Categories
Feature Health & Medicine Plants & Animals Researcher news

Study: Cells of three aggressive cancers annihilated by drug-like compounds that reverse chemo failure

Wet-lab experiments confirm the accuracy of an earlier computational discovery that three drug-like compounds successfully penetrate micro-tumors of advanced cancers to aid chemo in destroying the cancer.

Researchers at Southern Methodist University have discovered three drug-like compounds that successfully reverse chemotherapy failure in three of the most commonly aggressive cancers — ovarian, prostate and breast.

The molecules were first discovered computationally via high-performance supercomputing. Now their effectiveness against specific cancers has been confirmed via wet-lab experiments, said biochemistry professors Pia Vogel and John G. Wise, who led the study.

Wise and Vogel report the advancement in the Nature journal Scientific Reports.

The computational discovery was confirmed in the Wise-Vogel labs at SMU after aggressive micro-tumors cultured in the labs were treated with a solution carrying the molecules in combination with a classic chemotherapy drug. The chemotherapy drug by itself was not effective in treating the drug-resistant cancer.

“Nature designs all cells with survival mechanisms, and cancer cells are no exception,” said Vogel, a professor in the SMU Department of Biological Sciences and director of SMU’s Center for Drug Discovery, Design and Delivery. “So it was incredibly gratifying that we were able to identify molecules that can inhibit that mechanism in the cancer cells, thereby bolstering the effectiveness of chemotherapeutic drugs. We saw the drugs penetrate these resistant cancer cells and allow chemotherapy to destroy them. While this is far from being a developed drug that will be available on the market anytime soon, this success in the lab gives us hope for developing new drugs to fight cancer.”

The current battle to defeat cancer is thwarted by chemotherapy failure in advanced cancers. Cancer cells initially treated with chemotherapy drugs ultimately evolve to resist the drugs. That renders chemotherapy ineffective, allowing cancers to grow and spread.

Key to cancer cell resistance are often certain proteins typically found in all cells — cancerous or otherwise — that are outfitted with beneficial mechanisms that pump away toxins to ensure a cell’s continued survival. Nature has set it up that these pumps are prevalent throughout the body, with some areas naturally having more of the pumps than others.

“The cancer cell itself can use all these built-in defenses to protect it from the kinds of things we’re using to try to kill it with,” Wise said.

The most common of these beneficial defense mechanisms is a pump protein, P-glycoprotein or P-gp, as it’s called. Another is one seen in breast and many other cancers, called breast cancer resistance protein, BCRP. In the case of cancer cells on the first round of treatment, these pumps are typically not produced in high levels in the cells, which allows chemotherapy to enter most of the cells in the tumor. This often gives what looks like a good result.

Unfortunately, in the cancer cells that don’t die, the chemotherapeutic often changes the cell, which then adapts to protect itself by aggressively multiplying the production of its defensive pumps.

Upon subsequent rounds of chemo, the P-gp and BCRP pumping mechanisms have proliferated. They effectively resist the chemotherapy, which now is much less successful, or not successful at all.

“if enough of the pumps are present, the cancer isn’t treatable anymore,” said Wise, associate professor in the SMU Department of Biological Sciences. Researchers in the field have searched unsuccessfully for compounds to inhibit the pumps that could be used in the clinic as well.

The molecules that Wise and Vogel discovered stopped the pumps.

“They effectively bring the cancer cells back to a sensitivity as if they’d never seen chemotherapy before,” said Vogel. “And our data indicated the molecules aren’t cancer specific. They can be used to treat all kinds of cancers because they inhibit not just the P-gp pump, but also the breast cancer protein pump.”

To test the compounds, the researchers used amounts of chemotherapeutic that would not kill these multi-drug resistant cancers if the pumps were not blocked.

“We wanted to make sure when using these really aggressive cancers that if we do knock out the pump, that the chemotherapy goes in there and causes the cell to die, so it doesn’t just stop it temporarily,” Wise said. “We spent a fair amount of time proving that point. It turns out that when a cell dies it goes through very predictable morphological changes. The DNA gets chopped up into small pieces, and we can see that, and so the nucleus becomes fragmented, and we can see that. Under the microscope, with proper staining, you can actually see that these highly drug-resistant prostate cancer cells, for example, are dead.”

The Scientific Reports article, “Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells,” is available open access at this link.

Other co-authors are SMU Ph.D. doctoral candidate Amila K. Nanayakkara, and Courtney A. Follit and Gang Chen, all in the SMU Department of Biological Sciences; and Noelle S. Williams, Department of Biochemistry, UT Southwestern Medical Center, Dallas.

Getting at the heart of the problem
Unique to the experiment is that the molecules were also tested on three-dimensional micro-tumors. That is a departure from the usual cell-culture experiments, which are a two-dimensional film.

In two-dimensional experiments, every cell is exposed to the chemotherapeutic because the film is just one layer of cells thick. That method ignores one of the key challenges to reversing tumors — how to get drugs into the middle of a tumor, not just on its surface.

“We show that with the help of our inhibitor compounds, we actually make the tumor penetrable to chemotherapeutic,” Vogel said. “We can kill the cells in the middle of the tumor.”

A pathway to personalized medical treatments
Chemotherapy’s harmful side effects on non-cancerous organs is well-known. The discovery of molecules that target a specific pump may mitigate that problem.

A patient’s tumor can be sampled to see which pump is causing the drug resistance. Then the molecule that knocks out that specific pump can be added to the chemotherapy.

“That means you don’t open the door wide to toxins in the central nervous system,” Wise said. “That has some real implications for the future and for personalized medicine. In most of the previous clinical trials, inhibitors have opened the brain up to toxins. From what we can tell so far, our inhibitors do not increase the toxicity of chemotherapeutics in normal cells.”

An audacious discovery
P-gp is present in one form or another in everything that lives.

“It’s in your dog, it’s in your cat, it’s in yeast cells, it’s in bacteria, it’s everywhere,” Wise said. “Why is it everywhere? Because it’s a really wonderful solution to the problem of getting toxins out of a cell. P-gp is a tremendously sophisticated evolutionary solution to that problem. And as with most things in biology that work well, everybody gets it, because if you don’t have it, you didn’t survive.”

Biologists say that P-gp can pump out 95 of 100 chemotherapeutics, indicating it can grab almost any drug and throw it out of a cell.

“So there’s a certain audacity to say that we can use a computer and target one part of this protein — the motor — and totally avoid the part of the protein that has evolved to pump almost anything that looks like a drug out of the cell,” Wise said. “That’s an audacious claim and the findings surprised us.”

In their computational and wet-lab experiments, Wise and Vogel searched for molecules that inhibit ATP hydrolysis — the chemical energy reaction that powers the P-gp pump.

“We targeted the motor of the pump instead of the pump part of the pump because almost all the clinical trial failures in other studies were actually compounds that targeted the pump part of the pump — and they would just slow down the pumping of the chemotherapeutic,” Vogel said. “The time was ripe to do these structural models. We hypothesized that we could completely avoid the pumping mechanism and just target the motor.”

Computational method highly predictive
The wet-lab experiments confirmed the accuracy of the computational findings, Vogel said.

“The predictiveness of the computational methods was really high,” she said. “It completely exceeded my expectations. We had selected certain molecules that were predicted in those computational experiments to interact with the pump in certain ways and not in others, and we could show in our wet-lab experiments that the predictions were spot on.”

Fascinated by the novel approach to the research, the National Institute of General Medical Sciences funded much of the research.

Wise and Vogel tapped the high-performance computing power of SMU’s Maneframe, one of the most powerful academic supercomputers in the nation. Wise sorted through 15 million commercially available drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco.

Then, again using ManeFrame, Wise ran the compounds through a computer-generated model of P-gp. The virtual model, designed and built by Wise, is the first computational microscope of its kind to simulate the actual behavior of P-gp in the human body, including interactions with drug-like compounds while taking on different shapes. He reported the dynamic functioning of the model in 2015 in the journal Biochemistry in “Multiple drug transport pathways through human P-glycoprotein.”

Process of elimination finds needle in the haystack
Out of 15 million drug-like compounds that were virtually screened, the researchers found 180,000 that in the computer were predicted to interact strongly with the ATP harvesting power plant part of the pump motor. From those, Wise and Vogel eliminated the ones that interact well with the pump part. Roughly 0.15 percent survived — several hundred.

