietic system.
Identification of JAK2 mutations in canine primary polycythemia
Beurlet et al
Large animal models are a valuable addition to murine models for studying the impact of mutations on development of disease and in testing the efficacy of novel therapies. Mutations involving C-KIT and RAS or BCR-ABL rearrangement similar to ones found in human leukemias have been documented in canine leukemias. In this study, Beurlet et al identified that one of five dogs with primary polycytemia (PP) had a three-base change in codons 617 and 618 of JAK2, giving rise to V617F and C618L mutations. These mutations induced cytokine independence of transfected BaF3 cells and probably were directly responsible for constitutive activation of theJAK2 kinase, resulting in polycytemia. As we make molecular diagnostics from human diseases more available for veterinary medicine, many more oncogenes or mutations documented in human malignancies may be identified in dogs as well. Dogs with spontaneous primary polycythemia could provide an excellent large animal model to test novel compounds for targeted therapies.
A novel culture system promoting human T lymphopoiesis
Beaudette-Zlatanova et al
The commitment and maturation of T cells occur in thymus and thus improved culture systems that better mimic the thymic environment could aid in understanding the molecular regulation of T lymphopoiesis. In this study, Beaudette-Zlatanova et al developed a novel thymic stroma model using a human thymic epithelial cell (TEC) line expressing HLA-ABC and HLA-DR, engineered to overexpress Delta-like 1 gene (TEC-Dl1). They showed that these cells support de novo generation of many CD7+ CD1a+ T-lineage committed cells from CB and BM CD34+CD38-CD45RA+ cells. Interestingly, most of these cells were double positive for CD4 and CD8. This co-culture system did not support further maturation of T progenitors (low numbers of CD3+ and CD8 or CD4 single positive cells), presumably due to low levels of the Delta-like 4 gene. Moreover, parental TEC cells with low levels of Dl1 and 4 promoted the generation of B cell progenitors. This novel co-culture system mimicking in vivo thymocyte development will prove to be a useful tool for the generation of T progenitor cells in large numbers and their potential use may hold promise for patients with hematologic malignancies and T-cell immunodeficiencies.
The role of CD26 on megakaryocytes in mice
Kidd et al
CD26 is a membrane-bound extracellular peptidase that plays an important role in CXCL12/CXCR4 signaling, a key regulator of hematopoietic stem and progenitor cell trafficking in and out of the bone marrow. The role of CXCL12 in megakaryopoiesis has previously been documented: CXCL12 rescues platelet production in both TPO and Mpl deficient mice. Moreover, the combination of CXCL12 and TPO results in increased polyploidy in megakaryocytes generated from human progenitor cells compared to TPO alone. In their study, Kidd et al shed light on the role of CD26 in regulating megakaryopoiesis in CD26-/- mice. In the absence of CD26 there is a modest but significant expansion of megakaryocyte progenitors in the bone marrow and these mice show enhanced platelet recovery when they are challenged to become thrombocytopenic. Once studies determine similar effect in human cells, the transient inhibition of CD26 may become an exciting therapeutic target that would help to expedite the generation of many functionally intact megakaryocyte progenitors. This will be highly desirable following hematopoietic stem cell transplantation and post chemotherapy when the use TPO or MGDF are ineffective or insufficient in reducing the number of platelet transfusions in these patients.
A novel interaction for the adaptor protein Lnk: PDGF receptor
Gueller et al
The adaptor protein Lnk plays a critical role in hematopoiesis by negatively regulating signaling in HSC self renewal, megakaryopoiesis, erythropoiesis and B-lymphopoiesis through the interaction of its SH2 domain with the corresponding receptor pathway such as TPO-mpl, Epo/EpoR and SCF–c-Kit. Lnk is also involved in JAK2-mediated signaling in myeloproliferative neoplasms. In their study, Gueller et al identify a new pathway that Lnk negatively regulates, PDGF/PDGFR signaling. They show that the expression of Lnk inhibits proliferation of PDGF-dependent Ba/F3 cells as well as myeloid cells transformed with leukemogenic FIP1L1-PDGFRA and TEL-PDGFRB fusions proteins, seen in Hypereosinophilic Syndrome and Chronic Myelomonocytic Leukemia, respectively. Increased PDGFR activity has been associated with various pathological conditions including atherosclerosis, pulmonary hypertension and several malignancies such as lung and prostate cancer, renal cell carcinoma and glioblastoma. Lnk may be a novel therapeutic target and thus triggering or mimicking Lnk activity in malignant cells may prove to be useful in the treatment of diseases caused by activated kinases in combination with other modalities.
