In October we continued our Chromatin Coffee tradition with the first ever Chromatin Coffee to feature a Guest – Paul Giresi (CSO, Ravel Biotechnology; previously: Founder and CSO, Epinomics) joined us to share his experience in epigenomic science and industry.
By: Brad Gulko, Editor: Monika Maleszewska
Our Guest
We first heard from Paul about his background and adventure with epigenomics. Paul has worked in the field of epigenomics for 15-20 years. His adventure started with FAIRE and probing chromatin accessibility genome wide. He performed this assay across different cell types, contributing to the ENCODE consortium’s work, and observed cell-specific diversity. It was that work, and the limitations of the contemporary chromatin accessibility assays, that inspired him to invent ATAC-seq during his Post-Doc at Stanford, which later led him to starting his own company, Epinomics (today part of 10x Genomics).
Paul is interested in clinical applications of epigenomics. “What we know now is that cell’s chromatin accessibility changes all the time.” Paul told us. “When a cell dies it digests the accessible DNA elements and leaves the inaccessible elements (DNA bound by e.g. nucleosomes, or transcription factors (TFs)). This becomes available in the body and accessible for CF-DNA assays that identify the types of cells that are dying and infer nascent diseases.”
After Paul’s brief introduction, a long conversation ensued: we all made introductions and shared what interests us and what brought us to BACE. Below is a overview of topics we discussed.
Epigenetics and cancer
The role of epigenetics in cancer continues to gain recognition. An interesting aspect of that is the co-evolution of cancer and immune cells in the tumor environment, e.g. in many tumors cancer cells are known to suppress the function of immune cells.
And what about studies of chromatin accessibility in normal tissues, e.g. in normal developmental trajectories? There seems to be a lot of model systems, but less is known in human development, although new papers are appearing now. The focus seems to be on known regulatory elements, especially at variables sites (where mutations accumulate).
Further reading:
The evolutionary history of 2,658 cancers
Convergent Evolution, Evolving Evolvability, and the Origins of Lethal Cancer
Integrative analysis of 111 reference human epigenomes
Multi-omics for rare diseases
Late adult-onset rare disease might result from accumulation of structural changes influenced by the environment. In particular, autoimmune diseases show variants activated epigenetically in subsets of cell types relevant to the disease (e.g. T-cells).
Groups are seeking to gather a range of multi-omics, including, primary sequence, medical records, and imaging. However, investigations of the noncoding regions are still in their infancy. Unfortunately, it often takes 3-5 years to validate a study.
CRISPR technology-based permutation studies play an important role and rare disease may additionally serve as a fast-track route to validate important developments.
Further reading:
A scoping review and proposed workflow for multi-omic rare disease research
Epigenetics of aging
Paul reminisced about his past work, where in mice he investigated the Crypt stem cells that have the ability to regenerate, and found age-related epigenetic changes.
Much of the ageing-related work is still academic, but there seems to be potential for application. However, quality of life in aging is important to consider and you have to be careful about introducing any treatments that may have deleterious side-effects.
We discussed how some people today view aging as a disease, then seek a profile of change that might be modified. An extension of this perspective is to consider cancer as deriving from an accumulation of aging processes. From this perspective, directly treating cancer seems to address the symptom rather than the cause (aging).
This further sparked philosophical discussion on similarities and differences between ageing research and regenerative medicine approaches.
We also discussed how age may be reflected in T-cell repertoires, and how that may reflect the pathogenic and other challenges that the body has seen over the years.
Finally, there seems to be a lot of interest in the use of blood factors or bone marrow transplants to inhibit aging phenotypes. Measurable impact has been demonstrated in mice. It remains to be understood what the most important contributing factors are.
Further reading:
The attendees recommended the work of David Sinclair on autophagy, cell senescence, fasting, and exercise, to learn more about this topic.
Personal aging markers and ageotypes revealed by deep longitudinal profiling
Molecular and phenotypic biomarkers of aging
Blood-based therapies to combat aging
Synthetic organ generation. What prevents this?
Miniature organ elements called organoids have been developed and used more and more extensively in the past years. One of our attendees proposed: What if rather than attacking a hard problem, like cancer of a specific organ, we could just develop new replacement organs? After all, heart, lung and other organ disorders are major sources of adult disease.
Discussion ensued. Organs are complex. While organoid research is thriving, it seems that we also still struggle with simple processes, e.g. hair regrowth.
A startup company called IvyNatal was mentioned. The company’s seeking to revert skin cells to progenitors for reproductive oocytes and spermatocytes either’s skin (the precursor work for that was iPS generation using the Yamanaka factors). This is inspired by trans-differentiation experiments which demonstrate the ability to drive cells from one type directly to another desired cell type.
But what do we know about epigenetic development in synthetic organoids? The different tissue types composing them must have different epigenetic landscapes. Do the spatial organization and 3D interactions between different cell types inform the epigenetics? Answering those questions seems to be an interesting open issue.
Further reading:
A study indicates that hair loss might be prevented by regulating stem cell metabolism
Transplant induced germ cell mosaicism and germ line alteration
A recent paper identified donor DNA migrating into bone marrow-recipient’s cells, including sperm cells.
We thought that bone marrow stem cells themselves might migrate, but also when the donor cells die, they may release some of their DNA into the blood stream. We wondered if that DNA might in some circumstances be taken up by host’s stem cells during division. There is a related body of work studying pregnancy-induced mosaicism (see: Pregnancy-induced Microchimerism, Predictors of Male Microchimerism).
That discussion brought on another controversial topic of altering germline cells. That raises an enormous number of ethical and biological issues. Current technologies like CRISPR are powerful and hold enormous promise, but as of today they can also generate errors that must be carefully checked for.
Further reading:
Epigenetic treatment for disease and epigenomic reporters
Epigenetics serves as a gateway between sequence and biology, and we hypothesized that at some point we may know epigenetic variation so well that we could exert a phenotypic change by modifying epigenetic state. Such effects might well be gentler than some of more traditional medical approaches, and reversible, allowing for modulation over time.
To get there, we might need a theory of normal epigenetic development, looking at diseases as variations that might be corrected. There is evidence of epigenetically heritable traits such as those induced by parental experience of starvation.
It would also be interesting to couple epigenetic modulation with real-time measurements by means of a reporter system. Depending on targeted modifications, one could imagine different reporter systems.
Bio Bay Area 