“So that tells you how promiscuous that binding site is for compounds,” Wise said.

From there, they bought and tested in the lab a number of the remaining molecules.

“It was a process of elimination,” Vogel said. “Of the first 38 we tested, we found four. And because of the computational approach we took, it made failure relatively cheap. This is proof of principle that at least in those cases the compounds behave exactly in the lab as predicted in the computer. Which thrills the heck out of me — I never, ever would have thought that.”

The Vogel and Wise research labs are part of the Center for Drug Discovery, Design and Delivery in SMU’s Dedman College. The center’s mission is a novel multi-disciplinary focus for scientific research targeting medically important problems in human health. — Margaret Allen, SMU

Categories
Culture, Society & Family Feature Health & Medicine Learning & Education Researcher news SMU In The News Student researchers Technology

Dallas Innovates: SMU Researchers, Gamers Partner on Cancer Research

Adding the processor power of the network of “Minecraft” gamers could double the amount of computer power devoted to the SMU research project.

Reporter Lance Murray with Dallas Innovates reported on the research of biochemistry professors Pia Vogel and John Wise in the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall.

The researchers are leading an SMU assault on cancer in partnership with fans of the popular best-selling video game “Minecraft.”

They are partnering with the world’s vast network of gamers in hopes of discovering a new cancer-fighting drug. Vogel and Wise expect deep inroads in their quest to narrow the search for chemical compounds that improve the effectiveness of chemotherapy drugs.

A boost in computational power by adding crowdsourcing may help the researchers narrow their search.

The Dallas Innovates article, “SMU Researchers, Gamers Partner on Cancer Research,” published June 5, 2017.

Read the full story.

EXCERPT:

By Lance Murray
Dallas Innovates

Game developers and researchers at SMU are partnering with a worldwide network of gamers who play the popular game in a crowdsourcing effort to beat the disease.

The project is being led by biochemistry professors Pia Vogel and John Wise of the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall, the university’s graduate video game development program.

“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,” Vogel said in a release. “And gamers can take pride in knowing they’ve helped find answers to an important medical problem.”

Vogel and Wise have been utilizing the university’s ManeFrame supercomputer, one of the most powerful academic supercomputers in the country, to sort through millions of compounds that potentially could work in the fight against cancer.

Now, they’re going to try crowdsourced computing.

The researchers believe that the network of gamers will be able to crunch massive amounts of data during routine game play by pooling two weapons — human intuition and the massive computing power of the networked gaming machine processors.

Adding gamers could double processing power
That should more than double the amount of processing power aimed at their research problem.

“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,” said Clark, who is also an adjunct research associate professor in the Department of Biological Sciences.

“Integrating with the ‘Minecraft’ community should allow us to double the computing power of [SMU’s] supercomputer.”

The research labs of Vogel and Wise are part of the Center for Drug Discovery, Design, and Delivery in SMU’s Dedman College, whose mission is a multidisciplinary focus for scientific research that targets medically important problems in human health, the release said.

According to SMU, the research is partly funded by the National Institutes of Health.

The researchers narrowed a group of compounds that show potential for alleviating the issue of chemotherapy failure after repeated use.

Using gamers in research has happened before
Using human gamers to enhance data-driven research has been done before with success and is a growing practice.

Vogel cited the video game “Foldit.”

Read the full story.

Categories
Culture, Society & Family Feature Health & Medicine Learning & Education Mind & Brain Researcher news Student researchers Technology Videos

SMU Guildhall and cancer researchers level up to tap human intuition of video gamers in quest to beat cancer

Massive computational power of online “Minecraft” gaming community bests supercomputers

Video gamers have the power to beat cancer, according to cancer researchers and video game developers at Southern Methodist University, Dallas.

SMU researchers and game developers are partnering with the world’s vast network of gamers in hopes of discovering a new cancer-fighting drug.

Biochemistry professors Pia Vogel and John Wise in the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall, are leading the SMU assault on cancer in partnership with fans of the popular best-selling video game “Minecraft.”

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, also adjunct research associate professor in the Department of Biological Sciences. SMU Guildhall in March was named No. 1 among the Top 25 Top 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.”

The Vogel and Wise research labs are part of the Center for Drug Discovery, Design and Delivery (CD4) in SMU’s Dedman College. The center’s mission is a novel multi-disciplinary focus for scientific research targeting medically important problems in human health. Their research is funded in part by the National Institutes of Health.

The research question in play
Vogel and Wise have narrowed a group of compounds that show promise for alleviating the problem of chemotherapy failure after repeated use. Each one of those compounds has 50 to 100 — or even more — characteristics that contribute to their efficacy.

“Corey’s contribution will hopefully tell us which dozen perhaps of these 100 characteristics are the important ones,” Vogel said. “Right now of those 100 characteristics, we don’t know which ones are good ones. We want to see if there’s a way with what we learn from Corey’s gaming system to then apply what we learn to millions of other compounds to separate the wheat from the chaff.”

James McCormick — a fifth year Ph.D. student in cellular molecular biology who earned his doctoral degree this spring and is a researcher with the Center for Drug Discovery, Design and Delivery — produced the data set for Clark and Guildhall.

Lauren Ammerman, a first-year Ph.D. student in cellular and molecular biology and also working in the Center for Drug Discovery, Design and Delivery, is taking up the computational part of the project.

Machines can learn from human problem solving
Crowdsourcing video gamers to solve real scientific problems is a growing practice.

Machine learning and algorithms by themselves don’t always find the best solution, Clark said. There are already examples of researchers who for years sought answers with machine learning, then switched to actual human gamers.

Gamers take unstructured data and attack it with human problem-solving skills to quickly find an answer.

“So we’re combining both,” Clark said. “We’re going to have both computers and humans trying to find relationships and clustering the data. Each of those human decisions will also be supplied as training input into a deep neural network that is learning the ‘human heuristic’ — the technique and processes humans are using to make their decisions.”

Gamers already have proven they can solve research problems that have stymied scientists, says Vogel. She cites the video game “Foldit” created by the University of Washington specifically to unlock the structure of an AIDS-related enzyme.

Some other Games With A Purpose, as they’re called, have produced similar results. Humans outperform computers when it comes to tasks in the computational process that are particularly suited to the human intellect.

“With ‘Foldit,’ researchers worked on a problem for 15 years using machine learning techniques and were unable to find a solution,” Clark said. “Once they created the game, 57,000 players found a solution in three weeks.”

Modifying the “Minecraft” game and embedding research data inside
Gamers will access the research problem using the version of “Minecraft” they purchased, then install a “mod” or “plugin” — gamer jargon for modifying game code to expand a game’s possibilities — that incorporates SMUs research problem and was developed in accordance with “Minecraft” terms of service. Players will be fully aware of their role in the research, including ultimately leaderboards that show where players rank toward analyzing the data set in the research problem.

SMU is partnering with leaders in the large “Minecraft” modding community to develop a functioning mod by the end of 2017. The game will be heavily tested before release to the public the second quarter of 2018, Clark said.

The SMU “Minecraft” mod will incorporate a data processing and distributed computing platform from game technology company Balanced Media Technology (BMT), McKinney, Texas. BMT’s HEWMEN software platform executes machine-learning algorithms coupled with human guided interactions. It will integrate Wise and Vogel’s research directly into the SMU “Minecraft” mod.

SMU Guildhall will provide the interface enabling modders to develop their own custom game mechanic that visualizes and interacts with the research problem data within the “Minecraft” game environment. Guildhall research is funded in part by Balanced Media Technology.

“We expect to have over 25,000 people continuously online during our testing period,” Clark said. “That should probably double the computing power of the supercomputer here.”

That many players and that much computing power is a massive resource attacking the research problem, Wise said.

