A Conversation with SFARI Investigator Kevin Eggan

Kevin Eggan is a professor in the Department of Stem Cell and Regenerative Biology at Harvard University.

Human induced pluripotent stem (iPS) cells can be used to create neural precursors, neurons and glial cells, as well as brain organoids, and serve as a valuable cellular model system for studying brain processes and disorders. A few years ago, the Simons Foundation Autism Research Initiative (SFARI) began to establish iPS cell lines from participants in Simons Searchlight to aid research into the biology and physiology of neurodevelopmental conditions, including autism spectrum disorder (ASD). To ensure that the resource will serve as a robust and reliable, cellular model system, SFARI consulted with SFARI Investigator Kevin Eggan to provide a detailed characterization of these initial Simons Searchlight iPS cell lines. 

Eggan is a professor in the Department of Stem Cell and Regenerative Biology at Harvard University and a member of the Stanley Center at the Broad Institute. He is internationally recognized for his work in stem cell biology, performing fundamental work on the biology and reprogramming of iPS cells and their use in the study of neurological disease mechanisms.

I recently spoke with Eggan to learn more about his research on iPS cells and his collaboration with SFARI. The interview is summarized below.

Eggan's path

Eggan’s interest in harnessing the power of stem cells to study human biology began during his graduate work in SFARI Investigator Rudolf Jaenisch’s laboratory at the Massachusetts Institute of Technology (MIT). At the time, the high-profile cloning of Dolly the sheep by the Roslin Institute at the University of Edinburgh, Scotland, had aroused a great deal of excitement in the idea of, and inherent possibilities in, cellular reprogramming. Working on mouse embryonic stem cells and nuclear reprogramming methods, Eggan gained expertise that would propel him to a position at Harvard in 2003 just as Doug Melton and David Scadden were setting up the Harvard Stem Cell Institute. Continuing work on reprograming methods, Eggan’s laboratory was the first to demonstrate that human somatic cells could be switched to an embryonic stem (ES) cell state1. This demonstration helped lead others to the discovery, a few years later, of methods to reprogram somatic cells into iPS cells2-4. Eggan’s fundamental contributions were also recognized in 2006, when he was awarded a MacArthur Foundation “genius grant.” Not long after, his laboratory made another seminal breakthrough, becoming the first group to generate a neurological disease-based iPS cell line, one for the neuromuscular condition amyotrophic lateral sclerosis (ALS)5.

Understanding iPS cells variability

As iPS cell models became more widely utilized, different sources of somatic cells, and various reprogramming methods, were employed. These experimental differences aroused a fair bit of debate on the merits of each, and whether such methods might introduce sources of variability.

“Eggan found that all of the iPS cell lines, regardless of initial cell source or reprogramming method, showed comparable characteristics. ”

To better understand how variability may impact research using iPS cells, in 2017 SFARI commissioned Infinity BiologiX (formerly known as RUCDR/Infinite Biologics) and the New York Stem Cell Foundation to create iPS cells from three individuals from the Simons Searchlight cohort, using different approaches. These included three different cell sources (erythroblasts, CD4+ T cells and fibroblasts) and three different methods for the delivery of the reprogramming factors (transfection with episomes, modified RNAs or sendai virus transduction). The project created multiple iPS cell clones with each method that resulted in a total of 47 iPS cell lines from the Simons Searchlight cohort. In a carefully designed, blinded analysis, Eggan’s team then examined the genetic make-up, pluripotency potential and neural differentiation characteristics of these cell lines.

Eggan found that all of the iPS cell lines, regardless of initial cell source or reprogramming method, showed comparable characteristics. As Eggan and his team were blind to both cell source and reprogramming methods, these findings strongly argued that it is reasonable to use and compare iPS cells obtained from different sources and reprogramming methods.

A surprising finding

The study also uncovered something that Eggan found somewhat surprising. While iPS cell characteristics were similar from source to source, Eggan found that there was greater genetic variability across lines created from an individual’s skin cells than from their blood cells; this finding likely reflects sun-induced skin damage and has also been described by others6. Eggan argues this is a very encouraging finding when thinking about creating iPS cell lines from individuals with neurodevelopmental and neuropsychiatric conditions. While collection of skin cells requires donors to undergo an uncomfortable skin punch biopsy, something made even more difficult in individuals with sensory processing sensitivities like those occurring in autism, collection from blood simply requires that an additional tube of blood be taken during a routine blood draw.

