Gary Brubaker, director of the Guildhall, Corey Clark, Guildhall deputy director for research, and John Wise, associate professor of biological sciences, gathered in Plano for a special Facebook Live event on Sept. 28, 2017. Watch their discussion of how their partnership has turned the popular game Minecraft into a vehicle for cancer research – and effectively doubled the computing power available for this work.
The massive computational power of an online gaming community has even more clout than supercomputers in the fight against cancer, according to SMU biochemical researchers and video game developers. The two groups are partnering with the world’s vast network of gamers in hopes of discovering a new cancer-fighting drug.
With 122 million copies of the game sold worldwide and more than 55 million active players each month as of February 2017, Vogel and Wise expect deep inroads in their quest to narrow the search for chemical compounds that improve the effectiveness of chemotherapy drugs.
“Crowdsourcing as well as computational power may help us narrow down our search and give us better chances at selecting a drug that will be successful,” said Vogel. “And gamers can take pride in knowing they’ve helped find answers to an important medical problem.”
Up to now, Wise and Vogel have tapped the high-performance computing power of SMU’s Maneframe, one of the most powerful academic supercomputers in the nation. With ManeFrame, Wise and Vogel have sorted through millions of compounds that have the potential to work. Now, the biochemists say, it’s time to take that research to the next level — crowdsourced computing.
A network of gamers can crunch massive amounts of data during routine gameplay by pairing two powerful weapons: the best of human intuition combined with the massive computing power of networked gaming machine processors.
Taking their research to the gaming community will more than double the amount of machine processing power attacking their research problem.
“With the distributed computing of the actual game clients, we can theoretically have much more computing power than even the supercomputer here at SMU,” said Clark, who is also an adjunct research associate professor in the Department of Biological Sciences. In March, SMU Guildhall was named No. 1 among the world’s Top 25 Graduate Schools for Video Game Design by The Princeton Review.
“If we take a small percentage of the computing power from 25,000 gamers playing our mod we can match ManeFrame’s 120 teraflops of processing power,” Clark said. “Integrating with the Minecraft community should allow us to double the computing power of that supercomputer.”
Even more importantly, the gaming community adds another important component — human intuition.
Wise believes there’s a lot of brainpower eager to be tapped in the gaming community. And human brains, when tackling a problem or faced with a challenge, can make creative and intuitive leaps that machines can’t.
“What if we learn things that we never would have learned any other way? And even if it doesn’t work it’s still a good idea and the kids will still get their endorphin kicks playing the game,” Wise said. “It also raises awareness of the research. Gamers will be saying ‘Mom, don’t tell me to go to bed, I’m doing scientific research.’”
Under two previous NCI grants, Harrod’s lab discovered that the human T-cell leukemia virus type-1, HTLV-1, and high-risk subtype human papillomaviruses, HPVs, share a common mechanism that plays a key role in allowing cancers to develop. Now the lab will search for the biological mechanism — a molecular target — to intervene to block establishment and progression of virus-induced cancers. The hope is to ultimately develop a chemotherapy drug to block the growth of those tumor cells in patients.
“The general theme of our lab is understanding the key molecular events involved in how the viruses allow cancer to develop,” said Harrod, an associate professor in SMU’s Department of Biological Sciences whose research focuses on understanding the molecular basis of viral initiation of cancer formation.
While HTLV-1 and HPV are unrelated transforming viruses and lead to very different types of cancers, they’ve evolved a similar mechanism to cooperate with genes that cause cancer in different cell types. The lab discovered that the two viruses tap a common protein that cooperates with cellular genes to help the viruses hide from the immune system.
That common protein, the p30 protein of HTLV-1, binds to a different protein in the cell, p53, which normally has the job of suppressing cancerous growth or tumor development. Instead, however, p30 manages to subvert p53’s tumor suppressor functions, which in turn activates pro-survival pathways for the virus.
From there, the virus can hide inside the infected cell for two to three decades while evading host immune-surveillance pathways. As the cell divides, the virus divides and replicates. Then ultimately the deregulation of gene expression by viral encoded products causes cancer to develop.
