Blog

Department of Molecular Genetics

Dr. Jacob (Yaqub) Hanna, MD PhD

Department of Molecular Genetics

Born in Rama, a village in the Galilee region of Israel, Dr. Jacob (Yaqub) Hanna earned his BSc in medical science (2001), MSc in microbiology and immunology (2003), PhD in microbiology and immunology (2007) and MD in
clinical medicine summa cum laude (2007) from the Hebrew University of Jerusalem. He conducted postdoctoral research at the Whitehead Institute for Biomedical Research. He joined the Weizmann Institute in 2011.

Dr. Hanna is pioneering techniques in induced pluripotency and reprogramming of adult cells. Induced pluripotent stem (iPS) cells have regenerative properties almost identical to those of embryonic stem cells, but can be created from adult cells without using an egg or fetal material. Dr. Hanna was the lead researcher in a study that showed how further-modified iPS cells could be used to treat sickle-cell anemia in mice, the first proof of concept of the therapeutic application of iPS cells. Dr. Hanna has uncovered novel pathways regulating the reprogramming process, and was the first to show ability to boost it up to 100% efficiency. He was also the first to derive pristine “naïve” human pluripotent cells equivalent to those derived from mice, and can generate “humanized” mouse models that have human derived tissues. In addition to demonstrating the power of cell reprogramming, his work offers the promise of powerful new research models for infertility, degenerative diseases, such as type 1 diabetes and cancer.

During his postdoctoral work, Dr. Hanna was the first non-American graduate to receive a prestigious Novartis Fellowship from the Helen Hay Whitney Foundation, a Genzyme-Whitehead Fellowship, and was one of 35 people under the age of 35 recognized as Young Innovators of 2010 by MIT’s Technology Review magazine. In 2010, he was awarded the Sir Charles Clore Prize by the Weizmann Institute. As an Independent Investigator, he received a European Research Council Early Career Development Award (2011), Rappaport Prize in biomedical research (2013), Krill Prize by the Wolf Foundation for outstanding research achievements (2013), and the Kimmel prize research award (2013). In 2014 he was elected as a member of the Israel Young Academy and was featured among “40 under 40” innovative scientists by the prestigious journal Cell.

Natural Killer cells & Reproductive Immunology

MD-PhD student: 10/1998 – 03/2007

PhD advisor: Prof. Ofer Mandelboim – PhD

Chairman, The Lautenberg Center for General and Tumor Immunology

The Hebrew University of Jerusalem – Hadassah Medical School, Jerusalem, Israel

Field of Study: Natural Killer cells & Reproductive Immunology

            Summary of background and training:

I was born in a Palestinian Arab village in the northern part of Israel, and went on to study medicine at the Hebrew University, where I completed my undergraduate and graduate studies in biomedical and clinical studies (Summa Cum Laude). As I was always fascinated by the scientific findings that lead to the understanding of pathogenesis of human diseases, I simultaneously commenced work in Prof. Ofer Mandelboim’s lab as an M.D. Ph.D. student, studying the biology of natural killer (NK) cells. My research focused on understating the mechanisms underlying additional and alternative functions of human NK cells in the uterine mucosa during pregnancy and inflammatory tissues. By using combined genomic and proteomic approaches on unique human subsets of NK cells, I was able to establish previously unidentified roles for NK cells that go far beyond killing autologous infected or tumor cells. I identified their role as costimulatory and antigen presenting cells for activated T cells during inflammation (Hanna et al. J. Immunology 2004). I also defined mechanisms underlying their recruitment via chemokines to the maternal uterine mucosa (decidua), where they act as key players in promoting angiogenesis and tissue remodeling during pregnancy (Hanna et al. Blood 2003, Nature Medicine 2006). The latter work was voted in a special issue of Nature Medicine on reproductive biology, as the most influential paper in the field in the last 10 years.

In 2007, I decided to dedicate my career entirely for research, and joined the lab of Rudolf Jaenisch as a postdoctoral researcher.

Statement Regarding Publication 3

  1. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, Mansour AA, Caspi I, Krupalnik V, Zerbib M, Maza I, Mor N, Baran D, Weinberger L, Jaitin DA, Shipony Z, Mukamel Z, Tanay A, Amit I, Novershtern N & Hanna JH.

Deterministic direct reprogramming of somatic cells to pluripotency.

