The NIH defines, New Approach Methodologies (NAMs) as “complementary approaches to the use of animals in research.”
NAMs are an extension of the 3Rs in animal research: to reduce, refine, and replace animals whenever possible.
For investigators at WNPRC, the development and use of NAMs have long been a priority.
A good example of this is the application of stem cells for research, now evolving towards the creation of organoids, organ-on-a-chip devices, and others, emerged from Dr. Jamie Thomson’s discovery of how to generate and maintain embryonic stem cells at the WNPRC. In the 1990s, he first produced stem cells from common marmoset monkeys, then rhesus, followed by humans. These studies led to the transformative induced pluripotent stem cells used in medicine today.
Examples
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Emborg Lab
The Emborg lab is focused on understanding and finding solutions for neurodegenerative disorders., including Parkinson’s, Alzheimer’s and Frontotemporal dementia. Depending on the scientific question we use a variety of NAMs. For example, we use gels as “brain surrogates” for testing new instruments for intracerebral delivery of therapies, such as cells or viral vectors. We generate specific neuronal populations from human and monkey induced pluripotent stem cells to assess molecular pathways associated to disease and identify therapeutic targets. We use cell cultures for screening of disease-modifying molecules and to test gene editing methods. We also use mathematical models to predict outcomes.
Publications incorporating NAMs:
Tao Y, Vermilyea S, Zammit M, Lu J, Olsen M, Metzger J, Yao L, Chen Y, Phillips S, Holden J, Bondarenko V, Block W, Barnhart TE, Schultz-Darken N, Brunner K, Simmons H, Christian BT, Emborg ME, Zhang. S-C* (2021) Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys. Nature Medicine 2021; 27:632-639.
Vermilyea SC, Lu J, Olsen M, Guthrie S, Tao Y, Fekete EM, Riedel MK, Brunner K, Boettcher C, Bondarenko V, Brodsky E, Block WF, Alexander A, Zhang SC, Emborg ME. Real-Time Intraoperative MRI Intracerebral Delivery of Induced Pluripotent Stem Cell-Derived Neurons. Cell Transplantation 2017; 26:613-624.
Vermilyea SC, Emborg ME. In Vitro Modeling of Leucine-Rich Repeat Kinase 2 G2019S-Mediated Parkinson’s Disease Pathology. Stem Cells and Development 2018; 27:960-967.
Saalmann Lab
The Saalmann Lab uses in silico models to complement our non-human primate (NHP) and human brain research on cognitive control and consciousness. We build models across different scales, representing individual neurons (integrate-and-fire models) to large neuronal populations (neural mass models), to better understand information processing in brain circuits. This helps us refine hypotheses derived from in vivo experiments, and identify potentially new mechanisms to test in vivo, about brain functions in health and disease.
Cognitive control is the ability to flexibly adapt behavior according to goals and context, which involves selective attention, working memory and cognitive flexibility. With colleagues at Stony Brook University, we have modelled how the frontal lobe and deep brain areas interact to flexibly select rules guiding behavior and maintain behaviorally relevant information in working memory. This research advances our understanding and treatment of disorders of cognitive control, such as schizophrenia and attention-deficit hyperactivity disorder.
Information processing in the brain profoundly changes across different states of consciousness. With colleagues at the University of Sydney, we have modelled how interactions between the cerebral cortex and deep brain areas shape information processing in wakefulness and anesthesia, as well as how deep brain stimulation influences information processing. This research advances our understanding and treatment of disorders of consciousness, such as coma after traumatic brain injury or stroke.
Publications incorporating NAMs:
Phillips JM, Afrasiabi M, Kambi NA, Redinbaugh MJ, Steely S, Johnson ER, Cheng X, Fayyad M, Mohanta S, Carís A, Mikell CB, Mofakham S, Saalmann YB. Primate thalamic nuclei select abstract rules and shape prefrontal dynamics. Neuron 2025; 106:66-75.
Müller EJ, Munn BR, Redinbaugh MJ, Lizier J, Breakspear M, Saalmann YB, Shine JM. The non-specific matrix thalamus facilitates the cortical information processing modes relevant for conscious awareness. Cell Reports 2023; 42:112844.
Sousa Lab
The broad goals of our research program are to identify and characterize the molecular and cellular mechanisms that govern human brain development and evolution, and to apply that knowledge towards understanding neuropsychiatric and neurodevelopmental disorders, with a focus on Down syndrome and autism spectrum disorder.
The Sousa Lab has implemented several New Approach Methodologies to further our research program and reduce the number of animals needed. These include the utilization of several in vitro modalities, such as human and chimpanzee induced pluripotent stem (iPS) cells, and ReNcell human neural progenitor cells. We differentiate the iPS cells into several different types of neuronal cultures, including 2D excitatory neurons, 3D cortical organoids, 3D ventral forebrain organoids, and assembloids. We also implement the use of iPS cells from macaque and marmoset. We have collected fibroblasts from several specimens of each species, which we plan to reprogram to iPS cells.
Using these in vitro modalities, we perform several types of analyses, including functional genomics, metabolomics, electrophysiology, and morphology. The iPS cells also allow us more flexibility to manipulate the expression of genes of interest and interrogate their functions in neurodevelopment.
Publications incorporating NAMs:
Gao Y, Dong Q, Arachchilage KH, Risgaard RD, Sheng J, Syed M, Schmidt DK, Jin T, Liu S, Knaack S, Doherty D, Glass I, Levine JE, Wang D, Chang Q, Zhao X, Sousa AMM. Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex. Neuron 2025; 113:1-18.
Tao Y, Li X, Dong Q, Kong L, Peterse AJ, Yan Y, Xu K, Zima S, Li Y, Schmidt DK, Ayala M, Mathivanan S, Sousa AMM, Chang Q, Zhang S-C. (2023) Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells. Nature Biotechnology 2023; 42:1404-1416