San Francisco, California, USA, 8 July 2025 – In a detailed Genomic Press Interview featured in Brain Medicine, Dr. Michael C. Oldham discusses his atypical transition from advertising executive to computational neuroscientist and his pioneering contributions to elucidating the cellular and molecular architecture of the human brain via gene coexpression analysis.

Dr. Oldham’s journey to neuroscience traversed from Madison Avenue to molecular neuroscience, proving to be anything but linear. Upon graduating from Duke University at the age of 20 with a pre-med concentration, he realised he could not pursue medical school, acknowledging his absence of an inherent passion for patient care. After a period in San Francisco’s advertising sector during the dot-com boom, his intrigue with the evolution of human language and the distinctions between human brains and those of our nearest monkey cousins prompted his return to academia.

“The genetic changes that gave rise to the modern human brain were the catalyst for life as we know it,” Dr. Oldham reflects in the interview. He has pursued a PhD at UCLA.

Innovative gene coexpression network analysis

In collaboration with Dr. Dan Geschwind of UCLA and biostatistician Dr. Steve Horvath, Dr. Oldham conducted the inaugural genome-wide investigation of transcriptional covariation in the human brain. His epiphany occurred upon recognising that recurring gene activity patterns in brain samples aligned with the transcriptional fingerprints of distinct cell types.

“Variation in the cellular composition of bulk tissue samples should inevitably drive the covariation of markers for different cell types,” Dr. Oldham explains. This finding, reported in Nature Neuroscience in 2008, illustrated how gene coexpression analysis may identify ideal markers of cell types and states—a premise that remains the foundational thesis for his team at UCSF.

The methodology, termed Weighted Gene Coexpression Network Analysis (WGCNA), has emerged as a fundamental technique in genomic research. In contrast to conventional differential expression analysis that evaluates individual genes across cohorts, WGCNA discerns stable patterns of coordinated gene activity within biological systems. This technique has demonstrated significant efficacy in elucidating complex tissues such as the brain, where various cell types engage in intricate interactions.

Study: From brain evolution to brain tumors

Dr. Oldham’s initial research was on examining gene activity patterns in the brains of humans and various other species. These endeavours revealed functionally important alterations in gene expression in human radial glia (Nature, 2014), interneurons (Cerebral Cortex, 2018), and astrocytes (Nature Neuroscience, 2018), while presenting innovative techniques for synthesising and contrasting gene activity patterns across biological systems.

Recently, his scientific focus has transitioned from examining the uniqueness of human brains to addressing one of medicine’s most formidable diseases: malignant gliomas. As a faculty member in the UCSF Department of Neurological Surgery and Brain Tumour Centre, he employs computational methodologies to address these highly heterogeneous brain tumours.

His team has examined gene activity patterns from more than 17,000 human brain samples, comprising roughly 10,000 normal and 7,000 malignant glioma samples. This extensive project has resulted in the creation of OMICON (theomicon.ucsf.edu), a platform intended to render the patterns of gene activity in these intricate datasets available to the wider academic community. The collection has over 100,000 gene coexpression modules that have been thoroughly characterised using enrichment analysis using thousands of curated gene sets, offering researchers globally unparalleled insights into brain function and malfunction.

Dr. Oldham and his team are identifying consistently repeatable molecular alterations in certain cell types of the glioma microenvironment, such as vascular cells and neurones, by comparing gene activity patterns between normal human brains and malignant gliomas. These molecular characteristics present prospects for the development of innovative biomarkers and tailored therapeutic techniques for glioma patients. Cell-surface indicators of glioma vasculature offer a possible molecular ‘zip code’ for targeting gliomas through the circulation.

Confronting the reproducibility crisis

Dr. Oldham is concerned with what he describes as science’s reproducibility crisis. “If most of the findings we toil to produce cannot feasibly be reproduced, what is the point?” he asks, which highlights a challenge that extends far beyond neuroscience.

He has responded by assuming leadership positions to tackle these structural concerns. In his capacity as Vice Chair of UCSF’s Academic Senate Committee on Library and Scholarly Communication, he has initiated a university-wide Task Force focused on the standardisation of research data and metadata. Although the subject may appear technical, Dr. Oldham underscores its vital significance: these standards are fundamental precondition for enhanced transparency and reproducibility in science, more accurate representation of scientific knowledge, and improved collaborative efficiency.

“Although there are many factors that affect the reproducibility of published research findings, there is no reason in principle why data analysis should not be completely reproducible,” Dr. Oldham notes. “By standardizing how we package and describe our research data, we can accelerate data discovery and analysis, including the use of artificial intelligence. More generally, standardized data packages with persistent identifiers can serve as building blocks for new technology infrastructure to modernize scholarly communication around reproducible data analysis.”

The human aspect of scientific discovery

The interview discloses personal insights that influenced Dr. Oldham’s career path. His decision to extend his graduate studies by two years following his initial significant publication—a choice deemed “irrational” by some—culminated in a second, more influential paper that facilitated his appointment as a UCSF Sandler Faculty Fellow. This esteemed role granted him instant autonomy and resources to create his own laboratory.

Outside of his contributions to neuroscience, Dr. Oldham frequently traverses the trails of Marin County, his residence, often wandering solitary and absorbed in contemplation. He sustains personal friendships from his tenure in San Francisco’s advertising sector, upholding its motto: “ABC (always be celebrating!).”

Dr. Oldham anticipates that the integration of multiscale and multimodal data is essential for comprehending brain complexity. He promotes standardised data production methodologies that utilise robotic automation to create repeatable datasets on a large scale. Dr. Oldham contends that neuroscientists must transition from descriptive research of biological systems to predictive analysis utilising statistical models. “There is a significant distinction between articulating the implications of a dataset and forecasting the contents of the subsequent dataset,” he states.

Dr. Michael C. Oldham’s interview with Genomic Press is a segment of the broader series titled Innovators & Ideas, which showcases the individuals responsible for contemporary significant scientific advancements. Each interview in the series presents a synthesis of innovative research and personal insights, affording readers a thorough perspective on the scientists influencing the future. This interview approach merges professional accomplishments with personal reflections, fostering a more engaging and informative narrative for readers. This structure serves as an optimal foundation for profiles that examine the scientist’s influence on the discipline, while also addressing overarching human concerns.

About Brain Medicine: 

Brain Medicine (ISSN: 2997-2639 for online and 2997-2647 for print) is a peer-reviewed medical research journal published by Genomic Press in New York.

Original Publication
Journal: Brain Medicine
DOI: 10.61373/bm025k.0080
Method of Research: News article
Subject of Research: People
Article Title: Michael C. Oldham: Clarifying the cellular and molecular architecture of the human brain in health and disease through gene coexpression analysis
Article Publication Date: 8-Jul-2025
COI Statement: Dr. Michael Oldham disclosed that after he started taking nicotinamide riboside, he invested in shares of one of the companies that manufactures it.

Original Source: https://doi.org/10.61373/bm025k.0080