In this Issue – June 2011
A novel role of the histone demethylase Fbxl10 in the epigenetic regulation of hematopoietic stem cells
Konuma et al
Understanding the epigenetic regulation of normal and leukemic stem cells has attracted significant interest in stem cell research, but so far very little is known about the role of histone demethylases in this process. Fbxl10 (F-box and leucine-rich repeat protein 10, also known as Jhdm1b or Kdm2b) is a histone H3 lysine 36 dimethyl-specific demethylase expressed in various human leukemias, and plays a role in regulating cell proliferation and senescence. In this study, Konuma et al explored the role of histone demethylases in HSCs by microarray analysis and identified that only Fbxl10 is preferentially expressed in stem/progenitor cells. They showed that forced expression of Fbxl10 in murine HSCs expanded multipotent progenitors and maintained the long-term repopulating potential of HSCs during serial transplantation, similar to what was observed with Bmi1 overexpression. Further analysis showed that Fbxl10 regulated transcriptional repression of the Ink4 family genes through demethylation at H3K36 demethylase. While no leukemias were reported in these mice, a recent study published in April 7 2011 issue of Blood by He et al, showed that forced expression of Fbxl10 is sufficient to transform mouse hematopoietic cells and for development of acute myeloid leukemia in mice. The different results between these two studies may arise from differences in the transgene dose and the number of transduced cells each mouse had received.
Hematopoietic stem cell expansion
Walenda et al
Cord blood (CB) is an attractive source of hematopoietic stem cells (HSCs) due to its availability in many cord blood banks, and low rates of graft versus host disease (GVHD) seen following transplantation. Use of CB, however, has been limited to pediatric patients due the low number of HSCs per CB unit. Identification of conditions or molecules that expand HSCs ex vivo remains an important goal in the field, as this will offer a life-saving option for many patients with leukemia who do not have a suitable donor. Most recently, the small molecule aryl hydrocarbon receptor antagonist, SR1, was found to promote a 17-fold expansion of NOD-SCID-repopulating cells (SRC) at the end of three weeks in culture. The supportive role of mesenchymal stem cells (MSCs) for HSCs has been well documented and its use is already subject to a clinical trial in which patients receive two CB units, one expanded on MSCs and one unmanipulated unit. In this study, Walenda et al show a supportive role of MSCs in combination with cytokines: SCF, TPO, FGF-1, ANGPTL5 and IGFBP2. At the end of one week in culture, CB cells cultured on MSCs showed up to a 30-fold increase in the number of CD34+ cells and maintenance of SRCs. Despite the absence of net HSC expansion, this optimized combination of growth factors and MSCs may be useful during the genetic manipulations of HSCs over several days in vitro. It will also be interesting to incorporate MSCs in expansion cultures using SR1, and determine whether MSCs may help reduce the three-week culture time.
LYL-1 deficiency induces stress erythropoiesis
Capron et al
LYL-1, like SCL/TAL-1, is a bHLH motif containing transcription factor implicated in T-cell ALL. Previous studies showed that SCL is essential for embryonic and important, yet dispensable, for adult erythropoiesis, while LYL-1 is important for B cell development. Functional redundancy between these two genes in HSC function has been shown using conditional double knock out mice, suggesting that a similar redundancy may play a role in adult erythropoiesis. In this study, Capron et al show that LYL-1 has a definite role in erythropoiesis; it is indispensable for BM erythroid maturation and negatively regulates splenic erythropoiesis. LYL-1 KO mice had normal red blood cell indices, mild reticulocytosis and elevated erythropoietin levels, suggestive of stimulated erythropoiesis. LYL-1-/- HSCs revealed decreased erythroid differentiation in competitive repopulation assays. The number of erythroid progenitors was normal in the BM with impaired maturation, but were significantly increased in the spleen, and only the spleen erythroblasts were sensitive to phenylhyrazine induced hemolytic anemia. Identification of the common and distinct functions of these key bHLH proteins provides valuable insights into their roles in embryonic and adult hematopoiesis and may further help understand their roles in leukemogenesis.
