The stuff of life
Discovering the secrets of cells
Cells are among life’s fundamental mysteries — perhaps the fundamental mystery, given that cells are life’s most basic unit. Yet as technology advances and biologists adopt new methods, cells’ secrets are being revealed. At Stanford Medicine, the discoveries are shaping our understanding of biology and health and fueling new ways to treat disease.
Scientists can manipulate cells as never before, facilitating research and making new treatments possible. Genetically engineered immune cells, for example, are the basis of CAR-T cell therapy, a new therapy with high response rates for blood cancers, often leading to lasting remission for patients who have run out of other treatment options.
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“It’s a great time for cell biology,” said Markus Covert, PhD, the Shriram Chair of the Department of Bioengineering. “It used to be that biology was what you went into if you loved science but were scared of math. That’s changed. There’s an influx of people who are intellectually ambidextrous, and the field has become more quantitative. That has broken cell biology wide open.”
The field of biology got its start more than 350 years ago when, in 1665, scientist and expert microscopist Robert Hooke published his groundbreaking book, Micrographia, with engravings and descriptions of objects observed under magnification. When he examined a slice of cork, he saw boxlike structures that reminded him of monks’ quarters — so he dubbed them cells.
Cells came into clearer focus when, in 1674, Antonie Van Leeuwenhoek shook London’s Royal Society with his letter detailing the first documented observation of live cells. Using a microscope he built himself, he studied water from a nearby lake and saw green streaks made up of rows of cells (probably the alga Spirogyra) as well as “very many little animalcules, whereof some were roundish, while others, a bit bigger, consisted of an oval.”
Further microscopy studies led, in the 19th century, to the formulation of the cell theory, still recognized today. It holds that cells are the fundamental units of both plants and animals, that all cells are generated by existing cells, and that chromosomes in the cell’s nucleus are responsible for heredity.
Today, biologists benefiting from vastly improved methods for studying living cells are making headway in fathoming the many millions of biochemical reactions that occur in a cell every second.
Genomic sequencing, which took off in the early 2000s, has become a major tool, enabling scientists to identify the genetic transcripts in play and, with the help of other new technologies, watch the proteins and metabolites at work. Though these studies were first conducted on pooled batches, new methods target individual cells.
“There are so many new single cell techniques,” said Denise Monack, PhD, the Martha Meier Weiland Professor in the School of Medicine and chair of the Department of Microbiology and Immunology. “I am finding spatial transcriptomics, which maps gene activity at the single cell level in tissues, to be particularly exciting because we gain so much more information about the relationship between cells as well as their location in tissue — which is crucial for understanding normal development and disease pathology.”
Monack is using single-cell analysis, high-throughput screening and other tools of cell biology to ascertain how salmonella bacteria, including the serotype that causes typhoid fever, evade the immune system, persist inside of immune cells and finally transmit to new hosts.
Covert is using the reams of knowledge being produced by cell biologists to create computer models of the full gamut of a cell’s biochemical processes — in other words, creating artificial life. In 2012, he and his team completed a model of one of the simplest bacteria, Mycoplasma genitalium, and have since simulated a colony of Escherichia coli. He’s aiming to work his way up to modeling the behavior of mammalian cells that make up a tumor.
An important use for such models is to test-drive what happens when a cell is exposed to a drug or toxin or is given new genetic instructions — increasingly valuable as engineered cells are being applied as therapies.
“It’s amazing,” Covert said. “We’re recognizing that a medicine doesn’t have to be a molecule or protein. It can be a cell.”