Nature (2013) 502(7469):65-70. (322 citations)

http://www.nature.com/nature/journal/v502/n7469/full/nature12587.html

{Selected for Faculty of 1000 Biology} {Featured on: Nature news, Science news, LA Times, BBC news, Reuters, Haaretz}

  • Preview: Loh KM & Lim B. Close encounter with full potential. Nature 502(7496):41-42 (2013).
  • Preview: De Souza N. Roadblocks to reprogramming, cleared. Nature Methods 10(11):1051 (2013).
  • Preview: Brumbaugh J & Hochedlinger K. Removing reprogramming roadblocks Mbd3 depletion allows deterministic iPSC generation. Cell Stem Cell 13(4):379-81 (2013).
  • Preview: Eggan K. Picking the lock on Pluripotency. NEJM 399:2150-2151 (2013).

Summary and importance:

In the first manuscript published by my group, we began to dive deep in the molecular regulation and the developmental context of iPSC reprogramming. Our identification of the histone H3K27 demethylating enzyme Utx as an important de-repressor in the re-establishment of pluripotency in vitro and in the germ-line in vivo (Mansour et al. Nature 2012), allowed us to demonstrate the ability to dramatically overcome reprogramming barriers, and achieve up to 100% iPSC synchronized reprogramming efficiency via optimized hypomorphic depletion of the Mbd3/NURD repressor complex (Rais et al. Nature 2013). Remarkably, Wernig group has validated near 100% iPSC reprogramming of Mbd3flox/- cell reprogramming at single cell analysis with Ctyof technology (Lujan et al. Nature 2015). Grummt and Hochedlinger groups have independently identified a similar role for Mbd3/NuRD and Chd4 during reprogramming by using independent genetic lines (Luo et al. Stem Cells 2013, Sheloufi et al. Nature 2015). Finally, we have recently identified Gatad2a, another NuRD specific component whose complete ablation does not compromise somatic cell proliferation and still yields up to 100% iPSC reprogramming (Mor/Rais et al. 2016 Under Revision). The latter findings increase our knowledge on the Mbd3/NuRD complex and mechanisms of iPSC reprogramming.

These findings set the stage for follow-up studies that showed alternative methods to obtain near-deterministic reprogramming platforms. Graf group subsequently showed that activation of C/EBPα, previously highlighted by me as a booster for B cell reprogramming (Hanna et al. Cell 2008), can yield up to 100% iPSC reprogramming from B-lymphocytes (Di Stefano et al. Nature 2014). Hochedlinger and Stadtfeld groups devised small molecule based approaches to also achieve rapid and synchronized reprogramming from selected cell types (Bar-Nur et al. Nature Methods 2014, Vidal et al. Stem Cell Reports 2014).

Importantly, our initial discovery of this non-conventional and non-stochastic mode of reprogramming, not only enhances our knowledge on the molecular pathways regulating iPSC formation, but also offers other novel synchronized platforms for the unbiased high-resolution temporal dissection of epigenetic and biochemical dynamics leading to iPSC formation, which is critical for molecular deciphering of the black box of reprogramming.

Statement Regarding Publication 2

  1. Irie N*, Weinberger L*, Tang W, Viukov S, Kobayashi T, Manor Y, Dietmann S, Hanna JH*# and Surani A#.

(*#Equal contribution and *#Equal co-corresponding senior author)

SOX17 is a Critical Specifier of Human Primordial Germ Cell Fate.

Cell (2015) 160(1-2):253-268. (92 citations)

http://www.cell.com/cell/fulltext/S0092-8674%2814%2901583-9

{Featured on: Nature news, Channel 1 Israel news, LA Times, The Sunday Times, CBS news, MSNBC news, Yahoo news, Haaretz, Jerusalem Post, The Guardian}

  • Preview: Schubert C. The world of reproduction: Human primordial germ cells in a dish. Biology of Reproduction 91:114 (2015)
  • Preview: Deglincerti A & Brivanlu A. The generation of sex cells. Cell Research 25(3): 267-268 (2015).
  • Highlight: Baumann K. Human Primordial germ cells in a dish. Nature Reviews in Molecular and Cell Biology 16:68 (2015).
  • Selected for “Best of Cell 2015” top 10 published manuscripts list by Cell Editors (http://info.cell.com/best-of-cell-2015 ).