“They are essentially using a similar mechanism, p30, to deregulate those pathways from their normal tumor-suppressing function,” Harrod said.
Drugs important in the battle against cancer behaved according to predictions when tested in a computer-generated model of P-glycoprotein, one of the cell’s key molecular pumps.
The new model allows researchers to dock nearly any drug in the P-gp protein and see how it will actually behave in P-gp’s pump, said Associate Professor John G. Wise, lead author on the journal article announcing the advancement and a faculty member in SMU’s Department of Biological Sciences, Dedman College of Humanities and Sciences.
SMU biologists developed the computer generated model to overcome the problem of relying on only static images for the structure of P-gp. The protein is the cellular pump that protects cells by pumping out toxins.
But that’s a problem when P-gp targets chemotherapy drugs as toxic, preventing chemo from killing cancer cells. Scientists are searching for ways to inhibit P-gp’s pumping action.
“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”
The SMU researchers tested Tariquidar, a new P-gp inhibitor still in clinical trials. Inhibitors offer hope for stopping P-gp’s rejection of chemotherapeutics by stalling the protein’s pumping action. Pharmacology researchers disagree, however, on where exactly Tariquidar binds in P-gp.
When run through the SMU model, Tariquidar behaved as expected: It wasn’t effectively pumped from the cell and the researchers observed that it prefers to bind high in the protein.
“Now we have more details on how Tariquidar inhibits P-gp, where it inhibits and what it’s actually binding to,” Wise said.
D’Mello comes to SMU from the University of Texas at Dallas, where he was a professor in the Department of Molecular and Cell Biology. He is a longtime partner in research with SMU Professor of Chemistry Edward Biehl.
In December 2010, D’Mello and Biehl published in The Journal of Neuroscience Research their discovery of a family of small molecules that shows promise in protecting brain cells against nerve-degenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s.
“Professor D’Mello brings broad experience and an excellent record as a researcher and teacher to SMU,” said Dedman College Dean Bill Tsutsui. “His focus on building meaningful collaborations and his ambitious vision for the future of the Department of Biological Sciences impressed all of us on campus.”
D’Mello received his Ph.D. in biology from the University of Pittsburgh in 1989 and joined the faculty at UTD in 1998. Funding for his research has included support from the National Institutes of Health, the U.S. Department of Defense, the National Science Foundation and the Whitehall Foundation.
“Neurodegenerative diseases, which include Alzheimer’s disease, Parkinson’s disease, ALS, and Huntington’s disease, are characterized by the slow but relentless loss of brain cells,” D’Mello said. “There are no effective drugs or other therapeutic approaches to treat or prevent these progressive and fatal diseases. The goal of my lab is to understand neurodegeneration at the molecular level so that effective therapies can be developed.”
D’Mello said he was drawn to SMU because of the University’s strengths in several areas of the arts, humanities, and sciences. “I was particularly attracted by the collegial and talented faculty in the biology department, their keen interest in solving important biological problems, and their strong commitment to the teaching and training of students,” D’Mello said.
“I am honored to be named Chair of the Department of Biological Sciences and am very excited about the opportunity,” D’Mello said. “I look forward to working with the faculty, staff and students to build a strong multidisciplinary and collaborative research department with cutting-edge research performed by bright, talented, and motivated undergraduates, graduate students, and postdoctoral fellows.”
SMU biologists Pia Vogel and John Wise are using the computational power of the University’s high-performance supercomputer to screen millions of drug compounds, in search of one that will aid in the fight against recurring cancer.
Both teach in SMU’s Department of Biological Sciences: Vogel is an associate professor and director of SMU’s Center for Drug Discovery, Design and Delivery; Wise is a research associate professor.
Together, they are seeking a compound that can be developed into a drug that re-enables chemotherapy when cancer recurs and chemotherapy appears no longer effective.
In an interview for the SMU Research blog, Vogel and Wise discuss their quest, made possible by the massive computational power supplied by supercomputers — a technique not possible even a decade ago.