Progress towards gene therapy for chronic granulomatous disease (CGD)
Chatziandreou et al
CGD is a rare primary immunodeficiency caused by a defect in the nicotinamide dinucleotide phosphate (NADPH) oxidase complex, resulting in phagocytes with impaired antimicrobial activity. Patients with this disease suffer from recurrent life-threatening bacterial and fungal infections, and allogeneic hematopoietic stem cell transplantation is their only curative treatment option. Evidence from female carriers of X-CGD indicate that a relatively low percentage of neutrophils (10-25%) expressing wild-type levels of superoxide can decrease susceptibility to infections, and therefore, improve survival. Since 100% correction is not required, stem-cell based gene therapy seems an attractive therapeutic alternative for patients who do not have a suitable donor; however, the clinical outcome for 12 patients who received gammaretrovirus modified cells following nonmyeloablative conditioning has been quite disappointing. None of these patients had any long term benefits, and three of them developed MDS with an activating retroviral insertion, making it obvious that minimally toxic yet myeloablative conditioning regimens need to be combined with safer vectors for gene therapy to be beneficial. Foamy virus (FV) vectors based on the nonpathogenic FV, efficiently transduce large animal and NOD/SCID repopulating human hematopoietic stem cells, and may be a safer alternative to gammavirus vectors due to their integration preferences for nontranscribed genes. In this study, Chatziandreou et al explored the feasibility of using safety-enhanced FV vectors for transfer of the gp91-phox gene, and showed restoration of NADPH oxidase activity in vitro in the X-CGD PLB-985 cell line, and in vivo in the peripheral blood of X-CGD mice, at sufficient levels resulting in phenotypic correction. Additional studies incorporating FV vectors with myeloablative yet non-toxic conditioning regimens are urgently needed in mice and large animal models to further validate the use of FV vectors in clinical gene therapy trials for CGD and other genetic disorders.
The publishing team seeks manuscripts describing research involving in vivo and ex vivo studies in the following areas: cell cycle regulation, cytokines, erythropoiesis, gene therapy, general hematopoiesis, granulopoiesis, hematological malignancies, immunobiology, immunotherapy, lymphopoiesis, megakaryocytopoiesis, microenvironment, monocyte development, molecular genetics, signal transduction, stem cell biology, and experimental as well as clinical stem cell transplantation.
Visit the Experimental Hematology website for more information.
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Special Sessions Attract Young Investigators to Vancouver
Young investigators have many ways to maximize the value received from attending the Annual Scientific Meeting in Vancouver. For many, the now-annual Meet the Professors Breakfast is one of the best.
The Meet the Professors breakfasts take place over two days from 7:30-8:30 am. In a casual, small group setting, young investigators can gain insight into research areas and career development from these more senior scientists.
The following professors are scheduled:
Friday, 26 August
Mick Bhatia, McMaster Stem Cell and Cancer Research Institute, Canada
Iannis Aifantis, New York University School of Medicine, USA
Hal Broxmeyer, Indiana University School of Medicine, USA
Takashi Nagasawa, Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Japan
Amy Wagers, Harvard Stem Cell Institute, USA Chris Baum, Hannover Medical School, Germany
Thomas Graf, Center for Genomic Regulation, CRG Barcelona, Spain
Saturday, 27 August
Connie Eaves, BC Cancer Agency, Canada
Andreas Trumpp, German Cancer Research Center in the Helmholtz Association, Germany
Guy Sauvageau, Université de Montréal, Canada
Peggy Goodell, Baylor College of Medicine Center, USA
Susie Nilsson, Australian Stem Cell Centre, Australia
Toshio Suda, Keio University School of Medicine, Japan
There are two additional events just for young investigators – a panel of experts discussing career paths outside academia and an evening social event away from the Westin Bayshore (supported by STEMCELL Technologies Inc.). View the Schedule of Events.
And, of course, young investigators can attend all scientific sessions. The ISEH Annual Scientific Meeting is a unique and essential international gathering at which promising young investigators from around the world come together to meet with, learn from, and present their findings to prominent figures and leading researchers in the field.
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ISEH Leadership: Elections Open 28 June
The Nominating Committee is reviewing nominations for vice president and director for the 2011-2012 ISEH Board of Directors. Watch for an email announcing the open of the online balloting process later this month.
"During our call for nominations process, we asked members to put forth candidates with the skills and interest to manage and guide the Society,” states Elaine Dzierzak, chair, ISEH Nominating Committee.
Candidate information will be posted at iseh.org so that members can educate themselves about the candidates and vote accordingly during the election period, 28 June through 19 July. Results will be posted to the website and elected members will take office at the 40th Annual Scientific Meeting in Vancouver, 25-28 August.
Fellowship Applications Under Review
Applications for the ISEH Eugene Goldwasser Fellowship, supported by Amgen for an outstanding young investigator in the field of hematology, are in. They are currently being reviewed by the ISEH Awards Committee and ISEH Executive Committee.
This $50,000 fellowship will be announced at the 40th Annual Scientific Meeting in Vancouver, 25-28 August 2011.