Summary and importance:

In vitro captured mouse pluripotent cells reside into two states: naïve (Embryonic stem cell (ESC)-like)) or primed (Epiblast stem cells (EpiSCs)-like) pluripotent states, each retaining molecular features of in vivo pre- and post-implantation epiblasts, respectively. The fact that conventional human ESCs and iPSCs rather resemble murine primed EpiSCs, have underscored a hypothesis (Hanna et al. Cell Stem Cell 2009, PNAS 2010, Cell 2010) of whether unique conditions can be developed to isolate previously unidentified alternative naïve-like pluripotent states from humans. My team was the first to devise naïve conditions, termed NHSM (commercialized by Stem Cell Technologies INC. – RseTTM), which entail complete ablation of MEK/ERK signalling and are compatible with expanding genetically unmodified human ESCs/iPSCs (Gafni et al. Nature 2013). These conditions contain MEKi/GSK3i/LIF (termed 2i/LIF) together with P38i, JNKi, PKCi, ROCKi, FGF2 and TGFβ1/ACTIVIN, and render human PSCs more similar, but not identical, to murine naïve PSCs. Based on molecules identified by our group to boost naïve pluripotency (e.g. PKCi, ROCKi, ACTIVIN), several papers have improved qualitative features of naivety and derived naïve human PSCs with distinct molecular flavors, all of which are of importance to be analyzed (Takashima et al. Cell 2014, Theunissen et al. Cell Stem Cell 2014).

Further, in Irie et al. Cell 2015 we showed that our human naïve PSCs have an enhanced potential to recapitulate a differentiation protocol, that until recently was successful only with mouse naïve PSCs, but not with human primed PSCs. Specifically, primordial germ cell-like cells (PGCLCs) can be induced in vitro from mouse naïve PSCs, after “priming” for two days in FGF2/ACTIVIN, followed by BMP4 stimulation. While reconstituting the PGC lineage with conventional primed human PSCs in vitro by applying the latter protocol has not been conductive, when using human naïve PSCs expanded in NHSM conditions, we were able to reconstitute human PGCLCs in vitro that are indistinguishable from human in vivo derived PGCs. Not stopping there, we uncovered species-specific transcriptional regulators of PGC induction (SOX17) differing between human and mice, and thus provided an important example for utilizing human stem cells for in vitro epistatic dissection of early human development. This authentic PGC differentiation platform is also being used for biochemical dissection of human in vitro reprogramming and toward advancing novel iPSC based infertility modeling and treatments.

Finally, this study underscores the direct influence of context dependent interpretation of signaling inputs during human naïve to primed pluripotency dynamic transitions, on establishing or resolving functional differentiation competence of iPSCs (in this case, specifically toward PGCs). In depth understanding of the molecular events dictating changes in functional competence will be key for framing the challenge of enabling researchers and clinicians to control stem cell behavior at will.

Department of Molecular Genetics, Weizmann Institute of Science, Israel

Dr. Jacob H. Hanna, MD PhD

Department of Molecular Genetics, Weizmann Institute of Science, Israel

 

Dr. Jacob H. HannaDr. Jacob (Yaqub) Hanna earned his PhD in Immunology and MD in clinical medicine summa cum laude (2007) from the Hebrew University of Jerusalem. He conducted postdoctoral research at the Whitehead Institute for Biomedical Research –MIT, and joined the Weizmann Institute of Science in 2011 as an Assistant Professor.

Dr. Hanna is pioneering techniques in induced pluripotency and reprogramming of adult cells. Induced pluripotent stem (iPS) cells have regenerative properties almost identical to those of embryonic stem cells, but can be created from adult cells without using an egg or fetal material. Dr. Hanna was the lead researcher in a study that showed how further-modified iPS cells could be used to treat sickle-cell anemia in mice, the first proof of concept of the therapeutic application of iPS cells. Dr. Hanna has uncovered novel pathways regulating the reprogramming process, and was the first to show ability to boost it up to 100% efficiency. He was also the first to derive pristine “naïve” human pluripotent cells equivalent to those derived from mice, and can generate “humanized” mouse models that have human derived tissues. Dr. Hanna was recognized as Young Innovators of 2010 by MIT’s Technology Review magazine. He was awarded the Sir Charles Clore Prize (2011), Rappaport Prize in biomedical research (2013), Krill Prize by the Wolf Foundation (2013), the Kimmel prize research award (2013). In 2014 he was elected as a member of the Israel Young Academy and was featured among “40 under 40” innovative scientists by Cell journal.

