As cells divide and respond to environmental exposures, they accumulate somatic mutations that create a mosaic of genetic variation across tissues. Although most of these mutations have little effect, some can alter cellular behavior in ways that drive disease or protect against it.
Peter Campbell, PhD
Cofounder and Chief Scientific Officer
Quotient Therapeutics
In this Innovation Spotlight, Peter Campbell, the cofounder and chief scientific officer of Quotient Therapeutics discusses a new somatic genomics platform built to identify these mutations and translate them into drug targets. By combining highly accurate genome sequencing with computational analysis, Quotient Therapeutics aims to uncover the genetic signals embedded within individual cells that reveal how diseases arise and how they might be treated.
What is the somatic genome?
Each of us started life as a single cell, the fertilized egg, with half its genome inherited from our mother and half from our father. As we grow from that one cell into a new human, that genome is copied trillions of times. Each time it is copied, mistakes can be made. We call these mistakes mutations, and they change the sequence of that cell’s DNA. If we imagine the genome as a recipe book, then the process of cell division is like copying these recipes out by hand and a mutation is like a typo in one of the recipes. Every further time that recipe is copied, the typo propagates to the newly minted recipe book. The somatic genome, then, is the collection of mutations that have been acquired throughout the life history of that individual, tracing back to the fertilized egg.
What mechanisms drive this genomic diversity?
We know that mutation rates are constant over time. A blood cell in a 60-year-old person will have twice as many mutations as one from a 30-year-old. All cells accumulate somatic mutations in this steady, predictable fashion, even cells like neurons that have stopped dividing. Most of these mutations probably arise through the basic chemical processes of life leading to spontaneous and random DNA damage.
Superimposed on these intrinsic processes generating mutations are extrinsic lifestyle and environmental factors. For example, sunlight damages and mutates DNA in skin cells, chemicals in tobacco smoke cause extensive mutation in lung cells, and some childhood infections of the intestine can generate bursts of mutations in bowel cells.
To give some sense of the scale of the genomic diversity that results from these mutational processes, we can consider T lymphocytes, a type of blood cell central to immunity. An adult has about 10 billion T lymphocyte clones and by the age of 60 they have, on average, 2,000 mutations per cell. This equates to 10,000 mutations generated in T lymphocytes every second we are alive such that, by age 60, every one of the 3 billion bases in the genome is mutated 6,000 times on average.1 This means that there is more genetic diversity in one cell type in one organ of one person than all the inherited genetic diversity of all humans who have ever lived.
What evidence obtained from assessing somatic mutations is useful for understanding health and disease and identifying drug targets?
The vast majority of these somatic mutations do nothing to the cell. Returning to the recipe analogy, the typos do not meaningfully change the outcome of the recipe. Occasionally, a mutation in a critical gene in a specific cell might radically change that cell’s behavior, much in the way that a typo from 1 teaspoon to 1 tablespoon of salt in a recipe would radically change the taste of the resulting dish. Cells with mutations that promote their survival or proliferation can then outgrow their neighbors, leading to altered function locally. We have known for some decades that cancer arises from cells that have acquired somatic mutations in genes enhancing their selfish growth, blocking the effects of these mutations has been the cornerstone of some of the most exciting novel therapies in cancer in the last 25 years.
The exciting observation that underpins Quotient’s mission is that somatic mutations also play a causal role in the biology of many other diseases beyond cancer. We can see mutations that protect individual cells against disease processes such as metabolic liver disease—we can dream of developing a drug that mimics the effect of these mutations, extending their benefit to all cells rather than the few that happened to win the mutation lottery. On the flipside, we also see mutations that can drive diseases. Here, we can dream of developing therapies that reverse the effects of mutations, stopping the disease process.
By pairing ultra-accurate sequencing with computational analysis, scientists can identify rare somatic mutations that point to new, genetically validated drug targets.
©iStock, Andrii Yalanskyi
What technical barriers must be overcome to confidently identify mutations present in a tiny fraction of cells?
Our organs are comprised of a patchwork of cells, each of which has its own set of mutations. Our sequencing method therefore needs sufficient resolution to identify mutations from single DNA molecules. To do this, we have industrialized the world’s most accurate and sensitive sequencing technology, NanoSeq. The name comes from its error rate being about 1 in a billion, 100-fold lower than the true somatic mutation rate in an adult cell.2 The opportunity this affords us is to sequence many thousands of cells from a given patient sample very efficiently and cost-effectively.
How does Quotient’s platform work?
We pride ourselves on sequencing the cells that are right at the frontline of the disease process. For over 100 years, pathologists have been meticulously cataloging the microscopic features of every disease, describing the patterns of cellular abnormality in exquisite detail. With our platform, we can now extract those cells from patient biopsies and healthy controls and sequence their entire genetic code. At the risk of torturing the recipe analogy, we can compare the recipe for a successful dish, or the healthy control, with those that generated duds, or the diseased cells, and spot the recipes that had meaningful typos.
From any given disease, we might identify 5-30 genes that are enriched for mutations in the patient samples. We use state-of-the-art AI methods deployed across the world’s scientific knowledge banks to further contextualize these discoveries in the disease of interest and support these insights with high-throughput in vitro screening assays across the genes discovered. The most promising targets then begin drug discovery. From receiving a patient sample to target identification, biological validation, and drug design, we integrate AI and computational tools into our fully digital, data-driven workflows to accelerate our research and development. By identifying genetically validated targets from just a handful of patients, we gain deep biological insight into what, how, and where to target disease, enabling faster, smarter, and more precise drug discovery.
In which disease areas do the study of somatic genomics have the greatest impact?
Somatic genomics is not constrained to any disease area or cell type because mutations occur in all somatic cells and can alter the function of any cell. It could be a universal method to identify novel, genetically validated drug targets across a wide range of disease areas. Our approach has been validated so far across autoimmune disease, cardiometabolic disease, oncology, inherited disease, and many other areas. This breadth of application is hugely exciting—we believe that somatic mutations causally contribute to the biology of some of humanity’s most pressing general health problems, such as aging.
How will Quotient’s recent collaborations with pharmaceutical companies advance drug development?
Our Somatic Genomics platform can have a much broader impact on patients when we collaborate with partners. Our unprecedented biological insights, combined with deep disease and clinical expertise from large pharma companies, have the potential to lead to breakthrough novel therapies. We currently have pharma partnerships with Pfizer and GSK. Through our partnership with Pfizer, we are analyzing somatic mutations to inform the discovery and development of potential new therapies for cardiovascular disease. Our partnership with GSK is focused on discovering and validating new treatments for chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and metabolic liver disease (MASH). We look forward to additional collaborations in the future, extending the reach of somatic genomics into therapeutic areas with unmet medical needs.
- Machado HE, et al. Diverse mutational landscapes in human lymphocytes. Nature. 2022;608(7924):724-732.
- Abascal F, et al. Somatic mutation landscapes at single-molecule resolution. Nature. 2021;593(7859):405-410.