“The SMU computational system has 8,000 computer cores. Even if I had all of ManeFrame to myself, that’s still less computing and brainpower than the gaming community,” he said. “Here we’ve got more than 25,000 different brains at once. So even if 24,000 don’t find an answer, there are maybe 1,000 geniuses playing ‘Minecraft’ that may find a solution. This is the most creative thing I’ve heard in a long time.” — Margaret Allen, SMU

Categories
Health & Medicine Learning & Education Researcher news Slideshows Student researchers Videos

SMU biochemists, students probe membrane proteins that thwart cancer chemotherapies

“Recurring cancers have ‘learned’ how to evade chemotherapy by pumping it out of the cancer cells so that only sub-therapeutic concentrations remain in the cell, making the drug useless.” — SMU biochemist Pia Vogel

The SMU undergraduate students and Dallas-area high school students get hands-on experience working on cancer research in the combined SMU Department of Biological Sciences laboratories of Wise and Vogel.

The researchers and students are working to find ways to treat cancer patients whose cancer has either returned after initial chemotherapy or was initially hard to treat using chemotherapeutics. The research is funded in part by the National Institutes of Health.

SMU Cancer Research

Students recently in the lab included Victoria Bennet, Hockaday School, and Shaffin Siddiqui and Robert Luo, both from Highland Park High School. SMU undergraduates included Hamilton Scholar Alexis Sunshine, Clinton Osifo, Stefanie Lohse, Brianna Ramirez, Henry Thornton, Shirely Liu, Justin Musser, Jake Oien and Michael Fowler. Also currently working in the lab are M.S. student and Hamilton Scholar Collette Marchesseau (2016 SMU graduate), and Ph.D. students Amila Nanayakkara, Mike Chen, Courtney Follit, Maisa Oliveira and James McCormick.

“Often, recurring cancers have ‘learned’ how to evade chemotherapy by pumping the therapeutic out of the cancer cells so that only sub-therapeutic concentrations remain in the cell, making the drug useless,” said Vogel, a professor and director of the SMU interdisciplinary research institute, the Center for Drug Discovery, Design and Delivery.

The pumps that do the work are proteins that span the cell membranes and use the biological fuel ATP to actively pump chemotherapeutics and other toxins out of the cells.

“We like to compare these proteins to biological sump pumps,” said Wise, associate professor.

Wise and Vogel use a combination of computational, biochemical and human cell-based techniques to find new drug-like compounds that inhibit the action of the pumps. If successful, the novel drugs — or derivatives of them — will be given to patients with therapy-resistant cancer together with the chemotherapeutic.

“Since our novel compounds block the pumps, the chemotherapeutic will remain in the cell and kill the cancer that had not been treatable previously,” Vogel said.

The researchers have discovered drug-like compounds that can be modified and developed into medicines that target the protein, called P-glycoprotein.

The SMU researchers discovered the compounds after virtually screening more than 10 million small drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco.

Using SMU’s Maneframe high performance computer, Wise ran the compounds through a computer-generated model of the protein. The virtual model, designed and built by Wise, is the first computational microscope of its kind to simulate the actual behavior of P-glycoprotein in the human body, including interactions with drug-like compounds while taking on different shapes. The promising compounds were then tested in the lab.

“We have been quite successful and already have identified close to 20 novel compounds that block the pumps in our cell-based assays,” said Wise. “In these experiments we culture therapy-resistant prostate or ovarian or colon cancer cells in the lab and then show that we can kill these cancer cells using normal amounts of commonly available therapeutics in the presence of our novel compounds — even though in the absence of our novel compounds, the cancer cells would not be treatable.”

A pharmaceutical hit compound, like those discovered by Vogel and her co-authors, is a compound that is a promising candidate for chemical modification so it can eventually be delivered to patients as a therapeutic drug. In the case reported here, the compounds were commercially available for testing. The timeline from drug discovery to development to clinical trials and approval can take a decade or more.

SMU undergraduates and high school students experience world-class research
SMU undergraduate and high school students have been involved in different aspects of the research. Typically the beginning students work together with graduate or advanced undergraduate students to learn techniques used in the lab.

Some perform small research projects. Others have simply learned state-of-the-art techniques and “how science works” in the context of critical human health problems.

“High school student Robert Luo was interested in the computational side of our work, so he’s worked with senior SMU Ph.D. candidate James McCormick on trying to evaluate how strongly one of the therapy-sensitizing compounds we found potentially interacts with the pump protein at different proposed binding sites,” said Wise. “It is actually a significant project and will help with our research.”

The opportunities available for students to learn how science works using high performance computing, biochemistry and cell biology can be valuable even for those who won’t necessarily become practicing scientists, said Wise, citing as an example a recent SMU graduate who previously worked in the lab.

Ketetha Olengue (SMU ’15) is a good example,” he said. “She is now in her second year at the Keck School of Medicine at the University of Southern California, where she is pursuing her M.D. degree in a novel program with USC Engineering.” — Margaret Allen, SMU

Categories
Culture, Society & Family Earth & Climate Economics & Statistics Energy & Matter Events Fossils & Ruins Health & Medicine Learning & Education Mind & Brain Plants & Animals Researcher news Student researchers

SMU 2015 research efforts broadly noted in a variety of ways for world-changing impact

SMU scientists and their research have a global reach that is frequently noted, beyond peer publications and media mentions.

By Margaret Allen
SMU News & Communications

It was a good year for SMU faculty and student research efforts. Here is a small sampling of public and published acknowledgements during 2015:

Simmons, Diego Roman, SMU, education

Hot topic merits open access
Taylor & Francis, publisher of the online journal Environmental Education Research, lifted its subscription-only requirement to meet demand for an article on how climate change is taught to middle-schoolers in California.

Co-author of the research was Diego Román, assistant professor in the Department of Teaching and Learning, Annette Caldwell Simmons School of Education and Human Development.

Román’s research revealed that California textbooks are teaching sixth graders that climate change is a controversial debate stemming from differing opinions, rather than a scientific conclusion based on rigorous scientific evidence.

The article, “Textbooks of doubt: Using systemic functional analysis to explore the framing of climate change in middle-school science textbooks,” published in September. The finding generated such strong interest that Taylor & Francis opened access to the article.

bichaw_v054i049.indd

Research makes the cover of Biochemistry
Drugs important in the battle against cancer were tested in a virtual lab by SMU biology professors to see how they would behave in the human cell.

A computer-generated composite image of the simulation made the Dec. 15 cover of the journal Biochemistry.

Scientific articles about discoveries from the simulation were also published in the peer review journals Biochemistry and in Pharmacology Research & Perspectives.

The researchers tested the drugs by simulating their interaction in a computer-generated model of one of the cell’s key molecular pumps — the protein P-glycoprotein, or P-gp. Outcomes of interest were then tested in the Wise-Vogel wet lab.

The ongoing research is the work of biochemists John Wise, associate professor, and Pia Vogel, professor and director of the SMU Center for Drug Discovery, Design and Delivery in Dedman College. Assisting them were a team of SMU graduate and undergraduate students.

The researchers developed the model to overcome the problem of relying on traditional static images for the structure of P-gp. The simulation makes it possible for researchers to dock nearly any drug in the protein and see how it behaves, then test those of interest in an actual lab.

To date, the researchers have run millions of compounds through the pump and have discovered some that are promising for development into pharmaceutical drugs to battle cancer.

Click here to read more about the research.

SMU, Simpson Rowe, sexual assault, video

Strong interest in research on sexual victimization
Teen girls were less likely to report being sexually victimized after learning to assertively resist unwanted sexual overtures and after practicing resistance in a realistic virtual environment, according to three professors from the SMU Department of Psychology.

The finding was reported in Behavior Therapy. The article was one of the psychology journal’s most heavily shared and mentioned articles across social media, blogs and news outlets during 2015, the publisher announced.

The study was the work of Dedman College faculty Lorelei Simpson Rowe, associate professor and Psychology Department graduate program co-director; Ernest Jouriles, professor; and Renee McDonald, SMU associate dean for research and academic affairs.

The journal’s publisher, Elsevier, temporarily has lifted its subscription requirement on the article, “Reducing Sexual Victimization Among Adolescent Girls: A Randomized Controlled Pilot Trial of My Voice, My Choice,” and has opened it to free access for three months.

Click here to read more about the research.

Consumers assume bigger price equals better quality
Even when competing firms can credibly disclose the positive attributes of their products to buyers, they may not do so.

Instead, they find it more lucrative to “signal” quality through the prices they charge, typically working on the assumption that shoppers think a high price indicates high quality. The resulting high prices hurt buyers, and may create a case for mandatory disclosure of quality through public policy.

