How Stem Cells Make "Career" Choices

Elucidating how a single “naïve” cell at the beginning of development can ultimately give rise to an entire human comprising trillions of cells and over 200 functionally distinct cell types is one of the most fascinating pursuits in biology. This question has been contemplated since at least the mid-17th century when advances in microscopy led scientists to propose the “Cell Theory.” This theory is one of the key foundations of modern biology and posits that the cell is the basic unit of living organisms, that individual cells comprise all of the characteristics necessary for life, and that all cells come from the division of other cells. We now know that only four chemical units comprise DNA and that combinations of these are precisely arranged in a sequence along the DNA to form a genetic code, which represents the master blueprint of the cell. Every cell in the body holds an identical copy of these instructions, so how does a cell know what to become or how to perform specialized functions? Remarkably, our cellular machinery can selectively read these instructions to find the information that allows a heart cell to contract or a brain cell to send messages to the rest of your body.

Technological advances in genome sequencing have revolutionized modern biology and have helped us to understand how our genetic code (a.k.a. genome) can specify the diversity of cell types in the body. Current estimates indicate that the human genome contains ~30,000 protein-coding genes. However, the central dogma that a gene codes for a protein through an RNA intermediate has been challenged, and there is substantial evidence that not all genes code for proteins and that RNA itself carries important information for regulating the behavior and function of the cell. Thus, the genome produces many different types of messages, and we are only beginning to understand how to interpret this information. Genome sequencing has given investigators the syntax to begin to understand the language spelled out within the genetic code. These efforts have revealed many new insights into evolution and disease, but genome sequencing has also revealed that our DNA holds many more secrets. For example, the vast majority of DNA sequences in the human genome (~97%) have unknown functions and have often been referred to as “junk” DNA. Emerging evidence indicates that these sequences in fact have important roles and that there is a wealth of information yet to be discovered within this portion of the genome.

The problem of how cell fate is determined during development becomes even more complex to solve because there is an additional layer of information on top of the genetic code. For example, DNA is packaged within the cell by special proteins to form structures called chromatin. This packaging can have a profound impact on the cell’s ability to perform specific functions. The DNA in every cell type is packaged differently, resulting in a unique topographical landscape or chromatin map. Moreover, each map has key features or landmarks that direct the cellular machinery to read only the messages in the genome that are necessary to perform that cell’s function. Thus, understanding human development requires detailed knowledge of the entire set of instructions as well as knowledge of how the cellular machinery reads and interprets this code.

I am enormously fascinated by how cell identity is established, and research in my lab focuses on elucidating the molecular underpinnings that govern cellular decision-making during mammalian development. In particular, we are constructing maps of early development to help us navigate this question. To this end, we use Embryonic Stem Cells (ESCs) to generate these maps and to identify the key landmarks that control how the cell knows when a gene should be turned “on” or “off.” ESCs represent early developmental stage cells because, similar to the early embryo, these cells do not carry out specific functions, yet they have the capacity to become any specialized cell type in the body. Thus, ESCs are an extremely important system to decipher how a cell early in development decides what mature cell type to become in the adult. This is also why ESCs have tremendous potential for disease research and for the replacement of damaged or ageing cells.

Our recent work has demonstrated that many of the fundamentals of how cell identity is established during development can be discovered in ESCs. For example, in regions of the genome that previously had no known function, we have discovered key landmarks that control cellular messages that are critical for directing an ESC to become a functional cell.

We are also working to understand how the messages that are produced in ESCs differ from mature cell types and how this information can be further organized into gene networks or cellular circuits. For simplicity, each message (or expressed gene) can be compared to a particular word, and the network would thus represent the collection of words that make up a meaningful sentence. These gene networks carry the information for directing the function of that cell. Our analysis of gene networks in ESCs (and what regulates the expression of the genes in the network) has revealed important clues about how early embryonic cells can respond to developmental signals by re-wiring the network to direct cell fate. Thus, the core circuitry in ESCs represents the founding program for all development. Gene networks also help us to understand how mutations in a single gene can lead to a communication breakdown within a cell or between cells.

This is particularly important because developmental failure as well as diseases such as cancer can result from inappropriate propagation of cellular messages. It is our ultimate goal to exploit our growing knowledge of how landscapes and gene networks are organized to coax stem cells to become specialized cell types for therapy or to correct faulty wiring within a diseased cell.

I consider myself to be a life-long student of biology, as do most scientists with regard to their particular discipline. The opportunity to perform research in the Department of Biology and to be part of the broader scientific community at MIT is one of the most brilliant opportunities that I could ever imagine. The MIT School of Sciences fosters an environment where passion, commitment, and ingenuity can lead to unimaginable discoveries that have the potential to impact future generations. Thus, I believe that it is important to engage students at an early age and to introduce a modern view of science as well as career possibilities into the curriculum at all levels to promote the next generation of scientists.
 

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Elizabeth Chadis

Assistant Dean for Development
t: 617-253-8903
e: ECHADIS@MIT.EDU