New computer model tracks origin of cell changes that drive development

Scientists at Johns Hopkins Medicine say they have developed a computer model — dubbed quantitative fate mapping — that looks back in the developmental timeline to trace the origin of cells in a fully grown organism. The new model, they say, can help researchers more precisely spot which cells acquire alterations during development that change an organism’s fate from healthy to disease states, including cancer and dementia.

The achievement, described in the Nov. 23 issue of Cell, uses mathematical algorithms that take into account the general speed with which cells divide and differentiate, the rate at which mutations naturally accumulate and other known factors of organism development.

“We can use this method to examine the development of organisms from cell samples, including those from non-model organisms such as humpback whales that we don’t ordinarily study,” says Reza Kalhor, Ph.D., assistant professor of biomedical engineering, genetic medicine, molecular biology and genetics and neuroscience at The Johns Hopkins University and School of Medicine. “For example, with a cell sample from the carcass of a humpback whale, we can understand how it developed as an embryo.”

The new computer model is based on the fact that every complex living organism comes from a single, fertilized cell, or zygote. That cell divides, and the daughter cells continue dividing, eventually differentiating into specialized cells in tissues. Humans, for example, have about 70 trillion individual cells and several thousand types of cells.

Each time a cell divides, a mutation can occur, and that alteration gets passed on to the daughter cells, which divide again, perhaps acquiring a second mutation, both of which are passed to their daughter cells, and so on. The mutations act as a kind of barcode that is detectable with genomic sequencing equipment. Scientists can track these mutations in reverse order to construct a cell’s lineage, they say.

The quantitative fate mapping program has two parts. One is a computer program called Phylotime, which reads cell mutations as barcodes to infer the timescale associated with cell divisions. The name Phylotime stands for Phylogeny Reconstruction Using Likelihood of Time. In biology, phylogeny describes and depicts lines of evolutionary development. The second part developed by the Johns Hopkins team is a computer algorithm called ICE-FASE, which creates a model of the hierarchy and lineages of cells within an organism based on the timescales of cell divisions.

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