That was a finding of the research of Dedman College’s Santanu Roy, professor, Department of Economics. Roy’s article about the research was published in February in one of the blue-ribbon journals, and the oldest, in the field, The Economic Journal.

Published by the U.K.’s Royal Economic Society, The Economic Journal is one of the founding journals of modern economics. The journal issued a media briefing about the paper, “Competition, Disclosure and Signaling,” typically reserved for academic papers of broad public interest.

The Journal of Physical Chemistry A

Chemistry research group edits special issue
Chemistry professors Dieter Cremer and Elfi Kraka, who lead SMU’s Computational and Theoretical Chemistry Group, were guest editors of a special issue of the prestigious Journal of Physical Chemistry. The issue published in March.

The Computational and Theoretical research group, called CATCO for short, is a union of computational and theoretical chemistry scientists at SMU. Their focus is research in computational chemistry, educating and training graduate and undergraduate students, disseminating and explaining results of their research to the broader public, and programming computers for the calculation of molecules and molecular aggregates.

The special issue of Physical Chemistry included 40 contributions from participants of a four-day conference in Dallas in March 2014 that was hosted by CATCO. The 25th Austin Symposium drew 108 participants from 22 different countries who, combined, presented eight plenary talks, 60 lectures and about 40 posters.

CATCO presented its research with contributions from Cremer and Kraka, as well as Marek Freindorf, research assistant professor; Wenli Zou, visiting professor; Robert Kalescky, post-doctoral fellow; and graduate students Alan Humason, Thomas Sexton, Dani Setlawan and Vytor Oliveira.

There have been more than 75 graduate students and research associates working in the CATCO group, which originally was formed at the University of Cologne, Germany, before moving to SMU in 2009.

519ca82d-6517-4df9-b5ac-26e5458882ef

Vertebrate paleontology recognized with proclamation
Dallas Mayor Mike Rawlings proclaimed Oct. 11-17, 2015 Vertebrate Paleontology week in Dallas on behalf of the Dallas City Council.

The proclamation honored the 75th Annual Meeting of the Society of Vertebrate Paleontology, which was jointly hosted by SMU’s Roy M. Huffington Department of Earth Sciences in Dedman College and the Perot Museum of Science and Nature. The conference drew to Dallas some 1,200 scientists from around the world.

Making research presentations or presenting research posters were: faculty members Bonnie Jacobs, Louis Jacobs, Michael Polcyn, Neil Tabor and Dale Winkler; adjunct research assistant professor Alisa Winkler; research staff member Kurt Ferguson; post-doctoral researchers T. Scott Myers and Lauren Michael; and graduate students Matthew Clemens, John Graf, Gary Johnson and Kate Andrzejewski.

The host committee co-chairs were Anthony Fiorillo, adjunct research professor; and Louis Jacobs, professor. Committee members included Polcyn; Christopher Strganac, graduate student; Diana Vineyard, research associate; and research professor Dale Winkler.

KERA radio reporter Kat Chow filed a report from the conference, explaining to listeners the science of vertebrate paleontology, which exposes the past, present and future of life on earth by studying fossils of animals that had backbones.

SMU earthquake scientists rock scientific journal

Modelled pressure changes caused by injection and production. (Nature Communications/SMU)
Modelled pressure changes caused by injection and production. (Nature Communications/SMU)

Findings by the SMU earthquake team reverberated across the nation with publication of their scientific article in the prestigious British interdisciplinary journal Nature, ranked as one of the world’s most cited scientific journals.

The article reported that the SMU-led seismology team found that high volumes of wastewater injection combined with saltwater extraction from natural gas wells is the most likely cause of unusually frequent earthquakes occurring in the Dallas-Fort Worth area near the small community of Azle.

The research was the work of Dedman College faculty Matthew Hornbach, associate professor of geophysics; Heather DeShon, associate professor of geophysics; Brian Stump, SMU Albritton Chair in Earth Sciences; Chris Hayward, research staff and director geophysics research program; and Beatrice Magnani, associate professor of geophysics.

The article, “Causal factors for seismicity near Azle, Texas,” published online in late April. Already the article has been downloaded nearly 6,000 times, and heavily shared on both social and conventional media. The article has achieved a ranking of 270, which puts it in the 99th percentile of 144,972 tracked articles of a similar age in all journals, and 98th percentile of 626 tracked articles of a similar age in Nature.

It has a very high impact factor for an article of its age,” said Robert Gregory, professor and chair, SMU Earth Sciences Department.

The scientific article also was entered into the record for public hearings both at the Texas Railroad Commission and the Texas House Subcommittee on Seismic Activity.

Researchers settle long-debated heritage question of “The Ancient One”

The skull of Kennewick Man and a sculpted bust by StudioEIS based on forensic facial reconstruction by sculptor Amanda Danning. (Credit: Brittany Tatchell)
The skull of Kennewick Man and a sculpted bust by StudioEIS based on forensic facial reconstruction by sculptor Amanda Danning. (Credit: Brittany Tatchell)

The research of Dedman College anthropologist and Henderson-Morrison Professor of Prehistory David Meltzer played a role in settling the long-debated and highly controversial heritage of “Kennewick Man.”

Also known as “The Ancient One,” the 8,400-year-old male skeleton discovered in Washington state has been the subject of debate for nearly two decades. Argument over his ancestry has gained him notoriety in high-profile newspaper and magazine articles, as well as making him the subject of intense scholarly study.

Officially the jurisdiction of the U.S. Army Corps of Engineers, Kennewick Man was discovered in 1996 and radiocarbon dated to 8500 years ago.

Because of his cranial shape and size he was declared not Native American but instead ‘Caucasoid,’ implying a very different population had once been in the Americas, one that was unrelated to contemporary Native Americans.

But Native Americans long have claimed Kennewick Man as theirs and had asked for repatriation of his remains for burial according to their customs.

Meltzer, collaborating with his geneticist colleague Eske Willerslev and his team at the Centre for GeoGenetics at the University of Copenhagen, in June reported the results of their analysis of the DNA of Kennewick in the prestigious British journal Nature in the scientific paper “The ancestry and affiliations of Kennewick Man.”

The results were announced at a news conference, settling the question based on first-ever DNA evidence: Kennewick Man is Native American.

The announcement garnered national and international media attention, and propelled a new push to return the skeleton to a coalition of Columbia Basin tribes. Sen. Patty Murray (D-WA) introduced the Bring the Ancient One Home Act of 2015 and Washington Gov. Jay Inslee has offered state assistance for returning the remains to Native Tribes.

Science named the Kennewick work one of its nine runners-up in the highly esteemed magazine’s annual “Breakthrough of the Year” competition.

The research article has been viewed more than 60,000 times. It has achieved a ranking of 665, which puts it in the 99th percentile of 169,466 tracked articles of a similar age in all journals, and in the 94th percentile of 958 tracked articles of a similar age in Nature.

In “Kennewick Man: coming to closure,” an article in the December issue of Antiquity, a journal of Cambridge University Press, Meltzer noted that the DNA merely confirmed what the tribes had known all along: “We are him, he is us,” said one tribal spokesman. Meltzer concludes: “We presented the DNA evidence. The tribal members gave it meaning.”

Click here to read more about the research.

Prehistoric vacuum cleaner captures singular award

Paleontologists Louis L. Jacobs, SMU, and Anthony Fiorillo, Perot Museum, have identified a new species of marine mammal from bones recovered from Unalaska, an Aleutian island in the North Pacific. (Hillsman Jackson, SMU)
Paleontologists Louis L. Jacobs, SMU, and Anthony Fiorillo, Perot Museum, have identified a new species of marine mammal from bones recovered from Unalaska, an Aleutian island in the North Pacific. (Hillsman Jackson, SMU)

Science writer Laura Geggel with Live Science named a new species of extinct marine mammal identified by two SMU paleontologists among “The 10 Strangest Animal Discoveries of 2015.”

The new species, dubbed a prehistoric hoover by London’s Daily Mail online news site, was identified by SMU paleontologist Louis L. Jacobs, a professor in the Roy M. Huffington Department of Earth Sciences, Dedman College of Humanities and Sciences, and paleontologist and SMU adjunct research professor Anthony Fiorillo, vice president of research and collections and chief curator at the Perot Museum of Nature and Science.

