Blanchard Laboratory

Genetic and Environmental Vulnerability to Neurodegeneration

Research

The human brain of many individuals is genetically susceptible to neurodegenerative diseases like Alzheimer’s disease (AD) or poor recovery from traumatic injury and chemotherapy. However, pinpointing the genetic elements that promote this pathogenesis, establishing their underlying cellular and molecular mechanisms, and developing therapeutic strategies remain major challenges. These challenges are reflected in the growing patient population and complete absence of therapeutics for Alzheimer’s disease and related dementias. We need new approaches to understand the uniquely human biology that is fundamental to neurodegeneration and innovative technology that enables the development of effective therapeutic and preventative strategies. To fulfill this need, we engineer 3D models of human brain tissue from stem cells and apply these models to understand and therapeutically target risk factors for Alzheimer’s disease and other forms of cognitive impairment.

Our work specifically aims to (1) establish the cellular and molecular pathways underlying neurodegenerative risk factors, (2) target and modulate these pathways as potential therapeutic strategies, and (3) establish pioneering technology and tools that unravel complex genetic, cellular, and environmental interactions in the human brain. Ultimately, our goal is to facilitate a precision medicine approach to understanding and treating neurodegenerative disease.

Joel Blanchard, PhD

Assistant Professor, Neuroscience

joel.blanchard@mssm.edu

Publications

Blanchard J., Bula M., Akay, LA., Zhu L., Frank A., Velderrian JD., Victor, M., Bonner, JM., Mathys, H., Lin YT., Kellis, M., Cam, H., Tsai LH. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nature Medicine (2020)Link

Blanchard J., Tsai, LH., Unraveling the paradox of statins with human neurons: New leads in Alzheimer’s disease. Cell Stem Cell (2019). Link

Tsunemoto R.*, Lee S.*, Szűcs A., Chubukov P., Sokolova I., Blanchard J., Eade K., Bruggemann J., Su A., Sanna P., Baldwin K., Binary reprogramming codes for neuronal identity and diversity. Nature (2018). Link

Blanchard J., Xie, J., El-Mecharrafie, N., Lerner, RA., Baldwin K., Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries.  Nature Biotechnology (2017). Link

Blanchard J*., Eade K*., Szucs A., Lo Sardo V., Tsunemoto R., Williams D., Sanna P., Baldwin K. Selective conversion of fibroblasts into peripheral sensory neurons. Nature Neuroscience (2015) Link

Tsunemoto R., Eade, K., Blanchard J., Baldwin K. Forward engineering neuronal diversity using direct reprogramming. EMBO J (2015). Link

Wang Y., Davidow L., Arvanites A., Blanchard J., Lam K., Woo J., Coy S., Rubin L.L., McMahon A. Selective Identification of Hedgehog pathway antagonists by direct analysis of Smoothened Ciliary Translocation. ACS Chemical Biology (2012). Link

Wang Y., Davidow L., Arvanites A., Blanchard J., Lam K., Woo J., Ng J., Curran T., Rubin L.L., McMahon, A. Glucocorticoids Compounds Modify Smoothened Localization and Hedgehog Pathway Activity. Chemistry and Biology. (2012). Link

Ichida J. K*., Blanchard J*., Lam K*., Son E. Y*., Chung J. E., Egli D., Loh K. M., Carter A. C., Di Giorgio F. P., Koszka K., Huangfu D., Akutsu H., Liu DR., Rubin LL., Eggan  A Small-Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog. Cell Stem Cell (2009). Link

*These authors contributed equally to this work

Patents

2018 – Blanchard J., Tsai, LH. In vitro Human Blood Brain Barrier, US Application No. 62/795,520

2014 – Blanchard J., Eade K., Baldwin K., Methods and Compositions Related to Induced Sensory Neurons. PCT/US20160333311A1

2011 – Blanchard J., Lam K., Rubin L. Stable Reprogrammed Cells. PCT/US2011/036986

2009 Ichida, J., Blanchard J., Eggan K., Lam K., Rubin L.L. Efficient Induction of Pluripotent Stem Cells Using Small Molecule Compounds. PCT/US2009/057669

Projects

Areas of Investigation

Blood-Brain Barrier (BBB)

The BBB feeds the brain with nutrients and oxygen while also protecting it from peripheral pathogens and insults. It is increasingly recognized the BBB also has a prominent role in neurodegenerative disease. Numerous genes associated with risk for neurodegeneratoion are expressed in the cells that constitute the BBB where they likely directly influence disease susceptibility and pathogenesis. For example, APOE is highly expressed In the BBB and the APOE4 variants is known to correlate with increased amyloid deposition on cerebral vasculature. In addition to being a location of amyloid deposition, the BBB also forms a highly selective barrier that prevents more than 98% of all small molecules from entering the brain. By developing an iPSC-based model of the BBB, we aim to understand i) how the BBB contributes to neuorodegeneration susceptibility and pathogenesis and ii) develop a physiologically reliable test to asses drug-brain penetration across diverse genetic populations.

