Discovering new and improved cancer therapies is one of the major ambitions for researchers coming from a variety of scientific backgrounds. The disciplines involved that will most likely come to mind are medicine, biology, chemistry, and pharmacology--but cancer drug design can also provide a challenging dissertation topic for a student majoring in physics.
In my case it was not at all the field I had originally envisioned myself working in. I started graduate school with a much more traditional view on what kinds of problems are interesting and appropriate for physicists. I studied the highly mathematical and abstract world of elementary particles--and grew very frustrated with it. Then I learned about an opportunity to work with an interdisciplinary team on the ambitious task to develop a new form of chemotherapy. I was immediately interested and eager to acquire a new set of skills.
A deep feeling of satisfaction
Being part of cutting-edge research in drug design gives me a deep feeling of satisfaction that was missing from my previous work. Some of the aspects I like most are the interdisciplinary approach, team work, the real-life application, and being in an innovative field learning valuable job skills. It gives me a chance to get involved in biologic nanotechnology, an exciting, rapidly advancing field that combines many formerly disconnected branches of science.
The big picture behind my thesis research is the design and characterization of nanoparticles that function as targeted anticancer drugs. Conventional chemotherapeutics consist of drugs that kill or arrest uncontrolled cell growth thus killing the tumor. However, healthy cells with similar growth patterns are also affected during this treatment, thus hair and weight loss. Such severe side effects can be avoided by targeting the drug specifically to certain receptors overexpressed on the surface of cancerous cells.
This is achieved by linking the drug to a transport vehicle consisting of a dendritic polymer, or dendrimer. These branched polymers are spherical, several nanometers in diameter, and provide a large number of functional sites on the molecule's surface. Each of these sites can be used to attach other biologically active molecules to the dendrimer, such as the drug, cancer-specific antibodies, or similar targeting compounds. The resulting multifunctional nanodevice acts like a Trojan horse that selectively binds to tumor cells and kills them once it is internalized. Normal cells, without the targeted receptor, remain unharmed. In addition to transporting a drug inside the cell, the dendrimers can be equipped with several other functions for imaging, diagnostic, or therapeutic purposes.1-4
So how do my skills help to advance this project? The material covered in my coursework as part of the general physics curriculum did not explicitly address biological systems. Looking back now I regret not exploring the recent successes of biological physics earlier in my career. I think this type of work suits my skills very well, but at the time I was not aware of the possibilities for physicists in the life sciences.
During my education a lot of emphasis was placed on analytical problem solving skills as well as the mathematical formalism used to describe the world of submicroscopic systems. As a result, the natural instinct of physicists is to always look for the underlying principle behind natural phenomena and to construct simple models that capture the essential feature of a more complex system. This is a highly transferable skill, useful in many different research areas.
In the case of our proposed "smart drug," designed by a novel process of molecular engineering, it is not sufficient to just confirm efficacy. The therapeutic device also has to be accurately characterized and its mechanism of action documented. In fact, this is essential for eventual Food and Drug Administration approval for the new drug. Not surprisingly, many analytical tools commonly employed in drug design are based on discoveries in the physical sciences. Specifically, they include powerful imaging techniques that have helped in the recent dramatic progress in the life sciences.
One of these, routinely used in our work, is atomic force microscopy which allows us to image and manipulate single molecules, cells, and membranes. In addition to mastering these experimental techniques, my physics and mathematics background is useful for developing numerical methods describing the structure and function of biomolecules. Increased computing power and new parallel algorithms have made computer simulations important parts of drug design.
Obviously, I initially had very little knowledge of cell biology and biochemistry. So at first the amount of new material I had to learn in order to succeed with this project seemed overwhelming. For this reason good teamwork between the various subgroups of our collaboration is essential. Every member brings in his or her expertise. Whenever I have a question about chemistry or biology I always have a person I can talk to who is willing to help me. This creates a unique environment for students that forces us to think outside of our original discipline.
Strong funding base and multidisciplinary cooperation
Graduate students on the cancer project were fortunate to have a strong base of funding over the course of their thesis research, and thus they did not have to rely on teaching jobs for financial support. In my case the major source of funding comes from a grant by the Unconventional Innovations Program (UIP) from the National Cancer Institute. The purpose of this program is to "stimulate development of radically new technologies in cancer treatment." Only a few awards are granted every year to selected institutions.
At the University of Michigan, James Baker, professor of internal medicine and director of the Center for Biologic Nanotechnology, received an award for the proposal to use dendrimers to design targeted anticancer drugs in 1999 and 2002. We believe having all of the required disciplines represented and in close proximity helped the Center for Biologic Nanotechnology win that award. This is necessary to perform all the tasks involved in developing the smart anticancer drugs and documenting their function. These tasks include synthetic chemistry, cell culture and toxicology studies, analytical and imaging technologies, even animal testing.
Obviously, in a large multidisciplinary collaboration good communications skills are a must. The research would not be possible without effective interaction between subgroups and access to each other's labs. We take turns presenting recent results at weekly meetings so that everyone in the group is kept up to date. Once a year we host the UIP contact person to go over the progress made during the entire year.
One thing to keep in mind at these meetings is that the audience represents a wide variety of disciplines. The main challenge therefore is to find a common language to talk about your data and the conclusions that can be drawn from it. Some of your audience members will never have performed a Michael addition reaction or memorized the caspase 3 pathway of cell death. Others might not be aware of the significance of the point spread function of an imaging system or the Verlet integration algorithm.
This challenge extends beyond our own group. It is often harder to find the proper journal for a publication, or the right session at conferences to present interdisciplinary work. Scientists are not always willing to accept contributions outside of the established views of their own community. Hopefully, the pace of new breakthrough discoveries will rapidly change this situation.
To foster such research it is becoming more common for educational institutions to offer special academic curricula, such as the Applied Physics Program at Michigan, nanotechnology, biomedical sciences, biophysics, biochemical engineering, etc., aimed at a career in the life sciences. This offers students the possibility to explore research related to drug discovery from many different angles.
R. Langer, Science 293, 58 (2001) J. R. Baker Jr., A. Quintana, L. Piehler, M. M. Banaszak Holl, D. A. Tomalia, and E. Raczka, Biomed. Microdevices 3(1), 61 (2001) A. K. Patri, I.J. Majoros, and J. R. Baker Jr., Curr. Opin. Chem. Biol. 6, 466 (2002) A. Quintana, E. Raczka, L. Piehler, I. Lee, A. Myc, I. Majoros, K. Patri, T. Thomas, J. Mule, and J. R. Baker Jr., Pharmaceutical Research 19(9), 1310-1316 (2002)
R. Langer, Science 293, 58 (2001)
J. R. Baker Jr., A. Quintana, L. Piehler, M. M. Banaszak Holl, D. A. Tomalia, and E. Raczka, Biomed. Microdevices 3(1), 61 (2001)
A. K. Patri, I.J. Majoros, and J. R. Baker Jr., Curr. Opin. Chem. Biol. 6, 466 (2002)
A. Quintana, E. Raczka, L. Piehler, I. Lee, A. Myc, I. Majoros, K. Patri, T. Thomas, J. Mule, and J. R. Baker Jr., Pharmaceutical Research 19(9), 1310-1316 (2002)
Almut Mecke is a Ph.D. candidate and Next Wave campus representative at the University of Michigan.