Addressing Widening Health Disparities With Inclusive Stem Cell Models
Our understanding of disease varies dramatically across ethnic groups, contributing to widening health disparities.
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Advances in medicine and healthcare have decreased mortality rates for major diseases. However, racial disparities in mortality are increasing, as evidenced by the disproportionate impact of the COVID-19 pandemic on populations of color. This inequality has highlighted the need to understand how diseases and therapeutics affect different races.
To help researchers find new therapies for ethnic communities underrepresented in disease research, the Allen Institute for Cell Science has partnered with the New York Stem Cell Foundation (NYSCF). The partnership will produce DNA-edited ethnically diverse stem cell lines for disease research, to improve global health equity.
“Haplotypes unique to a few regions of the world are dramatically over-represented among donors who have contributed cells for deriving stem cell models,” Dr. Brock Roberts, scientist III at the Allen Institute for Cell Science, told Technology Networks.
“As stem cell science improves as a field, organ-like tissues derived from stem cells are predicted to be used for many safety studies. But it is not appropriate to test for safety in only one or a few genetic backgrounds.”
Human induced pluripotent stem cells (iPSCs) can be derived directly from adult tissue and reprogrammed to differentiate into various cell types. As human-derived iPSCs possess the donor's genetic information, they provide a more accurate way to evaluate individual responses to treatments.
“Current iPSC repositories/biobanks consist of low diversity iPSC lines, with the vast majority originating from white Europeans,” Dr. Josephine Wesely, principal scientist at NYSCF, told Technology Networks.
“The lack of diversity of cell lines used in research as well as drug discovery leads to an incomplete understanding of diseases and drug-related pathways and ultimately results in a biased approach to drug development.”
Creating more inclusive cellular models
In efforts to create a diverse and accessible stem cell resource, ethnically diverse stem cell lines produced by NYSCF will be gene-edited with structure tags produced by the Allen Institute for Cell Science. They will then convert the tagged stem cells into neurons and astrocytes, two cell types implicated in Alzheimer’s and Parkinson’s disease.
The initial phase of the collaboration will focus on enhancing 24 iPSC lines from diverse ethnic backgrounds, with less than 25% of the cell donors being of European origin. The cohort includes 12 lines from healthy subjects and 12 with Alzheimer’s and Parkinson’s relevant genotypes. These iPSCs were created by reprogramming adult skin or blood samples, using an automated platform developed by the NYSCF.
Gene tags will be introduced into the cell lines, allowing scientists to visualize under live imaging conditions two cell components: the nucleus (by tagging LAMININ B1) and lysosomes (by tagging LAMP1).
The tagging strategy will utilize CRISPR/Cas9 technology whereby “DNA is broken at specific locations in the cells using CRISPR, and DNA with the same sequence as the broken region plus a tag sequence is added to repair the break, in a process called homology driven repair,” explained Roberts.
“These tagging strategies are highly valuable to the scientific community as the cells can be more easily analyzed, imaged, and followed. However, they are laborious to generate and need some specific expertise to ensure high quality,” said Wesely.
By combining the Allen Institute for Cell Science’s structure tags and NYSCF’s stem cell automation technology, the partnership hopes to remove the hurdles of starting from scratch when transitioning to ethnically diverse stem cells.
“While the Allen Institute has put years of work into the generation and characterization of those tags (and therefore ensuring high quality and functionality), NYSCF has developed an automated gene editing pipeline that allows standardized, fully automated and high throughput generation of genetically modified iPSC clones,” Wesely commented.
“The two institutions are bringing this expertise together to provide genetically diverse tagged cell lines to the community.”
Tagged iPSCs allow researchers to look at the cell structure in many disease-relevant cell types, such as neurons and immune cells, at different stages of differentiation, or different time points of drug exposure.
“The tags give us the ability to look non-invasively at living human cells at the subcellular resolution where we believe neurodegenerative diseases start and progress,” Wesely said.
“The tags also give us the ability to study the same living cells over time, which is not possible with most approaches, because they require terminating the experiment to visualize cell structures. Thus, having these structure tags on iPSCs allows scientists to accelerate the amount of data they can generate, the number of questions they can ask and address within one or few experiments.”
By combining artificial intelligence and machine learning with these structure-tagged cells, Wesely hopes it will be possible to identify and understand phenotypes that we have not been able to by traditional microscopy analysis.
Cognitive diseases have no bias, but research often does
Producing diverse cell lines from healthy controls and neurodegenerative disease patients – in particular, patients with Alzheimer’s disease and Parkinson’s disease – will be the initial focus of the collaboration.
“Importantly these diseases have previously been studied in very non-diverse, mostly Western European patients and cell models. However, we know that there is substantial genetic heterogeneity,” explained Wesely. “That means that specific risk variants may either function similarly in patients with different genetic backgrounds or very differently, leading to different phenotypes and reactions to medication.”
Research has shown that ethnic minorities are at greater risk of dementia and Alzheimer’s disease. Studying the disease among a diverse population is therefore essential to understanding how an individual's genetic background could influence disease progression.
In addition to including ethnically diverse cell lines, phase one of the collaboration includes nine stem cell lines derived from nuns, priests and brothers aged 65 years and older participating in the Religious Orders Study/Memory and Aging Project. This unique cohort adds an additional layer of significance to the resource and could present new insights into aging and cognitive health.
“The benefit of understanding the diversity of disease biology will be global since no group is spared these diseases, and what we learn from each gives us a better understanding of, and thus ability to combat, the disease overall,” said Wesely.
Expanding to additional diseases and ancestral backgrounds
Future phases of the collaboration aim to expand the scope of the project to include additional diseases and minority groups. In addition, they hope to develop new tagging technologies and integrate more complex cellular models such as organoids.
Wesely concluded, “We would like to be an example of a collaboration where two institutions bring their expertise together to accelerate the scientific field, give to the science community and be an example of how we can overcome the low number of genetically diverse iPSC lines in our laboratories.”