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News from the Field
ISEH Presence at Workshop
By Keith Humphries
European Society of Hematology
Workshop on Leukemic and Cancer Stem Cells
29 April – 1 May, 2011
The concept of cancer stem cells continues to be a hot topic as illustrated by the well-attended European Society of Hematology Workshop on Leukemic and Cancer Stem Cells in the south of France with over 200 participants from Europe and North America. Experimental support for and insights into cancer stem cells was sparked by initial studies of hematologic malignancies and this was reflected by the strong presence of many members of ISEH both as presenters and active members of the audience.
Major topics covered in plenary sessions included the "signatures” of cancer/leukemic stem cells, in vivo imaging and monitoring of cancer stem cells, quantitation and heterogeneity of leukemic and solid tumor stem cells and targeting of cancer stem cells. One full afternoon was devoted to simultaneous workshops at which the major themes of the meeting (quantitation/assays, cell purification and banking, animal models) were discussed at the practical level.
We can expect that many of these topics will be revisited at the ISEH 40th Annual Scientific Meeting in August and through reviews and articles in our journal. Cancer stem cells as an important topic for basic and clinical investigation is here to stay. Now we just have to find a way to make them disappear from patients.
View the European workshop scientific program.
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ISEH, comprised of industry leaders in hematology, immunology, stem cell research, and cell and gene therapy, connects members worldwide for the opportunity to advance scientific knowledge. Each issue of Connections in Hematology & Stem Cells will introduce you to a few of those members. This issue, meet Hal E. Broxmeyer and Iannis Aifantis.
Hal E. Broxmeyer, Ph.D.
Chair, Professor and Scientific Director
Indiana University School of Medicine
Indianapolis, IN, USA
2011 Donald Metcalf Award winner
Established in 1999 in honor of Professor Donald Metcalf, "the father of hematopoietic cytokines," for his pioneering work on the control of blood cell formation, this award recognizes distinguished scientists in the field.
"I met Don Metcalf when I was at Memorial Sloan Kettering Cancer Center, and I have the greatest respect for him,” Dr. Broxmeyer states. "I was counting my colonies under a microscope and he came up to me and asked, ‘what are you looking at?' He added "those are really nice.' I truly admire him for all the work he did to start the field while still doing bench work throughout his career.”
Dr. Broxmeyer is internationally recognized for pioneering studies on hematopoietic stem cell biology that lead to clinical utility. His publications have been cited more than 27,000 times; 85 of these have been cited at least 85 times (H-factor of 85; 1974-present), with 67 of these cited from 100-1,006 times (as of May 23, 2011).
He discovered that cord blood contained transplantable stem cells (PNAS 1989, NEJM 1989). His laboratory studies on cord blood stem/progenitor quality and numbers, methods for their efficient cryopreservation, and development of the first cord blood bank as proof of principle (PNAS 1989, 1992, 2002) were determining factors in the first five transplants which provided long-term engraftment and led to greater than 25,000 cord blood transplants done to date to treat malignant and non-malignant diseases.
Dr. Broxmeyer demonstrated that antagonizing CXCL12/CXCR4 with AMD3100 rapidly mobilizes stem cells to blood, and enhanced G-CSF induced mobilization (JEM 2005), a clinical protocol now used worldwide. He discovered that inhibiting CD26 peptidase enhances stem cell homing/engraftment (Science 2004) needed when limiting numbers of stem cells are available, studies now being evaluated in the clinic. He established the concept of direct and indirect negative feedback regulation of hematopoiesis by iron-binding proteins, chemokines (JEM 1978, 1981; Blood 1990) and other cytokines, and the in vivo efficacy of growth factors working in synergistic combination (PNAS 1987). Dr. Broxmeyer continues to work to gain mechanistic insight into stem cell function, and with others, and as part of the National Marrow Donor Program (NMDP), and other advisory groups, to enhance the efficacy of cord blood and mobilized adult peripheral blood transplantation.
Microbiology was his initial field of study.
"When I was looking into where to go for my Ph.D., I met a woman that I've now been married to for 42 years,” Broxmeyer recounts. "Beth told me about this new field of experimental hematology. I followed her to New York University and began working in the laboratory doing hematological research.”
Toward the end of his Ph.D. work exploring the means to regulate the release of leukocytes from bone marrow, he got into his current emphasis on stem/progenitor cell biology. A post-doc position at Kingston General Hospital at Queens University in Kingston, Ontario, Canada, was followed by eight years at Memorial Sloan-Kettering Cancer Center before landing at the Indiana University School of Medicine in Indianapolis, Ind. He is working on how embryonic and induced pluripotent stem cells can be used to better understand hematopoietic stem cell biology.
