The adult human body is composed of trillions of cells that all originated from a single fertilized egg cell. In the adult, most tissues are in a state of constant flux, where old cells die and new cells are created from resident populations of stem cells, changing their identities in mysterious ways. The fluidity of change among cell populations initiate from the moment we are conceived- to our final breath of life. Multicellular life dances t the music of a highly ordered process, directed by a score that is not well understood. Disease such as cancer emerges when cells lose their directions, and divide in an uncontrolled manner, losing their identities. Other diseases are hallmarked by a loss of cells, triggered by unwanted self-elimination such as apoptosis or autoimmunity. One of the greatest struggles in biology is to understand these fundamental processes, at the cellular and molecular level. Our idea is to develop a new tool that will help us track the ancestry of individual cells, using a novel DNA barcoding technology. This proposal describes a new approach for tracking the evolutionary history of individual cells- at the most possible granular level, the individual cells. We take advantage of new technologies (deep sequencing and programmable DNA binding enzymes), combining them in a way to create a single cell lineage tracer in which each cell writes its own unique barcode. This system is comprised of a molecular 'typewriter'that types a unique barcode every time a cell goes into cell cycle. Moreover, this written barcode accumulates with each future generation. Our vision is to introduce this system into fertlized zygotes, were mouse lines will be developed. In essence every cell in the mouse will contain a unique barcode, and each barcode would contain information on its ancestral lineage, tracing back to the initial fertilized zygote. We believe that developing a quantitative approach for defining single cell inheritance lineages will transform how the next generation of developmental and disease biologists approach their problems.

Public Health Relevance

The adult human body is composed of trillions of cells that all originated from a single fertilized egg cell. In the adult, most tissues are in a state of constant flux, where old cells die and new cells are created from resident populations of stem cells. Multicellular life dances to the music of a highly ordered process, directed by a score that is not well understood. The goal of this proposal is to develop a transformative technology for tracking individual cells in the whole organism, and we expect to shed insight into fundamental developmental processes and in diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA195770-01
Application #
8755105
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Knowlton, John R
Project Start
2014-09-23
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$395,313
Indirect Cost
$125,679
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143