Jacobs and Fiorillo co-authored a study about the identification of new fossils from the oddball creature Desmostylia, discovered in the same waters where the popular “Deadliest Catch” TV show is filmed. The hippo-like creature ate like a vacuum cleaner and is a new genus and species of the only order of marine mammals ever to go extinct — surviving a mere 23 million years.

Desmostylians, every single species combined, lived in an interval between 33 million and 10 million years ago. Their strange columnar teeth and odd style of eating don’t occur in any other animal, Jacobs said.

SMU campus hosted the world’s premier physicists

The SMU Department of Physics hosted the “23rd International Workshop on Deep Inelastic Scattering and Related Subjects” from April 27-May 1, 2015. Deep Inelastic Scattering is the process of probing the quantum particles that make up our universe.

As noted by the CERN Courier — the news magazine of the CERN Laboratory in Geneva, which hosts the Large Hadron Collider, the world’s largest science experiment — more than 250 scientists from 30 countries presented more than 200 talks on a multitude of subjects relevant to experimental and theoretical research. SMU physicists presented at the conference.

The SMU organizing committee was led by Fred Olness, professor and chair of the SMU Department of Physics in Dedman College, who also gave opening and closing remarks at the conference. The committee consisted of other SMU faculty, including Jodi Cooley, associate professor; Simon Dalley, senior lecturer; Robert Kehoe, professor; Pavel Nadolsky, associate professor, who also presented progress on experiments at CERN’s Large Hadron Collider; Randy Scalise, senior lecturer; and Stephen Sekula, associate professor.

Sekula also organized a series of short talks for the public about physics and the big questions that face us as we try to understand our universe.

Click here to read more about the research.

Categories
Health & Medicine Videos

Drugs behave as predicted in computer model of key protein, enabling cancer drug discovery

New model allows pharmacological researchers to dock nearly any drug and see how it behaves in P-glycoprotein, a protein in the cell associated with failure of chemotherapy

Drugs important in the battle against cancer responded the way they do in real life and behaved according to predictions when tested in a computer-generated model of one of the cell’s key molecular pumps — the protein P-glycoprotein, or P-gp.

Biologists at Southern Methodist University, Dallas, developed the computer generated model to overcome the problem of relying on only static images for the structure of P-gp, said biologist John G. Wise, lead author on the journal article announcing the advancement.

The new SMU 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 Wise, an associate professor in SMU’s Department of Biological Sciences.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” he said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

P-gp 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 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.

SMU researchers report that their computer model simulation reveals the binding sites of Tariquidar — a P-gp inhibitor —  as the “pump” opens and closes. (Image:  James McCormick)
SMU researchers report that their computer model simulation reveals the binding sites of Tariquidar (orange blob) — a P-gp inhibitor. (Image: James McCormick)

Also using the model, the researchers discovered greater detail than previously known about the behavior of other drugs as well, and how those drugs bind in P-gp to stop its pumping action.

The study was funded in part by the National Institutes of Health. The lab was recently awarded a second NIH grant for the research.

The findings are published in the journal Biochemistry. The article, “Multiple drug transport pathways through human P-glycoprotein,” is published online in advance of print at NIH’s PubMed Central.

A still image of the modeled protein in action will appear on the cover of the October through December issues of Biochemistry.

Testing the virtual P-gp model by virtually docking real drugs
Wise and his colleagues tested one of the workhorse drugs of chemotherapy, daunorubicin, a close cousin of Adriamycin.

An aggressive chemotherapeutic, daunorubicin stops DNA replication in the cell, and is a classic target for P-gp to pump out of a cell, Wise said.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Wise said. “Sure enough, with our models, we found that daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil – a commonly prescribed blood pressure medicine – prefers the other side.”

SMU researchers report that their computer model simulation reveals the binding sites of Tariquidar — a P-gp inhibitor —  as the “pump” opens and closes. (Image:  James McCormick)
SMU researchers report that their computer model simulation reveals the binding sites of Tariquidar (orange blob) — a P-gp inhibitor — as the “pump” opens and closes. (Image: James McCormick)

Not only did the researchers show computationally that there are two different starting points for drugs, they also showed that there are two different pathways to get the drugs through.

“The two different drugs start at different sites and they’re funneled to the outside by being pushed by the protein,” Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Wise and his co-authors, SMU biologists Pia Vogel and James McCormick, created the P-gp computer-generated simulation using SMU’s High Performance Computer, ManeFrame.

Molecular model can aid in fight against multi-drug resistance of cancer cells
The capability of watching molecular machinery up close, while doing its job the way it does in real life, may spark new drug discoveries to fight cancer.

“Having an accurate model that actually moves – that shows the dynamics of the thing – is incredibly helpful in developing therapies against a molecular target to inhibit it. The only other ways to do it are blind, and the chances of success using blind methods are very low,” Wise said.

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing,” Wise said. “They found drugs that worked in the test tube and that worked in cultured cells, but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Vogel and Wise led a team of researchers in using the P-gp model to virtually screen millions of publically available drug-like compounds.

Verapamil (green blob), inhibits the P-gp pump. But until now, the workings of the pump could not be observed so researchers could only speculate where Varapamil “binds” in P-gp. SMU researchers report that their computer model simulation reveals Varapamil’s binding sites while the “pump” opens and closes. (Image: McCormick)
Verapamil (green blob), inhibits the P-gp pump. Until now, the workings of the pump could not be observed so researchers didn’t know exactly where Varapamil “binds” in P-gp. SMU researchers report that their simulation reveals the binding sites. (Image: McCormick)

They discovered three new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients. The researchers reported those findings this month in the journal Pharmacology Research & Perspectives, http://bit.ly/1XGjN5w.

New SMU model simulates molecular machinery in action
Researchers look for drug compounds that can temporarily stop or inhibit the P-gp pump, so that the chemotherapy drugs that enter the cancer cell will stay there and do the job of killing the cancer. Finding the right pump inhibitor requires understanding the pumping action. That’s difficult without seeing the pump at work.

The structures of proteins similar to P-gp have been previously available in a static state through X-ray crystallography. Scientists use X-ray crystallography as a tool that essentially draws the details of biological structures by identifying their atomic and molecular structure through diffraction of X-rays by the atoms themselves.

Scientists often contribute the resulting protein structures to the U.S. Protein Data Bank repository for public use.

Detailed data combined with several trillion calculations produced model
To build the P-gp model, Wise used structures from the repository, showing various stages of transport, to simulate four points of reference. From there, SMU’s ManeFrame supercomputer was fed parameters and characteristics of the protein as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature. The animated model resulted from calculating differences between two structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations and you arrive at the next structure,” Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein, and watched the drugs move through P-gp’s catalytic cycle.

“What happened was — the drugs moved,” Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Vogel added that, “in some of the zoom-ins of the model, you can actually see the amino acids paddle down the drugs.”

Further challenging and testing the model
The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through. So we put in something that is not a transport substrate of P-gp, something that biochemically would never be transported by P-gp,” Wise said. “We put it in, starting where daunorubicin is effectively pumped out, and very quickly the compound left the protein — but it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Wise admits that until he saw it for himself, even he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Wise said. “I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works — it moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Categories
Health & Medicine Researcher news Videos

Researchers discover new drug-like compounds that may improve odds for men battling prostate cancer

New drug-like compounds have low toxicity to noncancerous cells, but inhibit the human protein often responsible for chemotherapy failure

Researchers at Southern Methodist University, Dallas, have discovered three new drug-like compounds that could ultimately offer better odds of survival to prostate cancer patients.

The drug-like compounds can be modified and developed into medicines that target a protein in the human body that is responsible for chemotherapy resistance in cancers, said biochemist Pia D. Vogel, lead author on the scientific paper reporting the discovery.

So far there’s no approved drug on the market that reverses cancer chemotherapy resistance caused by P-glycoprotein, or P-gp for short, said Vogel, a biochemistry professor at SMU. One potential drug, Tariquidar, is currently in clinical trials, but in the past, other potential drugs have failed at that stage.

“The problem when a person has cancer, is that the treatment itself is composed of cellular toxins — the chemotherapeutics that prevent the cells from dividing. Usually upon the first chemotherapy treatment the cancer responds well, and initially goes away. Ideally it doesn’t come back,” said Vogel, director of SMU’s Center for Drug Discovery, Design and Delivery.

