By Madeleine Stone @themadstone

One of the great mysteries of biology is how the diverse cell types found in complex organisms emerge from the same underlying genetic code. The myriad types of cells that comprise the human body are a library of books, each with a different flashy cover but the exact same letters on each page. Embryonic stem cells diverge into wildly different functions as they mature, for example, bone-growing osteoblasts and heart-forming cardiomyocytes, but all have the same DNA sequence.

It’s the complex biochemical code on top of the DNA sequence, collectively known as the “epigenome,”that ultimately directs a cell’s fate and fascinates University of Pennsylvania bioengineer Jennifer Phillips-Cremins.

“You can think of the epigenome as additional information layered on top of DNA. The epigenome is what makes the letters on your book page come alive, assembling unique sentences that influence the book’s cover,” Phillips-Cremins says.

Phillips-Cremins, an assistant professor in the School of Engineering and Applied Science’s Department of Bioengineering and the Epigenetics Program in Penn’s Perelman School of Medicine, has just been named one of the three 2014 New York Stem Cell Foundation Robertson Stem Cell Investigators. The New York Stem Cell Foundation has granted Phillips-Cremins $1.5 million for the next five years to study how the three-dimensional organization of DNA within cells directs the development of the human brain.

In one sense, our DNA can be thought of as a long string of letters. Stretched out end to end, the epigenome would decorate this string as a series of ornaments at discrete distances from one another. But if that string was wound up, different parts of the epigenome would come into contact and interact, creating an additional layer of information, a “3-D epigenome.” This is what happens in human cells, where linear DNA is wound into tight spools that are in turn packaged into higher-order topological configurations.

“The classic approach is to study epigenetic modifications in the context of the linear DNA,” says Phillips-Cremins. “Our lab takes a different top-down approach in which we first map the 3-D folding of DNA in the nucleus and then use data mining principles to understand how epigenetic marks interact across long distances to regulate neuron differentiation and function during early brain development.”

Phillips-Cremins hopes this knowledge will one day allow scientists to engineer the epigenome in order to prevent or reverse neurological disorders such as Alzheimer’s or schizophrenia.

With an undergraduate degree in chemical engineering and a minor in math, Phillips-Cremins discovered she could apply her analytical skills to biological systems while studying biomedical engineering in grad school.

“As a young chemical engineer, I first became interested in biology when I learned about the fields of tissue and genetic engineering, where you could manipulate the genome of cells to change their function and then grow them on biomaterial scaffolds in a dish to make miniature 3-D organs,” she says. “Although we made progress in our efforts to create semi-functional tissues, I felt that more sophisticated spatiotemporal control would be required for the next big innovation. The nucleus was a black box to me at that point, so I pursued postdoc training on in epigenetics and genomics.”

In her lab at Penn, Phillips-Cremins has assembled a diverse cohort of scientists who use computational, molecular and cellular tools to better understand the mysteries of brain development.

“We are now poised to open that black box by leveraging the tremendous technological advances in DNA sequencing and our computational and engineering skills to find patterns in large epigenomic data sets.

“Bringing together talented people with diverse ways of thinking — engineers, computer scientists, biologists — is critical for tackling complex topics such as the link between 3-D epigenomics and neuron function,” she says.

NYSCF’s Robertson Stem Cell Investigator Award was created to support talented scientists as they make the transition from post-doctoral research to establishment of their own laboratories. The Investigator awards build off NYSCF’s Postdoctoral Fellowship Program, the largest program of postdoctoral support for stem cell researchers in the United States.

“NYSCF's support is of immense value at this critical early juncture in my career and is a testament to the fantastic environment here at Penn,” says Phillips-Cremins. “The award will empower the students in my lab to pursue high-risk, high reward ideas and potentially make some real breakthroughs that could benefit those who suffer from debilitating neurological disorders.”