#290 ‒ Liquid biopsies for early cancer detection, the role of epigenetics in aging, and the future of aging research | Alex Aravanis, M.D., Ph.D.
Feb 19, 2024
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Delve into liquid biopsies for early cancer detection and the role of epigenetics in aging with expert Alex Aravanis. Explore DNA sequencing, tumor sequencing, cell-free DNA, DNA methylation, specificity, and sensitivity of tests. Discover the potential of cellular reprogramming to reverse aging changes. Uncover the advancements in universal blood tests for cancer detection using next-generation sequencing and AI. Explore the critical role of high specificity in detecting cancer accurately.
Liquid biopsies in cancer detection offer non-invasive early screening based on cell-free DNA.
DNA methylation influences gene expression and cellular differentiation, playing a key role in aging.
Cellular reprogramming through iPSCs offers potential for regenerative medicine and tissue replacement therapies.
Advances in epigenetic editing and targeted delivery systems show promise for rejuvenation therapies in aging research.
Deep dives
The emergence of liquid biopsies
Liquid biopsies, which involve the sequencing of tumor DNA in the blood, were developed as a non-invasive alternative to tissue biopsies for late-stage cancer patients. The presence of cell-free DNA in the blood, released from dying cancer cells, made it possible to detect tumor DNA. The initial focus was on identifying mutations in late-stage cancers and selecting targeted therapies based on the genomic profile. However, there was curiosity about whether liquid biopsies could be used for early cancer detection. Incidental findings in non-invasive prenatal testing, where fetal DNA was detected in maternal blood, hinted at the possibility of identifying cancer in asymptomatic individuals using cell-free DNA. The birth of Grail, an independent company, was motivated by the need to explore the feasibility of a universal blood test for cancer based on liquid biopsies.
Research and development of liquid biopsies
Grail embarked on an extensive research and development plan to evaluate various features of cell-free DNA. They assessed fragment length, genetic sequence, chromosomal changes, methylation patterns, and even the presence of cell-free RNA from tumors. Large cohorts were recruited for comprehensive studies to train machine learning algorithms and determine the most effective combination of features for high sensitivity and specificity. The research phase took several years and involved blinded studies to eliminate bias. The analysis and comparison of different features provided insights into the potential of liquid biopsies for broad-based cancer screening.
Understanding methylation and its role
DNA methylation, a chemical modification of DNA, played a crucial role in liquid biopsies. It involves adding a methyl group to cytosine, one of the nucleotides in the DNA code. Approximately 28 million positions in the human genome can be methylated, and methylation impacts gene expression and cellular differentiation. Methylation patterns provide epigenetic information and contribute to the control of gene transcription. Grail's research included the evaluation of methylation patterns and their usefulness in detecting cancer.
Achievements and challenges in liquid biopsy development
Grail's extensive research efforts led to significant advancements in liquid biopsy technology. They established the ability to detect tumor DNA in the blood and explored the diagnostic potential of various features like mutations, chromosomal changes, methylation, and RNA presence. However, the development of a universal blood test for cancer using liquid biopsies presented challenges such as achieving high specificity, addressing tumor heterogeneity, and using AI or machine learning effectively. The focus on large-scale studies, assay development, and blinded analysis enabled Grail to determine the best approach for developing accurate and reliable liquid biopsy tests.
Methylation patterns determine cell identity and state
Methylation patterns on the DNA determine the identity and state of cells. When a cell replicates, the methylation patterns are also replicated, ensuring that the cell retains its specific function.
The potential of epigenetic reprogramming
Epigenetic reprogramming, such as the use of Yamanaka factors, can revert differentiated cells back to a stem cell-like state, known as induced pluripotent stem cells (iPSCs). Through iPSCs, cells can be redifferentiated into specific cell types, offering potential for tissue and cell replacement therapies.
The relationship between methylation and aging
The epigenome, including DNA methylation, plays a crucial role in aging. Methylation patterns change with age, and these changes are correlated with aging-related phenotypes and diseases. Understanding and manipulating the epigenome may provide opportunities for age-related interventions and rejuvenation therapies.
Future prospects and challenges
In the next decade, there is optimism for the development of rejuvenation therapies targeting specific tissues and cell types. Advances in epigenetic programming and editing technologies, along with targeted delivery systems, may enable the rejuvenation of joint tissues, retina, immune cells, and other organs, leading to improvements in health span.
Alex Aravanis is a leader in research and development of technologies and clinical tests utilizing the latest tools in DNA analysis and data science. In this episode, Alex delves into two interconnected topics: liquid biopsies and epigenetics. He begins by tracing the trajectory of genome sequencing and tumor sequencing, setting the stage for a detailed exploration of liquid biopsies as an early cancer detection method. The discussion encompasses key concepts such as cell-free DNA, DNA methylation, sensitivity, specificity, and the predictive values associated with liquid biopsies. Transitioning to epigenetics, Alex examines the intricate interplay of DNA methylation and aging biology and explores the possibility of using cellular reprogramming to reverse epigenetic changes that occur with aging.
We discuss:
Alex’s background in applying engineering to problems in medicine [3:15];
A primer on human genetics, and the history and current landscape of DNA sequencing [11:00];
The advent and evolution of liquid biopsies for early detection of cancer [23:15];
The role of cell-free DNA in cancer detection: how incidental findings in non-invasive prenatal testing led to the development of liquid biopsies [40:15];
The development of a universal blood test for cancer detection and a discussion of specificity of tests [46:00];
Advancements in cell-free DNA analysis and development of a multi-cancer screening test at GRAIL [51:00];
DNA methylation explained [58:15];
Optimizing cancer detection with methylation analysis of cfDNA in small blood samples [1:02:45];
The importance of understanding sensitivity, specificity, positive predictive value, and negative predictive value in cancer screening [1:08:00];
The performance of the GRAIL Galleri test and its ability to detect various types and stages of cancer [1:21:00];
Do early cancer detection methods, like liquid biopsies, translate to improvement in overall survival? [1:27:45];
The role of epigenetics in aging [1:39:30];
How cell-free DNA methylation patterns can help identify a cancer’s tissue of origin [1:45:30];
Cellular and epigenetic reprogramming and other exciting work in the field of aging [1:52:30]; and