Three drug-like compounds bind in human P-glycoprotein, reversing chemotherapy resistance in prostate cancer cells in culture. (Image, James McCormick)
Three drug-like compounds bind in human P-glycoprotein, reversing chemotherapy resistance in prostate cancer cells in culture. (Image, James McCormick)

“Sometimes, however, the cancer returns,” she said. “The reason often is that some of the cancer cells “learn,” after the first rounds of chemotherapy, how to make a lot of this P-gp pump. The normal function of P-gp is to pump toxins from cells, so it has evolved to protect cells against a large variety of toxins, including almost all currently available chemotherapeutics. After initial exposure, the cells surviving the chemo make so much P-gp that it allows the cells to pump the chemotherapy drugs straight back out of the cells during subsequent rounds of treatment.”

As a result, P-gp causes resistance of the diseased cells to a majority of drugs currently available for the treatment of cancer, as well as drugs used for treatment of infectious diseases like HIV/AIDS.

Using computer-generated model speeds up the drug discovery process
The new drug-like compounds discovered by Vogel and her co-authors offer hope that using a computer-generated P-gp model, developed to accurately mimic the physical, chemical and biological functions of the protein in the human body, will speed up the drug discovery process and work in real life as well.

P-glycoprotein's pumping action is stalled, when a drug-like compound (dark blue) prevents the power source (red) from being used by P-glycoprotein, the protein that transports toxins from a cell. (Image: James McCormick)
P-glycoprotein’s pumping action is stalled, when a drug-like compound (dark blue) prevents the power source (red) from being used by P-glycoprotein, the protein that transports toxins from a cell. (Image: James McCormick)

“These are not drugs yet. We still have to develop them before they can go in the clinic,” Vogel said. “But what we know now is that they’re not toxic — they have low toxicity to noncancerous cells, so that’s a pretty good predictor that they may be good candidates for drug development. But we need to do much more work.”

A pharmaceutical hit compound, like those discovered by Vogel and her co-authors, is a compound that is a promising candidate for chemical modification so it can eventually be delivered to patients as a therapeutic drug. In the case reported here, the compounds were commercially available for testing. The timeline from drug discovery to development to clinical trials and approval can take a decade or more.

Vogel and her co-authors, SMU biologist John G. Wise, and doctoral candidates Courtney A. Follit and Frances K. Brewer, reported their findings in the journal Pharmacology Research & Perspectives. The article, “In silico identified targeted inhibitors of P-glycoprotein in culture,” is published online at http://bit.ly/1JjFizg.

The research was funded in part by the National Institutes of Health. The lab was recently awarded a second grant from the Institute.

Researchers virtually screened 15 million drug-like compounds via SMU supercomputer
The SMU researchers discovered the three hit compounds after virtually screening more than 15 million small drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco.

Using SMU’s ManeFrame high performance computer, Wise ran the compounds through a computer-generated model of P-gp. The virtual model, designed and built by Wise, is the first computational microscope of its kind to simulate the actual behavior of P-gp in the human body, including interactions with drug-like compounds while taking on different shapes.

The ultra-high throughput computational searches by ManeFrame led the researchers to 300 compounds that looked like they may inhibit P-gp. The researchers then tested 38 of those in their physical lab and found four that inhibited the biochemical function of P-gp, stopping it in its action.

Each of the four compounds was then tested in the lab to see how it would affect a line of prostate cancer cells relatively sensitive to the chemotherapeutic Paclitaxel, commonly used to treat prostate cancer patients. Also, each was tested on a companion cell line already multi-drug resistant, as if the patient already had undergone chemotherapy using Paclitaxel.

The researchers found that with three of the four compounds, they were able to push back the sensitivity of the resistant cancer line to the level of the non-resistant one.

“So the compounds re-sensitized the cancer cell lines to a really high degree, just as if the cancer was seeing the chemotherapy for the first time,” Vogel said.

About 14 percent of men will be diagnosed over their lifetime with prostate cancer, according to the National Cancer Institute. Survival is highest if diagnosed early before it has spread, the institute reports.

Categories
Learning & Education Researcher news Technology

The power of ManeFrame: SMU’s new supercomputer boosts research capacity

950x150 ManeFrame_v2 rev

The enormous capacity of SMU’s new supercomputer ranks it among the largest academic supercomputers in the nation.

ManeFrame, previously known as MANA, was relocated to Dallas from its previous location in Maui, Hawaii. (Courtesy of mauinow.com)
ManeFrame, previously known as MANA, was relocated to Dallas from its former location in Maui, Hawaii. (Courtesy of mauinow.com)

SMU now has a powerful new tool for research – one of the fastest academic supercomputers in the nation – and a new facility to house it.

With a cluster of more than 1,000 Dell servers, the system’s capacity is on par with high-performance computing (HPC) power at much larger universities and at government-owned laboratories. The U.S. Department of Defense awarded the system to SMU in August 2013.

SMU’s Office of Information Technology added the system to the University’s existing – but much smaller – supercomputer. The system is housed in a new facility built at the corner of Mockingbird and Central Expressway. In a contest sponsored by Provost and Vice President for Academic Affairs Paul W. Ludden, faculty and students chose the name “ManeFrame” to honor the Mustang mascot.

The enormous capacity and speed of HPC expands scientific access to new knowledge around key questions about the universe, disease, human behavior, health, food, water, environment, climate, democracy, poverty, war and peace.

“World-changing discoveries rely on vast computing resources,” says President R. Gerald Turner. “ManeFrame quintuples the University’s supercomputing capacity. Our scientists and students will keep pace with the increasing demand for the ever-expanding computing power that is required to participate in global scientific collaborations. This accelerates our research capabilities exponentially.”

ManeFrame potential
With nearly 11,000 central processing unit cores, ManeFrame boasts 40 terabytes (one terabyte equals a trillion bytes) of memory and more than 1.5 petabytes of storage (a petabyte equals a quadrillion bytes), says Joe Gargiulo, SMU’s chief information officer, who led the installation team.

The sciences and engineering primarily use supercomputers, but that is expanding to include the humanities and the arts. So far, SMU’s heavy users are researchers in physics, math, biology, chemistry and economics.

“This technologically advanced machine will have an impact on shaping our world,” says Thomas M. Hagstrom, chair of the Department of Mathematics in Dedman College and director of SMU’s Center for Scientific Computing. “This makes research that solves problems on a large scale much more accessible. ManeFrame’s theoretical peak would be on the order of 120 Teraflops, which is 120 trillion mathematical operations a second.”

Supercomputers can use sophisticated software and step-by-step procedures for calculations, called algorithms, to solve complex problems that can’t be managed in a researcher’s lab, Hagstrom explains.

“We can’t put the Earth’s climate system or study the evolution of the universe in a physical lab,” he says. “You can only study these and other systems in a comprehensive way using high-performance computing.”

Making SMU competitive
Supercomputing gave University physicists a role in the Higgs Boson research at the Large Hadron Collider in Geneva, Switzerland. Joining the collaboration with thousands of scientists around the world, SMU’s team was led by Physics Professor Ryszard Stroynowski. SMU’s physicists tapped the existing HPC on campus to quickly analyze massive amounts of data and deliver results to their international colleagues.

SMU’s team will use ManeFrame to keep pace with an even larger flood of data expected from the Large Hadron Collider.

“ManeFrame makes SMU – which is small by comparison with many of its peer institutions at CERN – nimble and competitive, and that lets us be visible in a big experiment like CERN,” says Stephen Sekula, assistant professor of physics. “So we have to have ideas, motivation and creativity – but having a technical resource like ManeFrame lets us act on those things.”

SMU physicist Pavel Nadolsky has conducted “big data” analyses of subatomic particles on the supercomputer as part of an international physics collaboration. Big data refers to probability distributions that depend on many variables. As users ranging from retailers to the health industry collect multitudes of transactional data every day, requirements for big data analysis are rapidly emerging.

“To keep up in our field, we need resources like ManeFrame,” says Nadolsky, associate professor of physics.