The team did, however, find that spontaneous mutations arose in culture, prior to reprogramming. While Eggan points out that this was a largely expected finding, he suggests that the best way to overcome this complexity is to create iPS cell lines from numerous individuals rather than relying on lines created from multiple clones from a single individual. In keeping with this viewpoint, SFARI recently announced a new collaboration with the Nancy Lurie Marks Family Foundation to generate iPS cell lines from individuals with autism and related neurodevelopmental conditions, using blood samples collected from participants in Simons Searchlight. These cell lines will become available to researchers starting in 2021.

The promise of iPS cell models

With the availability of these autism iPS cell lines comes the question of their utility in answering questions about the basic biology of autism and advancing potential therapies for the condition. In this, Eggan’s ongoing work to understand ALS using iPS cell lines highlights the strong potential of such disease-based iPS cell models.

ALS is a progressive neurodegenerative disease that targets motor neurons within the spinal cord and brainstem, leading to muscle wasting and eventual death from respiratory failure. Like ASD, ALS is a complex genetic condition, though rare monogenic forms exist. Eggan and his colleagues at Harvard University have been examining molecular, cellular and physiological mechanisms in motor neuron cultures derived from iPS cells obtained from individuals with distinct forms of ALS.

“These findings demonstrate the opportunity of going from iPS cell work directly to clinical trials, supporting similar efforts in ASD. ”

His work on these cell lines has provided valuable insights into how ALS mutations cause functional changes in motor neurons7, as well as demonstrated the viability of using co-culture systems derived from iPS cells to address questions of communication between neurons and other brain cell types in disease pathology8 and resulted in the development of an all-optical electrophysiology technique that permits high-throughput functional characterization of human iPS cell–derived neuronal cultures9.

Such findings have also led to potential treatment options in ALS. A collaboration with Clifford Woolf’s laboratory at Harvard demonstrated that the disease-based motor neuron cultures recapitulate hyperexcitability effects seen in clinical settings10, and that this phenotype could be corrected using a known antiepileptic drug (ezogabine)7,10. Going directly from their findings in the motor neurons derived from iPS cells, Eggan, Woolf and colleagues were able to begin a clinical trial of ezogabine for the treatment of ALS (https://clinicaltrials.gov/, NCT02450552)11.

These findings demonstrate the opportunity of going from iPS cell work directly to clinical trials, supporting similar efforts in ASD.

The time is ripe

Until recently, much of the work in Eggan’s laboratory was focused on understanding the cellular mechanisms of ALS. When asked about this initial focus, Eggan talked about the state of the field when he set out to use iPS cells to understand human disease. Eggan commented that, through the work of Tom Jessell and others, there was a great deal known about the development of motor neurons at that time, but less about other cell types. This made motor neurons a good choice for generation via iPS cell differentiation.

“The numerous advances in iPS cell biology make the time right to study neurodevelopmental and neuropsychiatric conditions using iPS cell models. ”

Since then, through the work of many laboratories, studies of numerous excitatory neuronal cell types have been assessed using cultures derived from iPS cells. Eggan particularly highlighted recent work from Elena Cattaneo’s laboratory and others where great strides have been made in differentiating inhibitory neuron types from iPS cells — an important consideration given suggestions of excitatory/inhibitory imbalances in autism, schizophrenia and other neurodevelopmental conditions12. Advances in brain organoid systems are also making it possible to assess questions related to brain circuitry-based disease mechanisms with iPS cell platforms (Reviewed in Hartlaub A.M. et al.13).

Eggan argues that the numerous advances in iPS cell biology make the time right to study neurodevelopmental and neuropsychiatric conditions using iPS cell models.  And indeed, a collaboration with Ralda Nehme at the Broad Institute and SFARI Investigator Steve McCarroll at Harvard Medical School has resulted in the creation of the Stanley Center Stem Cell Biobank, an effort to scale up the development and availability of iPS cellular models to understand neurodevelopmental and neuropsychiatric conditions.

Eggan and colleagues have gone on to demonstrate that these iPC cell model studies can provide valuable insights into schizophrenia pathogenesis. Using iPS cell lines derived from individuals with schizophrenia, Eggan and Bruce Cohen’s laboratories have recently uncovered deficits in oligodendrocyte development and function in schizophrenia14, and a collaboration with Sangmi Chung’s group has linked an intrinsic defect in cortical interneuron protocadherin signaling to defective synaptic development in schizophrenia15.

SFARI’s collaboration with the Nancy Lurie Marks Family Foundation — developing hundreds of distinct autism iPS cell lines from participants for whom phenotypic and genetic information is also available — should prove a similarly valuable resource to help investigators understand the cellular and physiological bases of autism.


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