BIU

The human brain is constantly and automatically forming predictions (e.g., how a ball will bounce off soccer turf or what another person will say). In cognitive neuroimaging studies of Dr. Jääskeläinen (Experienced Researcher) and colleagues at Aalto University, Finland, it has become one of the most central research questions how the brain predicts complex dynamic events unfolding in naturalistic stimuli such as movies. Here, our main objective is that Dr. Jääskeläinen will acquire the specific expertise to address this question by working for one year in Gonda Multidisciplinary Brain Research Center of Bar-Ilan University, Tel Aviv, Israel, where there is unique empirical-theoretical expertise on predictive brain mechanisms. Work by the Director of Gonda Center, Prof. Moshe Bar (Supervisor), suggests that rapid derivation of analogies (“what does this object resemble”) from sensory inputs and associative linking of these to memory representations supports predictions (e.g., seeing a kettle predicts cooking rather than swimming activity). We hypothesize that distributed patterns of brain activity, generated by the associative process, underlie the memory representations that support predictions. To test this, experimental paradigms developed by Prof. Bar et al. will be combined with data analysis methods used by Dr. Jääskeläinen et al. In addition to ambitious science, the proposed fellowship has the following objectives: 1) significant deepening and diversification of Dr. Jääskeläinen’s cognitive neuroscience expertise at Gonda Center, 2) transfer of data analysis and cognitive neuroscience expertise of Dr. Jääskeläinen to Gonda Center, 3) networking of scientists between Bar-Ilan and Aalto for further collaboration, 4) opening up of a new important research area, and 5) catalyzing of Dr. Jääskeläinen’s scientific career. The fellowship also contributes to knowledge-based economy and society by building foundation for artificial intelligence and clinical research.

The severe combined immunodeficiencies (SCIDs) are a set of life threatening genetic diseases in which patients are born with mutations in single genes and are unable to develop functional immune systems. While allogeneic bone marrow transplantation can be curative for these diseases, there remain significant limitations to this approach. Gene therapy using viral vectors containing a corrective transgene is being developed for some of these disorders, most successfully for ADA-SCID. However, for other SCID disorders, such as those caused by genetic mutations in RAG1 and RAG2, the transgene needs to be expressed in a precise, developmental and lineage specific manner to achieve functional gene correction and to avoid the risks of cellular transformation. In contrast to using viral vectors to deliver transgenes in an uncontrolled fashion, we are working towards using genome editing by homologous recombination (HR) to correct the disease causing mutation by precisely modifying the genome. We have shown that by using clustered, regularly interspaced, short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system we can stimulate genome editing by HR at frequencies that should be therapeutically beneficial (>10%) in hematopoietic stem and progenitor cells (HSPCs). The overall focus of the proposal is to translate our basic science studies to use in RAG-SCID patient-derived HSPCs in methodical, careful and pre-clinically relevant fashion. The fundamental approach is to develop a highly active functional genome editing system using CRISPR-Cas9 for RAG-SCIDs and complete pre-clinical efficacy and safety studies to show the approach has a clear path towards future clinical trials. Our goal with this proposal is to develop the next wave of curative therapies for SCIDs and other hematopoietic disorders using genome editing.