“The world is moving into big-data analysis, whether it’s Google, Facebook or the National Security Administration,” Nadolsky says. “We learn a lot about the world by studying multidimensional distributions: It tells about the origins of the universe; it can win elections by using data mining to analyze voting probabilities over time in specific geographical areas and targeting campaign efforts accordingly; and it can predict what people are doing. To make students competitive they must be trained to use these tools efficiently and ethically.”

ManeFrame will have a high-profile role in the U.S. Department of Energy experiment called NOvA, which studies neutrinos, a little-understood and elusive fundamental particle that may help explain why matter, and not just light, exists in the universe today. SMU will contribute four million processing hours each year to the experiment, says Thomas E. Coan, associate professor of physics and a member of the international team.

“We’re in good company with others providing computing, including California Institute of Technology and Harvard,” Coan says. “It’s one way for SMU to play a prominent role in the experiment. We get a lot of visibility among all the institutions participating in NOvA, which are spread out across five countries.”

Advancing discovery
One of the heaviest users of SMU’s HPC is John Wise, associate professor of biological sciences, who models a key human protein to improve chemotherapy to kill cancer cells. Wise works with the SMU Center for Drug Discovery, Design and Delivery in Dedman College, an interdisciplinary research initiative of the Biology and Chemistry departments and led by Professor of Biological Sciences Pia Vogel.

Within the Mathematics Department, Assistant Professor Daniel R. Reynolds and his team use high-performance computing to run simulations with applications in cosmology and fusion reactors.

Looking to the future, high-performance computing will be increasing in research, business and the arts, according to James Quick, associate vice president for research and dean of graduate studies.

“High-performance computing has emerged as a revolutionary tool that dramatically increases the rates of scientific discovery and product development, enables wise investment decisions and opens new dimensions in artistic creativity,” says Quick, professor of earth sciences. “SMU will use the computational power of ManeFrame to expand research and creativity and develop educational opportunities for students interested in the application of high-performance computing in their fields – be it science, engineering, business or the arts.” – Margaret Allen

Follow SMUResearch.com on twitter at @smuresearch.

SMU is a nationally ranked private university in Dallas founded 100 years ago. Today, SMU enrolls nearly 11,000 students who benefit from the academic opportunities and international reach of seven degree-granting schools. For more information see www.smu.edu.

SMU has an uplink facility located on campus for live TV, radio, or online interviews. To speak with an SMU expert or book an SMU guest in the studio, call SMU News & Communications at 214-768-7650.

Categories
Health & Medicine Technology Videos

Moving 3D computer model of key human protein is powerful new tool in fight against cancer

Powerful discovery tool is at work screening millions of drugs in the search to reverse chemotherapy drug resistance in cancer

A picture is worth 1,000 words when it comes to understanding how things work, but 3D moving pictures are even better. That’s especially true for scientists trying to stop cancer by better understanding the proteins that make some chemotherapies unsuccessful.

Researchers for decades have had to rely at best on static images of the key proteins related to recurring cancers.

Now SMU biochemist John G. Wise at Southern Methodist University, Dallas, has brought to life in a moving 3D computer model the structure of human P-glycoprotein, which is thought to contribute to the failure of chemotherapy in many recurring cancers.

“This is a very different approach than has been used historically in the field of protein structure biochemistry,” Wise said. “Historically, proteins are very often viewed as static images, even though we know that in reality these proteins move and are dynamic.”

The model is a powerful new discovery tool, says Wise, particularly when combined with high-performance supercomputing. The dynamic 3D model already has made it possible for Wise to virtually screen more than 8 million potential drug compounds in the quest to find one that will help stop chemotherapy failure. (Youtube video) (Flickr images)

So far, the supercomputer search has turned up a few hundred drugs that show promise, and Wise and SMU biochemist Pia Vogel have begun testing some of those compounds in their wet lab at SMU.

“This has been a good proof-of-principle,” said Wise, a research associate professor in the SMU Department of Biological Sciences.

“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.”

Wise describes his research findings in Biochemistry in the article “Catalytic Transitions in the Human MDR1 P-Glycoprotein Drug Binding Sites” online.

The research is funded by the National Institute of General Medical Sciences, National Institutes of Health.

Seeking new drugs that would allow chemotherapeutic compounds to enter and destroy cancer cells
Since the 1970s it has been known that the so-called multidrug resistance protein, P-gp, is most likely responsible for the failure of many chemotherapy drugs. P-gp is nature’s way of pumping toxins from a cell, but if cancer cells express more P-gp than cells normally would, the chemotherapy is no longer effective because the protein considers it a toxin and pumps it out before it can destroy the cancer.

“We’re looking for small molecules that will temporarily inhibit the pump; a new drug that could be co-administered with the chemotherapeutic and that stops the sump pump in the cancer cell so that the cancer chemotherapy can remain in the cell and kill the cancer,” Wise said.

High-performance computer enables millions of digital screenings
Wise has run about 10.5 million computational hours since August 2009 and has screened roughly 8 million potential drugs against different protein structures.

SMU biochemists Pia Vogel and John Wise have paired a moving 3D computer model of a key human protein together with the SMU supercomputer to search for potential drugs to stop chemotherapy failure.
(Image: Hillsman Jackson, SMU)

“We are currently screening about 40,000 compounds per day on SMU’s High Performance Computer,” Wise said.

“We found a couple hundred compounds that were interesting, and so far we chose about 30 of those to screen in the lab,” Vogel said. “From those, we found a handful of compounds that do inhibit the protein. We were thrilled. Now we’re going back into the models and looking for other compounds that might be able to throw a stick in the pump’s mechanism.”

Massive increases in computational power in recent years have made the screening research possible, Wise said. “Ten years ago you couldn’t have docked 8 million compounds — there just wasn’t enough computational power.”

Human P-gp: “We don’t know what it looks like exactly.”
Every organism has a version of P-gp. Its structure has been previously determined for some organisms — mostly bacteria, but also in mice — by studying the arrangement of atoms within protein crystals. However, the exact structure of the human enzyme remains unclear. Wise deduced the structure of human P-gp by relying on evolutionary relationships and scientific understanding of how proteins are put together. He then used computer programs to model the protein in a way that brings the static picture of the human pump to life in the computer. (Youtube: Moving model)

To develop the model, Wise used freely available simulation software developed by researchers at the University of Illinois, the National Institutes of Health and the Scripps Research Institute. Wise and Vogel use compounds from ZINC, a free database of more than 21 million commercially available compounds for virtual screening. ZINC is provided by the Department of Pharmaceutical Chemistry at the University of California, San Francisco.

“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 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,” Wise said. “The software is good enough that the model will move according to the laws of physics and the principles of biochemistry. In this way we can see how these compounds interact with the protein in a dynamic way, not just in a snapshot way.”

Even with the 3D dynamic model and a supercomputer, the odds are stiff
Theoretically, if a drug can be found that temporarily knocks out the sump-pump proteins, then all those cancer chemotherapies that don’t work for a patient will work again.

“The ultimate goal of our research would be to find a compound that is safe and effective,” Wise said. Even with a supercomputer, however, the odds are steep.

“Out of a hundred good inhibitors that we might find, 99 of them might be extremely toxic and can’t be used. In the pharmaceutical industry there are many, many candidates that fall by the wayside for one reason or another,” he said. “They metabolize too quickly, or they’re too toxic, or they’re not soluble enough in the acceptable solvents for humans. There are many different reasons why a drug can fail. Finding a handful has been a great confirmation that we’re on the right track, but I would be totally amazed if one of the first we’ve tested was the one we’re looking for.”

Vogel is an associate professor and director of SMU’s Center for Drug Discovery, Design and Delivery. CD4 was launched by SMU’s Biological Sciences and Chemistry departments and has as its mission the search for new drug therapies and delivery methods that can be developed into clinical applications. — Margaret Allen

Categories
Health & Medicine Researcher news

Modeling the human protein in search of cancer treatment: An SMU Researcher Q&A

SMU biologists tap supercomputer in fight against recurring cancer when chemotherapy fails

SMU biologists Pia Vogel and John Wise in the SMU Department of Biological Sciences are using the computational power of the SMU high-performance supercomputer to screen millions of drug compounds. They hope to find one that will aid in the fight against recurring cancer.

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 the following interview, 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 (NAMD 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.