Statement Regarding Publication 1

  1. Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G and Hanna JH.

m6A mRNA Methylation Facilitates Resolution of Naïve Pluripotency 9Toward Differentiation. 

Science (2015) 347(6225):1002-1006. DOI: 10.1126/science.1261417 (60 citations)

http://science.sciencemag.org/content/347/6225/1002

  • Preview: Stunnenberg GH, Vermeulen M & Atlasi Y. A Me6Age for pluripotency. Science 347 (6222):614-615 (2015).
  • Preview: Zhao BS& He C. Fate by RNA methylation: m6A steers stem cell pluripotency. Genome Biology 16:43 (2015).
  • Highlight: Sheppard TL. M6A partial differential. Nature Chemical Biology 11:175 (2015). 

Summary and importance:

Our lab is deeply interested in epigenetic pathways regulating stem cell transitions. While the roles of epigenetic modifications on DNA or proteins (i.e. histones) continue to be extensively studied, the role of RNA modifications is only starting to be unveiled. There are more than 100 types of RNA epigenetic modifications, and m6A is the most abundant one on mRNA. The importance and function of m6A in mammalian development remained unclear until this study.

We identified Mettl3, an m6A writer, as a critical regulator for terminating naïve (inner-cell-mas-like) pluripotency and enabling differentiation, both in vitro and in vivo. Mettl3 knockout ESCs completely lack m6A in mRNAs and are viable. Yet, they fail to terminate the naïve pluripotent state, and subsequently undergo aberrant lineage priming at the post-implantation (primed) stage, leading to embryonic lethality. m6A predominantly restrains naïve pluripotency genes’ transcript stability, rather than translation efficiency. This study provided the first proof for critical importance of RNA epigenetics in mammalian development in vivo, and an indispensable role for m6A in pluripotent cell transitions.

Finally, we showed that distinct murine naïve and primed pluripotent states retain opposing dependence on a variety of epigenetic repressors (Mettl3, Dnmt1, Polycomb). Naïve ESCs tolerate loss of such repressors, while primed pluripotent cells are destabilized in response to the same manipulations. Thus, we identified for the first time multiple mechanisms that functionally regulate mouse naïve and primed pluripotency in an opposing manner. At the conceptual level, this work established the notion of naïve (inner-cell-mass-like) pluripotency as a unique “basal” synthesis with a minimal requirement for epigenetic repression.

We are currently using tolerance of human pluripotent cells to lack of such epigenetic repressors as a functional assay to evaluate and enhance several of the newly devised protocols to derive “mouse-like” naïve human pluripotent cells (Gafni et al. Nature 2013).

FORMAT – A novel medium for revolutionizing stem cell manufacturing technologies

Researcher (PI)

Jacob Hanna (Yaqub Hanna)

Host Institution (HI)

Weizmann Institute Of Science, Israel

Call details

Proof of Concept (PoC) Grant, ERC-2015-PoC

Details

Summary

In my ERC-funded research project (acronymed CELLREPROGRAMMING), we made a revolutionary discovery that can transform the enormous potential of stem cell science into viable and sustainable treatments for degenerative and age-related diseases. In

particular, we were the first group worldwide who successfully managed to generate Extracellular-signal-Regulated Kinases (ERK) signalling independent human naïve PSCs (both ESCs and iPSCs), a completely new category of human stem cells that is characterized by an earlier developmental stage, i.e. they are more “primitive” than typical human PSCs. We managed to do so by employing a panel of different inhibitors and cytokines to produce a novel Naïve Human Stem cell Medium (NHSM) that allows the acquisition of many apparent naïve features that were previously observed only in mice . Importantly, this new pluripotent configuration, not only comes in different molecular flavours, but also has different functional properties. For instance, we were able to successfully reconstitute in vitro the early human cells that give rise to either oocytes or spermatozoa, known as Primordial Germ Cells (PGCs). Driven by our passion to help people leave better and longer, we want to make our novel NHSM promptly available to both researchers and clinicians. As such, the goal of this PoC project, entitled as “a novel medium For Revolutionizing stem cell MAnufacturing Technologies” – FORMAT, is two-pronged. The first goal is to establish the technical feasibility of the novel NHSM and create a commercial-like prototype for enhanced expansion and derivation of human naïve iPSCs. This includes generating Xeno-free NHSM conditions and making NHSM compatible for expanding human iPSCs in bioreactors . The second goal of the PoC project is to establish the commercialization potential of NHSM. In summary, the PoC idea is clearly derived from our ERC-starting project acronymed CELLREPROGRAMMING.

