Scientists at Johns Hopkins Medicine say they have developed a computer model. called quantitative fate mapping -; looking back at developmental timelines and tracing the origins of cells in fully grown organisms. The new model, they say, will help researchers more precisely identify which cells acquire changes during development that shift an organism’s fate from healthy to diseased states, such as cancer and dementia. It is said to be useful for
Achievements described in the November 23 issue of cellusing a mathematical algorithm that takes into account the general rate at which cells divide and differentiate, the rate at which mutations naturally accumulate, and other known factors in biogenesis.
This method can be used to examine the development of organisms from cell samples. This includes organisms from non-model organisms, such as humpback whales, which are not normally studied. For example, cell samples from a humpback whale carcass can be used to understand how it developed as an embryo. ”
Dr. Reza Kalhor, Assistant Professor of Biomedical Engineering, Genetic Medicine, Molecular Biology, Genetics and Neuroscience, Johns Hopkins University and School of Medicine
A new computer model is based on the fact that all complex organisms arise from a single fertilized cell, the zygote. The cell divides, daughter cells continue to divide, and eventually differentiate into specialized cells within the tissue. For example, humans have approximately 70 trillion individual cells and thousands of cell types.
Each time a cell divides, a mutation occurs, the change is passed on to the daughter cell, which divides again, possibly acquiring a second mutation, and both are passed on to the daughter cell. Mutations act as a kind of barcode that can be detected by genome sequencing machines. Scientists can trace these mutations in reverse order to build cell lineages, they say.
The quantitative fate mapping program has two parts. One, a computer program called Phylotime, reads cellular mutations as barcodes and infers the timescales associated with cell division. The name phylotime stands for phylogenetic reconstruction using the possibilities of time. In biology, phylogeny describes and depicts lineages of evolutionary development. His second part, developed by a team at Johns Hopkins University, is a computer algorithm called ICE-FASE that creates a model of the cell hierarchy and lineage within an organism based on the timescale of cell division.
To test the computer model, the Johns Hopkins team induced mutations at specific locations and random times in the genome of human induced pluripotent cells (iPSCs). Such iPSCs give rise to nearly every cell in the human body. They cultured the cells and caused them to divide according to the original mutation and subsequent spontaneous mutations in daughter cells.
At the end of the experiment, the researchers performed genome sequencing on the final group of daughter cells and entered the discovered mutations into a computer model.
As a result, a kind of extended family tree was created from the original human iPSCs.
Researchers can build mature cell ancestors by comparing combinations of mutations, giving a much more accurate picture of how organisms developed. They tested the model in computer simulations of mouse cells and human iPSCs.
Kalhor says the new tool will help scientists compare the normal and disease states of organisms, including humans. “This tool could help show when and how cells deviate from their normal pathways, and could aid in the development of disease prevention tools and curative therapies,” he says. I will add.
So-called cell ‘fate maps’, developed by quantitative fate mapping tools, provide a history of cell fate decision events that occurred during the development of an organism, but unlike genome sequencing studies alone, the new tools are capable of determining fate decisions. Weixiang Fang, Ph.D., a postdoctoral fellow in the Department of Biomedical Engineering at Johns Hopkins University and lead author of the study, said:
Computer models can construct when and how cells develop within an organism, but they cannot determine whether spontaneous mutations occur due to external, internal, or random factors.
Fang and Kalhor made Phylotime freely available to other scientists and made it available online.
This research was supported by The Simmons Foundation, the National Institutes of Health, and the David and Lucille Packard Foundation.
Other scientists who contributed to the study include Dr. Hongkai Ji, Claire Bell, Abel Sapirstein, Soichiro Asami, and Kathleen Leeper, professors of biostatistics at the Johns Hopkins Bloomberg School of Public Health who co-directed the study. will be Donald Zack from Johns Hopkins.
Fang, W., and others. (2022) Quantitative fate mapping: a general framework for analyzing progenitor cell state dynamics via retrospective lineage barcoding. cell. doi.org/10.1016/j.cell.2022.10.028.