Measuring Life: From Single Cells to Liquid Biopsies

# From immune systems to microbiomes: what else can sequencing reveal? Watch the video first. Use this companion to revisit the reasoning and its evidence limits. Your adaptive immune system keeps a library. Each B cell makes one kind of antibody, and each T cell carries one kind of T cell receptor, assembled by shuffling gene segments as the cell develops. That creates an enormous diversity of receptor sequences. The whole collection is called the immune repertoire. When a cell's receptor recognizes a target, the cell divides into a clone: many cells sharing that receptor sequence. In B cells, the copies also mutate and are selected, forming a family tree. Sequencing millions of receptors gives a census of these clones. Some clones expand. In 2013, Jiang, Quake and colleagues analyzed about five million antibody sequences from volunteers of different ages, around influenza vaccination, and mapped the lineage structure of their repertoires. Older volunteers had fewer lineages, and in some, a few clones dominated. Follow-ups pushed further. A 2017 study found that antibody repertoires become more specialized but less flexible over the decades. And a 2025 study by Cvijović, Swift and Quake traced B cell lineages across bone marrow, lymph nodes, spleen and blood from six organ donors, showing the limits of monitoring immunity from blood alone. One caution. A receptor sequence tells you a clone exists and has expanded. By itself, it usually doesn't tell you what that receptor binds. Finding the target generally takes separate experiments. Now, a surprise hiding in the same blood samples. Not every DNA fragment is human. A small fraction comes from bacteria and viruses, including bacteriophages, that live in and on us. Metagenomics means sequencing the genetic material of a mixed microbial community directly, without first growing each organism in a lab, which matters because many microbes have never been cultured. In 2017, Kowarsky, Quake and colleagues pooled cell-free DNA sequencing from 1,351 blood samples from 188 patients. They assembled 7,190 stretches of sequence longer than a thousand bases; 3,761 looked like little or nothing in existing databases, pointing to many uncharacterized microbes in the human body. The group brought microfluidics here too. In 2017, Yu and colleagues split hot spring samples from Yellowstone into tiny chambers of five to ten cells each, and recovered 29 new microbial genomes. And in lung transplant patients, non human cell-free DNA flagged viral infections, offering hypothesis-free infection monitoring. Keep three things apart. Microbial DNA detected is not the same as a living organism; fragments can come from dead cells, or from contamination. And a living organism isn't necessarily the cause of a disease. An association is a lead, not proof of causation. That's the pattern of the whole course: a new tool, a new measurement, new data, new biology, and sometimes a new diagnostic possibility. ## Evidence guide COLLABORATIVE PRIMARY RESULT: historical influenza and aging repertoire studies differ from the 2025 six-donor Quake-lab study. Receptor sequence does not automatically identify antigen, and blood is incomplete tissue coverage. QUAKE-LAB PRIMARY RESULT: metagenomic observations detect sequences. DNA detection, viability, active infection and causation are separate; contamination and dead organisms remain alternatives. Sources: [jiang2013], [debourcy2017], [cvijovic2025], [kowarsky2017], [yu2017], [devlaminck2015]. See the course bibliography and claim audit.