Faculty Spotlight: Sheereen Majd Studies the Gatekeepers of the Cell
Every cell in our body has a cellular membrane that keeps the inside of the cell separated from the outside. The membrane is made up of fatty material called lipids, one end of which is attracted to water and the other end of which is repelled by water. Two rows of lipids with their water-loving heads facing both out toward the external world and in toward the cell and their water-hating tails facing each other make up the cellular membrane. These same types of membranes wrap around all mammalian cells.
“Membranes are interesting because they not only define the shape of the cell, like a sack that keeps everything within the sack together, but they are also like gatekeepers that control tightly what comes in and goes out of the cell,” says Sheereen Majd, who is an assistant professor of biomedical engineering whose group is studying the complex structure of cellular membranes.
Studded throughout the membrane like raisins in a croissant are proteins that are critical to the functioning of the cell. Some of the proteins act as gates, others as sensors, and through these proteins, cells signal to each other and the surrounding support system called the extracellular matrix. Majd and her students build cell-mimicking liposome vesicles that are spherical capsules with water on the inside and outside with a membrane made of lipids and proteins. Their size and composition closely resemble actual cell membranes.
“We started from something very simplistic, just the lipid, but we are trying to make it more and more complex,” she says. “As we throw in proteins, it becomes a more realistic model.”
Majd’s group focuses on a very important group of proteins called multi-drug resistant transporters. These proteins, which sit on the cell’s membrane, are involved with the drug resistance that develops in cells of cancer patients being treated with chemotherapy. Although these proteins are typically found in cells, in cancer cells they are overexpressed, there are many more of them. Their role is to pump out anything that they identify as not belonging inside the cell. As the concentration of the chemo inside the cell is reduced, the cell becomes resistant, and even the most effective chemotherapy won’t kill the cell.
The way that the proteins can recognize the alien chemo molecule, along with a wide range of other drugs that are not even structurally similar, remains something of a mystery. In order to help understand the process, Majd’s group uses micro- and nanofabrication techniques to make platforms on which they study these proteins at a level that was not possible before, that is, the single protein level. At the level of one or a few proteins, they hope to gain information that otherwise would be averaged out over multiple dissimilar proteins.
Multi-drug resistant transporter proteins, and one in particular called p-glycoprotein, or Pgp, are major obstacles to cancer treatment. Pgp has become a necessary step in testing potential cancer drugs, and the FDA requires testing all drugs against this protein to determine whether it will pump the drugs back out of the cell or not. The normal way of doing tests, which involves traditional assays using lots of cells with the protein in their membrane and seeing whether or not they survive, is time consuming, labor intensive, and costly, Majd says.
“We hope to be able to replace that system with a much simpler model system that mimics the cell membrane very well in an environment similar to the cell environment,” she says.
Finding some way to inhibit Pgp and other proteins won’t be an easy matter. For one thing, these proteins are important in protecting the nervous system. She hopes to find a way to fine-tune the physiological function of the protein in cancer cells, without damaging healthy cells. Also, the proteins are hard to handle. She is collaborating with Frances Sharom, a molecular biologist at University of Guelph in Canada, to provide Majd with highly purified proteins to incorporate into vesicles. Majd’s Penn State collaborators on this project include Peter Butler in biomedical engineering and Manish Kumar in chemical engineering.
Membrane drug delivery and hydrogel stamping
In addition, Majd’s group is developing nanoparticle drug delivery systems based on the same components as their cell membranes but loaded with toxic drugs. In this project, she and several of her students are working with James Connor, a Penn State neurosurgeon, with support from a Woodward Award. Their target is a deadly brain cancer called a glioblastoma. While there are many groups working on drug delivery systems for cancer, using membranes to target brain cancers is relatively new.
“It’s exciting to work with neurosurgeons, and if I’m making something that is useful to them, I see that as progress,” she says. A third collaboration is with Mohammad Abidian, also in biomedical engineering, in which she is using soft lithography to create surfaces functionalized by biomolecules on conductive polymers and using gradients to control the growth of cells. Abidian is using her substrates to guide neuron growth. “We’re using some relatively novel tricks and tweaks in hydrogel stamping to create the substrate,” she says. They use a novel approach for patterning conductive polymer film using a hydrogel stamp to deposit multiple bioactive molecules in precise patterns using a one-step process.
A little background
“I grew up in Tehran, Iran, and went to Amir Kabir Institute of Technology in mechanical engineering. I got interested in mechanical engineering because I was good in math and physics. When I was younger, I watched my older brother, who was in university studying electrical engineering, solving problems, and that excited me. I wanted to solve math and physics problems too. And while I loved studying dynamics, in the end I became more interested in working on health-related issues,” she says.
Arriving in the U.S. in 2003, she switched gears in order to study biomedical engineering at the University of Michigan, where she earned her Ph.D. and did a short post-doc. “That was the most exciting turn for me. I used a lot of the analytical skills from my rigorous mechanical engineering training and applied them to a more health-related field.”
Asked if STEM education is encouraged in Iran, Majd lights up. “I’m really pleased with the number of women in STEM fields in Iran. We have a national exam for university entrance each year. The past few years you will see more and more females in the top rankings, and they will end up in the top public universities. I believe that today more than 60 percent of university students are women. It is an exciting time in Iran.” Although the schools are highly competitive, once students gain entrance, their four year education is completely paid for, she adds. Majd joined Penn State in 2011as assistant professor in the Department of Biomedical Engineering. In 2012, she also joined the Department of Engineering Science and Mechanics.
Hers is a diverse group, with several undergrads in various departments, including biomedical engineering, chemical engineering, mechanical engineering, physics, and biochemistry and molecular biology. Her graduate students are all from biomedical engineering. In group meetings, she has noted, questions that arise that are outside of one student’s field are often background knowledge for another student. The diversity extends to their nationalities -- Korean, Chinese, and American, with a near equal distribution of males and females.
“One thing that I really like about my group is that they have a very good relationship, and support one another,” Majd says, noting that during her recent maternity leave this support kept the group functioning in her absence.
“I try to give my group a lot of space in their research,” she says. “I do guide them and advise them in what direction to take or in how to design their experiments, but I try to give them space to struggle with their challenges, come up with their own solutions, and only give them feedback after they have thought the issues through. I tell them I don’t care how many hours you put in, I want to see you are making progress and learning.”
With her students, Majd hosted a biomedical engineering workshop in her lab this past February for about 70 female middle school students who were interested in exploring STEM careers. To see photos of the workshop and learn more about her research, visit the Majd Research Group website at bioe.psu.edu/labs/Majd-lab.
Majd’s funding is provided by The Pittsburg Foundation, Grace Woodward Grants, the Materials Research Institute, and the College of Engineering. Contact her at email@example.com.