Myelination

It is emerging that oligodendrocytes (OLs) and myelin degeneration play a central role in neurodegeneration and cognitive aging. In the human brain, the total myelin volume increases until around the fourth or fifth decade of life after which it sharply declines. Therefore, myelin degeneration is thought to be a fundamental mechanism leading to cognitive changes associated with aging. In most neurodegenerative diseases, myelin degeneration is accelerated. For example, the majority of Alzheimer’s disease (AD) patients exhibit deficits in white matter compared to healthy individuals of the same age. Surprisingly, in populations at high risk for developing AD, several imaging studies identified that the loss of white matter begins prior to cognitive decline. Likewise, in rodent AD models, myelin deficits are observed prior to the formation of amyloid plaques and neurofibrillary tau tangles, the classical pathological hallmarks of AD. At the molecular level, many of the genes implicated in the development of sporadic AD could directly influence OL biology and/or myelination. Collectively, this suggests that myelin degeneration may be one of the earliest biomarkers and a key pathological mechanism underlying cognitive decline in AD and aging. Despite these implications the role of OLs and myelin degeneration in AD pathogenesis remain largely unclear. This is likely due to species differences in myelin biology, difficulty in procuring mature OLs, and limited assays for human myelination. Through developing technology to study human myelination in a dish we aim to gain deeper insight into how myelination is altered during neurodegeneration and the effect of genetics and the environment on these processes. 

Neuro-Immune-Vascular Brain

In the human brain, neurons, microglia, and the blood-brain barrier are dynamically interconnected. How these connections are formed during development, maintained in homeostasis, and degenerate with age remain poorly understood. It is also largely unclear how human genetic diversity alters neuro-immune-vascular interactions to influence susceptibility to disease and age-related cognitive impairments. To approach these questions, we have developed an in vitro Neuro-Immune-Vascular tissue. 

Multi-cellular integrated brain tissue (miBRAIN)

Numerous preclinical drugs have effectively cured Alzheimer’s disease in mice and other vertebrate models. However, all of these once-promising candidates have ultimately failed to show efficacy in human clinical trials. There are general concerns about the fidelity of rodent models and most of the genetic variants associated with increased risk for Alzheimer’s disease in humans are not conserved between species. Therefore, intermediate models that exhibits AD pathology in human tissues may better predict clinical outcomes. To address this, we are creating a multicellular integrated Brain tissue (miBRAIN) composed of seven disease-relavent cell-types. Future studies will apply this models to 1) pinpoint cellular and molecular mechanisms that promote risk for age-related cognitive impairment 2) screen and stratify drug response and efficacy across diverse genetic backgrounds 3) investigate how adverse life events such as traumatic brain injury or chemotherapy increase susceptibility to age-related neurodegeneration.

Awards

2019 – ISSCR Merit Award

2019 – ISSCR Travel Award, International Society for Stem Cell Research meeting, Los Angles, CA.

2018 – Postdoctoral Fellowship in Aging Research, Glenn Foundation of Medical Research

2014 – Betty Jean Ogawa Memorial Poster Award, International Society for Stem Cell Research

2014 – ISSCR Travel Award, International Society for Stem Cell Research meeting Vancouver, BC.

2014 – Keystone Scholarship, Keystone symposia on Stem cells and Reprogramming, Olympic Valley, CA.

2011 – Pre-doctoral Fellowship, California Institute of Regenerative Medicine.

2010 – ISSCR Travel Award, International Society for Stem Cell Research meeting San Francisco, CA.

2010 – Biotechnology Master’s Thesis Honorable Mention, Harvard University

2009 – ISSCR Travel Award, International Society for Stem Cell Research meeting, Barcelona Spain.

In the News Archives

In vitro Cerebrovasculature Drawing by Leyla Akay

Study finds path for addressing Alzheimer’s blood-brain barrier impairment Link

Human Blood-Brain Barrier Model Blames Pericytes for CAA Link

                               

Blood-Brain Barrier-in-a-Dish Leads to Alzheimer’s Discovery Link

    Human Brain Models

Modeling Alzheimer’s Disease complexity on a chip Link

Investigating the Neurological Effects of COVID-19 Link

Induced Sensory Neurons

Team Replicates Pain in a Lab Dish Link

Pain and itch neurons grown in a dish Link

A Basket Full of Nociceptors: Reprogramming Yields Pain Neurons from Mouse and Human Fibroblasts Link

Chemical and Antibody Reprogramming

RepSox hits a home run Link

New steps forward in cell reprogramming Link

Antibodies trigger reprogramming Link

Outside-in reprogramming Link

Job opportunities

If you are passionate about scientific research, innovative, and driven we want you to be part of our team. We are currently recruiting post-docs for the fall of 2021. Interested candidates should contact Dr. Blanchard. Please include a CV, 3 potential references, and a brief statement describing your research interests and goals.