Q: You’re searching for a cancer drug that provides hope for chemotherapy failure? Vogel: Yes. Since the 1970s it’s been known that a sort of sump pump, the protein called P-glycoprotein, is most likely responsible for the failure of many chemotherapies — the drug is being pumped out of cancer cells by this sump pump that occurs naturally within all cells, even cancer cells.
Q: Tell us about P-glycoprotein.
Wise: This particular protein is one of nature’s great solutions to the problem of getting toxic things out of the cell. When a toxic substance enters a cell, the protein pumps it out.
This process may become a problem, however, once a cancer patient has been treated with chemotherapy, and appears to be cured. If the cancer later returns, the cancer cells may express more P-glycoprotein than cells normally would. For that reason, chemotherapy is no longer effective because the protein considers it a “toxin” and pumps it out of the cells before the chemotherapy can destroy the cancerous cell.
Theoretically, if we can knock out the sump-pump proteins, then all those cancer chemotherapies that don’t work anymore, will work again.
Q: How does the sump pump work?
Wise: P-glycoprotein has a generic binding site for drugs. When the drug binds, that activates the part of the protein that uses the energy in ATP energy molecules by breaking the ATP down. This release of energy from ATP then moves the drug from one side of the protein to the other. It turns out that the “other side” of the protein is on the outside of the cell, so the drug has just been pumped out of the cell. The process takes only a fraction of a second and moves the drug from inside the cell, where it would kill the cancerous cell, to the outside where it is essentially harmless to the cancer.
So nature’s kind of outfoxing us here, because the pump has this beautiful generic toxin-binding site that allows the cells to survive. The downside is in cancer chemotherapy. Here the “toxin” is actually the drug we are hoping will kill the cancer and it will also be pumped out. So what we are doing is we’re looking for drugs that will temporarily inhibit the pump. What we’re hoping for is a new drug that stops the sump pump in the cancer cell so that the cancer chemotherapy can remain in the cell so it can kill the cancer.
Q: Tell us about the search.
Wise: Everything that lives has a version of this type of protein. So there are evolutionary connections between bacterial versions of this protein and the human versions. They all seem to work the same way, and are close in structure and function.
No one has actually determined the structure of the human P-glycoprotein directly. We don’t know what it looks like. Relying on these evolutionary relationships and with our understanding of how proteins are put together, I’ve deduced a structure of the human protein. We then use computer programs to model the protein in a way that brings the static picture of the human pump to life in the computer.
This is a very different tack than has been used historically in the field of protein structure biochemistry. Historically, proteins are very often viewed as static images, even though we know that in reality these proteins move and are dynamic.
Using simulation software (Forcefield Molecular Dynamics, a freely downloadable software developed by researchers at the University of Illinois), we can physically build these molecules in the computer, in silico, and computationally we can model a variety of conditions: We can raise the temperature to 37 degrees centigrade, we can have the right pH, the right salts and all the right conditions, just like in a wet lab experiment. We can watch them thermally move and we can watch them relax.
The software is good enough that the model will relax and move according to the laws of physics and biochemistry. In this way we can see how these compounds interact with the protein in a dynamic way, not just in a snapshot way.
Q: How many screenings have you carried out on the supercomputer?
Wise: So far we’ve run about 8.8 million computational hours since August 2009, and screened roughly 8 million drugs. We are currently screening about 50,000 drugs per day on SMU’s High Performance Computer.
Vogel: We found a couple hundred compounds that were interesting, and so far we chose about 30 of those to screen in the lab. From those, we found a handful of compounds that do inhibit the protein. So we were very thrilled about that. Now we’re going back into the models that John has created and we’re looking for other compounds that might be able to throw a stick in the pump’s mechanism. We’re going at it in a selective way, so we don’t waste money with huge high-throughput screening assays in the lab.
Q: What have you learned so far?
Wise: This has been a good proof-of-principle. We’ve seen that running the compounds through the computational model is an effective way to rapidly and economically screen massive numbers of compounds to find a small number that can then be tested in the wet lab.
Q: Why is this kind of research possible now?
Wise: There have been huge increases in computational power in recent years. Ten years ago you couldn’t dock 8 million drugs — there just wasn’t enough computational power. Now SMU owns enough to do that.