Galileo and his team track these cells with time-lapse microscope images.
They grow a single layer of cells in a dish, then wipe away part of
them, leaving an edge. They take images of that edge every five or 10
minutes over a 24-hour period and track the cells along that edge to see
where they have migrated. They measure the cells' velocity and pathways
and manipulate the L1 protein to see how increases and decreases affect
They have shown that restraint of the L1 protein reduces both the speed and the rate of cell division.
Galileo is working now to learn more about the interaction of
glioblastoma stem cells and L1, create experimental tumors and determine
how various modifications change cell behavior.
The computer model uses freely available software called NetLogo,
which in this case takes biological rules and integrates them with
glioblastoma cell data gathered in Galileo's lab. The program looks at
each cell as a separate agent and accounts for random or stochastic
behaviors that biological systems often exhibit.
It does not account for every conceivable biological possibility,
however, and is - at this two-dimensional stage - a fairly simple
representation. There are plans to advance to a three-dimensional model
using NetLogo 3D.
"We are not interested in stopping cells in a dish, but in a brain,"
Galileo said. "The next step is to go into a somewhat three-dimensional
brain slice model and ultimately we want to model the total
three-dimensional behavior of how cells move around. But we have to
start simply and that's how we'll progress this model."
As the research advances, the models will improve accordingly.
"The model is determined by assumptions," Dhurjati said. "We're trying to simplify it so we can still work with it."
Assumptions have significant impact on the results shown by any given model.
"Tens of thousands of models predicted Hillary Clinton would win the
election in 2016," Dhurjati said. "Each model had a different
assumption. But who the agitated, unhappy, motivated-to-vote people were
was not part of the modeling assumption of the models that failed."
This model lends itself to changes in assumptions, percentages, rates
and other values. Researchers can make adjustments to immediately see
what impact those and other changes have on cell behavior.
Justin Caccavale, a senior engineering major from Long Island, New York, got involved
after listening to a guest lecture Dhurjati delivered to a
pharmacokinetics class he was taking at UD. Pharmacokinetics is the
study of how drugs and other substances move through the body and what
happens to them along the way.
"He was full of this energy and so passionate about this work he was doing," Caccavale said. "I wanted to help."
He met with Dhurjati for the first time during winter session in
early 2017 - not for academic credit or money but "for the betterment of
mankind, for the advancement of knowledge. I did it because I thought
it was cool."
"And at that meeting, Dr. Dhurjati said, 'We've got 10 minutes and
I'm going to teach you everything you need to know about modeling,’ "
Caccavale said with a smile. "I used the notes I took that day - on
little pieces of paper - throughout the project and I still use them
Building on a mathematical model produced by UD alumnus David "Jake"
Fiumara, Caccavale started meeting with Galileo to understand and add
the biological rules and data the model would need. It took a long time
to get things right.
"There was problem after problem," Caccavale said. "And every time
I'd meet with him about a problem two more would come up. How do you
address all that in code? I'm not a biologist, so I had a lot of
questions.... We were dedicated to making sure the biology makes sense
and we wanted to make sure every single calculation had a purpose."
As model development continued,
multiple revisions were needed. If the simulation wasn't making
biological sense, Caccavale said he would rip the math apart and rework
the code so that it was true to the science. His old Asus laptop bore
the brunt of this labor and eventually the screen separated from the
frame. It still worked, so he soldiered on.
"A lot of times a single line of code was missing," he said. "But
once a rule was missing and I had to go back to the beginning of the
cell cycle. I think I've addressed every single concern now."
There are other models out there, Caccavale said, but this one is
"agent-based," he said, "which means it simulates outcomes by simulating
each individual agent - each cell on its own."
The model can run a 24-hour cycle of cell life in about five minutes,
Caccavale said, and with a super computer more possibilities could be
Caccavale said he was inspired by the work and the passion both
professors invested in their work - and amused by their back-and-forth
bickering and teasing.
"They are both very gifted," he said. "And I don't even know how to explain their relationship."
Also contributing to the work and the article were Michael Stapf
(mathematical sciences), Liedeke Switzer (mathematical sciences), Hannah
Anderson (biological sciences) and Jonathan Gorky (Thomas Jefferson
About the researchers
Prasad Dhurjati is a professor of chemical and biomolecular
engineering, with joint appointments in mathematical sciences and
biological sciences. He has been on the UD faculty for 35 years and is a
past president of the Faculty Senate. He specializes in biotechnology,
systems biology and computer modeling of biological and engineering
systems. He is a prolific author, often cited, a fellow in the American
Institute of Medical and Biological Engineering and the 1986 winner of
the National Science Foundation Presidential Young Investigator Award.
He has served as a visiting scientist and visiting professor in France,
India and Canada. He earned his bachelor's degree at the Indian
Institute of Technology in Kanpur, India, and his doctorate at Purdue
Deni Galileo is a neurobiologist and associate professor in
the department of biological sciences, focusing on the study of
migrating cells during brain development and glioblastoma brain cancer.
He has been on the UD faculty for 17 years, is a past president of the
Faculty Senate and current president of the UD chapter of AAUP. He was
part of the early collaborations that joined Delaware State University
and the University of Delaware in a National Institutes of Health grant
that was recently renewed and has been a mentor to junior faculty and a
member of the Internal Advisory Committee. He earned his bachelor's
degree at New College of Florida, his doctorate at the University of
Florida College of Medicine and Whitney Laboratory and did postdoctoral
work at Washington University School of Medicine in St. Louis.
Article by Beth Miller; photos by Kathy F. Atkinson and Evan Krape