Q: Has anyone else used the software in this way?
Wise:
I don’t think anyone else has looked at 8 million drugs. And I’m almost positive that no one has looked at drug binding dynamically on that scale.

Q: How have you tested it in the lab?
Vogel:
We use the purified protein itself and see whether those compounds really inhibit the power stroke, the ATP hydrolysis. We work with mouse protein, which is closely related to the human protein, but a little more stable.

Q: What’s the next step?
Vogel:
We’ll collaborate with cell culture researchers here at SMU’s Center for Drug Discovery, Design and Delivery* and see if the compounds are toxic to cultured cancer cells and whether they will reverse chemo-resistance in some cell lines that we know do not respond to chemotherapeutics.

Wise: The ultimate goal of our research would be a compound that is safe and effective. To give an idea of the odds, out of a hundred good inhibitors that we might find, 95 of them might be extremely toxic and can’t be used. In the pharmaceutical industry, there are many, many candidates that fall by the wayside for one reason or another. They metabolize too quickly, or they’re too toxic, or they’re not soluble enough in the acceptable solvents for humans. There are many different reasons why a drug can fail. Finding a handful has been a great confirmation that we’re on the right track, but I would be totally amazed if one of the first we’ve tested was the one we’re looking for. — Margaret Allen

Categories
Energy & Matter Health & Medicine Plants & Animals Student researchers

Aids, cancer targeted by biology researchers

In his third-floor laboratory in Dedman Life Sciences Building, biologist Robert Harrod and his team are zeroing in on a new way to inhibit the virus that causes AIDS. They already have shown that their approach, which involves the rare genetic disorder Werner syndrome, works when the disorder’s enzyme defect is introduced into cells.

Now they are trying to find practical ways to use this pathway to inhibit the AIDS virus. The beauty of this approach is that the AIDS virus will not be able to mutate in a way that can defeat this treatment, says Harrod, associate professor in the Biological Sciences Department of Dedman College.

Harrod%2CRobert%20lab2.jpg

Down the hall from Harrod’s lab, Assistant Professor of Biological Sciences Jim Waddle is preparing to file for a patent on a tiny “worm” that is expected to be highly useful in drug-testing, producing results far more quickly than tests run on larger lab creatures.

Meanwhile, their colleagues, Associate Professor Pia Vogel and her husband, John Wise, a lecturer in the Biological Sciences Department, are conducting work that may have implications for cancer treatment.

In university laboratories throughout the world, enormous strides have been made in biology research in recent years, including the mapping of the human genome. With young faculty members like Harrod, Waddle and Vogel working on cutting-edge conundrums, and a recent $3.6 million gift to Biological Sciences, SMU’s department is poised to play a high-profile role in biology advances in coming years, says William Orr, chair and professor of biological sciences.

The gift from philanthropist and SMU Board of Trustees member Caren Prothro and the Perkins-Prothro Foundation includes $2 million for an endowed chair, $1 million for an endowed research fund, $500,000 for a graduate fellowship fund and $100,000 for an undergraduate scholarship fund.

The endowment will enable the University to attract a biologist with a national reputation in research to join a faculty that is strong in cellular and molecular biology and biochemistry and is doing research that could have practical applications in medicine, Orr says.

john.jpg

For example, Vogel and Wise are looking for a way to improve the long-term efficacy of chemotherapy treatments. Wise uses a nautical metaphor to explain their work: “Picture a cancer cell as a ship on a sea and the chemotherapy being dumped into the ship, there’s a mechanism like a sump pump that will dump that chemical back overboard,” he says.

That cellular “sump pump” is important to normal cell health because it keeps toxins out.

“Of course, with cancer cells that are targeted for destruction by chemotherapeutics, you’d like to be able to turn off that mechanism,” Wise adds.

John Wise

Vogel explains that many cancer cells respond to treatment by pumping out more and more of the toxins as time goes on, so that a cancer treatment that works well initially might not work as well in later stages.

“Switching chemotherapy drugs doesn’t help because the cancer cells just pump out everything, resulting in multi-drug resistance,” she says.

pia.jpg

Using Electron Spin Resonance Spectroscopy, a biophysical technique that obtains structural information about the cellular pump, Vogel’s research group is trying to find a way to shut off the ATP energy usage by this cellular sump pump.

“If you can knock out the pump, you can sink the cancer ship,” she says.

Harrod, who studies retroviruses that infect humans and who is focusing on transcriptional gene regulation, is working on a mechanism that might sidestep a more specific type of multidrug resistance — of the virus that causes AIDS to the conventional HAART (highly active antiretroviral treatment) drug regimen.

Pia Vogel

His approach is related to a rare genetic disorder called Werner syndrome, which causes premature aging in those who have the disease. Researchers have noted that individuals who are carriers for Werner syndrome do not develop AIDS. Harrod hypothesized that the enzyme involved in Werner syndrome is necessary for transcription of the retrovirus.

caenorhabditis-elegans.jpg

Using cells that had the Werner syndrome defect inserted into them, his lab was able to confirm this link, and last year he and co-researchers published the findings in “The Journal of Biological Chemistry.” Now his group is looking for molecules that might be used to block this transcription-necessary enzyme. Included among the researchers cited in the journal article were several biological sciences students. Both graduate and undergraduate students assisted Harrod in his lab work on retroviral transcription.

Ask Assistant Professor Jim Waddle about the contributions made by students, and he’ll talk about the weird “worm” discovered by one of his graduate students. Waddle, whose Ph.D. work was in molecular genetics, has been studying the nematode Caenorhabditis elegans as a model for food absorption in the human gut.

Fingerlike projections called microvilli, which are necessary for the absorption of nutrients, line the human gut; nematodes have microvilli on every gut cell.

jim.jpg

As part of their research, Waddle’s lab doused the nematodes in mutation-causing chemicals and examined them via a fluorescent protein.

Ph.D. candidate Christina Paulson looked at 20,000 nematodes in this manner and came up with one that had a nematode version of diverticulosis, with outpouchings all along the gut.

Disappointingly, the mutated worm turned out to be normal in terms of lifespan, reproduction and absorption of nutrients. But, Waddle says, “we threw our heads together and thought about conditions the nematode might encounter in the wild” versus the laboratory setting. He wondered if the worm might have trouble eliminating toxins. It did.

Jim Waddle

Normal nematodes eliminate toxins too quickly for the worms to be useful in drug testing, but toxins stay in the weird worms long enough to have an effect on them. And that means the millimeter-long creature likely will be highly useful in drug-testing situations, because a nematode’s life cycle is so much shorter than that of the larger animals, such as mice, that generally are used to test drugs.

christina-paulson-150.jpg

The student who identified the worm is one of 18 graduate students in the Department of Biological Sciences. Nine are working on Master’s degrees, nine on Ph.Ds. With 126 undergraduates, the department enrolls the largest segment of undergraduate majors in the natural sciences at SMU. Undergraduate students who intend to go into biological research can apply for the BRITE (Biomedical Researchers in Training Experience) program, a collaboration between SMU and the University of Texas Southwestern Medical Center that leads to acceptance into a UT Southwestern Ph.D. program.

Orr believes the department is poised for a leap forward in size and stature. Administrative support to boost research has come from Provost Paul Ludden, whose background is in biochemistry. Current research projects are supported by $4.3 million from agencies that include the National Institutes of Health and the National Science Foundation.
Christina Paulson

Orr’s dream for the department is to double the current tenured and tenure-track faculty to 18 members. Of the nine, seven conduct ongoing research projects, five of which are funded by federal agencies. The department will add an assistant professor in spring 2009. Later that year, a national search will be conducted to fill the new Distinguished Chair of Biological Sciences.

william.jpgAlthough the department is small, a synergy has developed from building a faculty that is focused on cellular and molecular biochemistry, Orr says.

Researchers can work together on projects, brainstorming ideas for new areas of investigation. More grants can be applied for, which means more grants awarded.

“We have a strong group that is focused on certain areas. By adding new faculty we will be able to boost the overall stature of the department,” Orr says. “If we increase the academic stature and the amount of research, we can provide more opportunities for graduate students and for undergraduates. It all works together.” — Cathy Frisinger

William Orr

Related links:
Robert Harrod
Jim Waddle
Pia Vogel
John Wise
William Orr
Biological Sciences Department
Dedman College of Humanities and Sciences