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Reetika Dutt, a doctoral student in biochemistry, works with petri dishes as part of Prof. Deni Galileo's research team.
brief chat at a Faculty Senate meeting put two University of Delaware
researchers onto an idea that could be of great value to cancer
The collaboration of Prof. Prasad Dhurjati, a chemical engineer who has done extensive computer modeling of biological and engineering systems, and Prof. Deni Galileo,
a neurobiologist whose expertise is in cell motion and behavior in the
brain, has produced a new and freely available computer program that
predicts cancer cell motion and spread with high accuracy.
An article on their model was recently published in BMC Systems Biology.
Galileo has been studying the
movement and spread of glioblastoma tumors - an aggressive and
devastating form of brain cancer that has claimed thousands of lives,
including those of Delaware Attorney General Beau Biden, U.S. Sen. Ted
Kennedy and two Phillies greats - pitcher Tug McGraw and catcher Darren
Daulton, to name just a few. U.S. Sen. John McCain was diagnosed with
this kind of cancer in 2017.
A significant challenge for physicians and their patients is that
this cancer spreads rapidly, reducing the effectiveness of surgery,
chemotherapy and radiation.
"You need at least 50,000 cells in one spot to pick it up in an MRI,
so surgeons can't see where small numbers of cells have invaded the
brain beyond the main tumor," Galileo said. "If you could stop the cells
from moving beyond that initial tumor, the surgeon could go in a second
time and take the second tumor out. As it is now, they can keep
spreading in every direction and it's a pretty hard problem to solve."
Galileo and his research team have been studying what triggers the
rapid spread of these cells - aiming to disrupt their aggressive advance
- and have demonstrated the significant role of a cell membrane protein
called L1CAM (L1 cell adhesion molecule). Ordinarily, this molecule
contributes to development of the nervous system, Galileo said. But it
acts differently in glioblastoma and other cancer cells, accelerating
their growth and spread.
Dhurjati and Galileo met at a meeting of the Faculty Senate,
which both have served as president. Dhurjati looked at Galileo's work
and realized it was a strong candidate for the kind of mathematical
modeling he does with biological systems. He has worked with specialists
in osteoporosis and the human gut microbiome - that stew of microbes
that live in the bellies of humans and animals - and has helped
researchers simulate biological behavior to see predicted responses to
Galileo wasn't an easy sell, all involved agree. Biologists, in
general, don't have an easy relationship with mathematics, he said, and
mathematics is central to computer models.
But Dhurjati persuaded him to give it a go, and undergraduate
chemical engineering major and Honors degree candidate Justin Caccavale
worked with Galileo to add the biological rules to the mathematical
"Biological details put me to sleep," Dhurjati said with a grin.
"Mathematical equations put some biologists to sleep. But we all have
something to contribute.... I've been a missionary to bring modeling
into the world where people don't use models."
Together, with the help of undergraduate and graduate-level students,
they constructed a computer model of Glioblastoma cells that accurately
reflects what Galileo sees live cells doing under a microscope. And
that opens new opportunities for researchers.
"When your model represents real systems, you can play with the model
in ways you cannot play with a human brain," Dhurjati said.
Move this whole section up, swapping places with the section above it.
The computer model is based on the biological rules that
glioblastoma cells follow and can be used to simulate what those cells
would do under variable experimental conditions. That could help
researchers see which avenues are most promising for shutting the cancer
down. The model can also be adapted for other forms of cancer cells.
The simulation gives researchers
new ways to ask many different questions: What if we disrupted this
growth or motility signal? What if we added a chemotherapy drug here?
How would those changes play out?
"Is there a way through this molecule - L1CAM - to reduce the rate of spreading and the rate of growth?" Dhurjati said.
Possibly, Galileo said. When that molecule is restrained, the speed
and proliferation of these cells is reduced by up to 50 percent, he
said. More research is needed to understand this better.
"But he has convinced me that modeling has good value in
understanding how cells make decisions to be highly motile or
proliferative," Galileo said. "This really does simulate why they move
the way they do in a dish. They follow a simple set of rules.
"Biologists need to use more math and more modeling than what they
do." Galileo said. "If the only models that come out are scary because
of all the equations, they're never going to do that. If it's not too
hard to modify for their purposes, there's a much greater chance they
are going to adopt modeling as Prasad convinced me to do."
model is based on the biological rules that glioblastoma cells follow
and can be used to simulate what those cells would do under variable
experimental conditions. That could help researchers see which avenues
are most promising for shutting the cancer down. The model can also be
adapted for other forms of cancer cells.
This model can be adapted to help researchers looking at other
kinds of cells and is ideal for education purposes as biologists look
for tools to enhance and strengthen their research capabilities.
"A university is different than a cancer research lab," Dhurjati
said. "It's a place to train students, to solve problems, to have the
love of learning - and there's no better way to like a subject than to
actually do experiments. We're here not only to solve big problems but
to motivate students to solve problems on their own."
Galileo's research focuses on cell behavior in the brain. For his
research on glioblastoma tumors, he uses brain cancer stem cells removed
from patients during surgery through the Helen Graham Cancer Center and
Research Institute at Christiana Care. The cells are injected into
chicken embryos, where they grow from tumors, spread and reveal their
In normal brain cells, the protein
he has studied in this research - L1CAM - is produced and used in
healthy ways, promoting growth and development. But in these cancer
cells, some of the L1CAM is exaggerated and cut off from the cell
membrane. Fragments of L1 then attach to the same cell or to nearby
cells, triggering new signals among those cells and resulting in much
more aggressive multiplication and spread of the cancer cells.
Some cells move away from the main tumor - including glioblastoma
stem cells, which produce new tumors as the spread accelerates. Those
stem cells are the primary culprits in this cancer and the tumors they
produce are often more aggressive than the original tumor, Galileo said.
Profs. Prasad Dhurjati (left) and Deni Galileo examine a research poster.
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
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