ERC funding: 150,000Euro

Duration Start date: 2017-01-01, End date: 2018-05-31

CellNaivety- Deciphering the Molecular Foundations and Functional Competence of Alternative Human Naïve Pluripotent Stem Cells

Researcher (PI)

Jacob Hanna (Yaqub Hanna)

Host Institution (HI)

Weizmann Institute Of Science, Israel

Call details

Starting Grant (CoG), LS7, ERC-2016-CoG

Details

Summary

An important goal of stem cell therapy is to create “customized” cells that are genetically identical to the patient, which upon transplantation can restore damaged tissues. Such cells can be obtained by in vitro direct reprogramming of somatic cells into embryonic stem (ES)-like cells, termed induced pluripotent stem cells (iPSC). This approach also opens possibilities for modelling human diseases in vitro. However, major hurdles remain that restrain fulfilling conventional human iPSC/ESC potential, as they reside in an advanced primed pluripotent state. Such hurdles include limited differentiation capacity and functional variability. Further, in vitro iPSC based research platforms are simplistic and iPSC based “humanized” chimeric mouse models may be of great benefit.

The recent isolation of distinct and new “mouse-like” naive pluripotent states in humans that correspond to earlier embryonic developmental state(s), constitutes a paradigm shift and may alleviate limitations of conventional primed iPSCs/ESCs. Thus, our proposal aims at dissecting the human naïve pluripotent state(s) and to unveil pathways that facilitate their unique identity and flexible programming.

Specific goals: 1) Transcriptional and Epigenetic Design Principles of Human Naïve Pluripotency 2) Signalling Principles Governing Human Naïve Pluripotency Maintenance and Differentiation 3) Defining Functional Competence of Human Naïve Pluripotent Stem Cells in vitro 4) Novel Human Naïve iPSC based Cross-species Chimeric Mice for Studying Human Differentiation and Disease Modelling in vivo. These aims will be conducted by utilizing engineered human iPSC/ESC models, CRISPR/Cas9 genome-wide screening, advanced microscopy and ex-vivo whole embryo culture methods. Our goals will synergistically lead to the design of strategies that will accelerate the safe medical application of human naive pluripotent stem cells and their use in disease specific modelling and applied stem cell research.

ERC funding: 2,000,000 Euro

Duration Start date: 2017-03-01, End date: 2022-02-28

CELLREPROGRAMMING – Uncovering the Mechanisms of Epigenetic Reprogramming of Pluripotent and Somatic Cell States

Researcher (PI)

Jacob Hanna (Yaqub Hanna)

Host Institution (HI)

Weizmann Institute Of Science, Israel

Call details

Starting Grant (StG), LS3, ERC-2011-StG

Details

Summary

The generation of animals by nuclear transfer demonstrated that the epigenetic state of somatic cells could be reset to an embryonic state, capable of directing the development of a new organism. The nuclear cloning technology is of interest for transplantation medicine, but any application is hampered by the inefficiency and ethical problems. A breakthrough solving these issues has been the in vitro derivation of reprogrammed Induced Pluripotent Stem “iPS” cells by the ectopic expression of defined transcription factors in somatic cells. iPS cells recapitulate all defining features of embryo-derived pluripotent stem cells, including the ability to differentiate into all somatic cell types. Further, recent publications have demonstrated the ability to directly trans-differentiate somatic cell types by ectopic expression of lineage specification factors. Thus, it is becoming increasingly clear that an ultimate goal in the stem cell field is to enable scientists to have the power to safely manipulate somatic cells by “reprogramming” their behavior at will. However, to frame this challenge, we must understand the basic mechanisms underlying the generation of reprogrammed cells in parallel to designing strategies for their medical application and their use in human disease specific research. In this ERC Starting Grant proposal, I describe comprehensive lines of experimentation that I plan to conduct in my new lab scheduled to open in April 2011 at the Weizmann Institute of Science. We will utilize exacting transgenic mammalian models and high throughput sequencing and genomic screening tools for in depth characterization of the molecular “rules” of rewiring the epigenome of somatic and pluripotent cell states. The proposed research endeavors will not only contribute to the development of safer strategies for cell reprogramming, but will also help decipher how diverse gene expression programs lead to cellular specification during normal development.

Website (HI)

ERC funding: 1,960,000 Euro

Duration Start date: 2011-11-01, End date: 2016-10-31