"I love research; it excites me,” he follows. "I love to be the first one to learn what's going on so I still score some experiments.”
Dr. Broxmeyer is a long-time supporter of ISEH, having attended his first meeting in 1976 and served as president in 1991. He especially likes that the Society is not too big, allowing members to interact easily with one another and form lifelong relationships.
Outside of science, Dr. Broxmeyer has numerous interests including weightlifting, taking long walks with his wife, reading and watching movies when he just needs to relax. From 1994 to 1999, he took one of the top three spots in his age and weight division for Olympic style weightlifting at the U.S. National Master's Weight-Lifting Championships.
"When I was younger, I could clean and jerk 265 pounds, clean and press 245 pounds and snatch 205 pounds in New York City and state competitions at a body weight of about 170 pounds,” he states. "I wish I could still lift these poundages!”
Take a peek at a May 2010 video with Dr. Broxmeyer talking about cord blood banking and transplantation.
ISEH members: Connect with Hal through the ISEH member database. Click here to learn more about him or to build your personal profile.
Iannis Aifantis, Ph.D.
Associate Professor of Pathology
New York University School of Medicine
Early Career Scientist
Howard Hughes Medical Institute
New York, NY, USA
2011 McCulloch and Till Award winner
Established in 2004 in honor of Professor Ernest McCulloch and Professor James Till, this award recognizes junior scientists in the field of hematology and stem cells.
Dr. Aifantis has been on a fast moving train….studying biology, molecular biology and genetics in his home country's University of Crete, Dr. Aifantis then went to the University of Paris for his Ph.D. in immunology. Following his Ph.D., he took his post-doc at Harvard University's Dana Farber Cancer Institute and then had his own lab in the Department of Medicine at the University of Chicago.
He is currently an associate professor of pathology at the New York University (NYU) School of Medicine, co-director of the Cancer Stem Cell Program of the NYU Cancer Institute and an early career scientist at the Howard Hughes Medical Institute.
Dr. Aifantis' laboratory focuses on mechanisms of differentiation and transformation of hematopoietic stem cells and progenitors. More specifically they focus on the molecular mechanisms of both lymphoid (ALL) and myeloid (AML, CMML) leukemia induction and maintenance. Their work has identified and studied novel oncogenes, tumor suppressors and downstream signaling pathways. They have also used these pathways to design molecularly targeted therapeutic protocols that could inhibit the induction or affect the maintenance of the disease. Moreover, the laboratory is studying mechanisms of hematopoietic stem cell differentiation and self-renewal using both genomic and genetic approaches.
"The biggest challenge for a researcher is that you end up realizing that to do science correctly, you will have to try to cover multiple fields and disciplines and that requires extensive collaborative effort,” Dr. Aifantis states.
Dr. Aifantis talked about changes he has seen even in his relatively short career.
"When I started 10 to 12 years ago, you could try to address questions by yourself or within your own laboratory,” he remembers. "That is almost impossible today. Today you must go outside of your lab, outside of your institution and outside of your city to find people who are willing to work together and cover all the different aspects of a project.”
ISEH has been a source of inspiration and collaboration.
"I am inspired by and follow a number of Society members who have done amazing work,” he adds. "And, I'm currently collaborating with some members. I will attend my first ISEH member in Vancouver and look forward to meeting many more colleagues.”
In his Vancouver presentation, Dr. Aifantis will likely cover his most recent findings on transformation of hematopoietic stem cells by epigenetic mechanisms. He'll also address enzymes that affect DNA methylation in myeloid leukemias.
His most recent publication in Nature discusses the origins of a type of myeloid leukemia and states that novel mutations in an intracellular communication pathway called Notch led to the cancer, pointing to a potential new target for treating this disease. Notch was already implicated in T-cell acute lymphoblastic leukemia, but the new research found an unexpected role for it in chronic myelomonocytic leukemia (CMML). Read more in the May 12, 2011 issue of Nature.
Outside of science, Dr. Aifantis points to dining and music as favorite activities.
"I truly enjoy dining, and that is why big cities like New York appeal to me,” he says. "I am always looking for different tastes as well as excellence in food preparation techniques. Music is important to me too. I used to be a DJ when I was younger, and I still follow new trends in music.”
Dr. Aifantis also includes traveling on his list of activities, especially to his home country Greece where his family still resides.
"In our field, our jobs take us to very interesting places,” he recounts.
ISEH members: Connect with Iannis through the ISEH member database. Click here to learn more about him or to build your personal profile.
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