Tag: SMU Department of Biological Sciences

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

Post author By Margaret Allen
Post date January 23, 2018

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

Tags Center for Drug Discovery Design and Delivery, Dedman College, John Wise, Pia Vogel, SMU Department of Biological Sciences

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Dallas Innovates: SMU Researchers, Gamers Partner on Cancer Research

Post author By Margaret Allen
Post date June 7, 2017

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.

Tags Center for Drug Discovery Design and Delivery, Corey Clark, Dedman College, John Wise, Pia Vogel, SMU Department of Biological Sciences, The Guildhall, The Guildhall at SMU

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

Post author By Margaret Allen
Post date May 8, 2017

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

Tags Center for Drug Discovery Design and Delivery, Corey Clark, Dedman College, James McCormick, John Wise, Lauren Ammerman, Pia Vogel, SMU Department of Biological Sciences, The Guildhall, The Guildhall at SMU

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NCI grant funds SMU research into cancer-causing viruses that hide from the immune system

Post author By Margaret Allen
Post date November 8, 2016

Genes common to both the human T-cell leukemia virus and high-risk human papillomaviruses activate survival mechanisms in cancer cells. An SMU lab, with National Cancer Institute funding, is hunting ways to inhibit those genes to halt the development of cancer.

SMU virologist and cancer researcher Robert L. Harrod has been awarded a $436,500 grant from the National Cancer Institute to further his lab’s research into how certain viruses cause cancers in humans.

Under two previous NCI grants, Harrod’s lab discovered that the human T-cell leukemia virus type-1, HTLV-1, and high-risk subtype human papillomaviruses, HPVs, share a common mechanism that plays a key role in allowing cancers to develop.

Now the lab will search for the biological mechanism — a molecular target — to intervene to block establishment and progression of virus-induced cancers. The hope is to ultimately develop a chemotherapy drug to block the growth of those tumor cells in patients.

“The general theme of our lab is understanding the key molecular events involved in how the viruses allow cancer to develop,” said Harrod, an associate professor in SMU’s Department of Biological Sciences whose research focuses on understanding the molecular basis of viral initiation of cancer formation.

While HTLV-1 and HPV are unrelated transforming viruses and lead to very different types of cancers, they’ve evolved a similar mechanism to cooperate with genes that cause cancer in different cell types. The lab discovered that the two viruses tap a common protein that cooperates with cellular genes to help the viruses hide from the immune system.

That common protein, the p30 protein of HTLV-1, binds to a different protein in the cell, p53, which normally has the job of suppressing cancerous growth or tumor development. Instead, however, p30 manages to subvert p53’s tumor suppressor functions, which in turn activates pro-survival pathways for the virus.

From there, the virus can hide inside the infected cell for two to three decades while evading host immune-surveillance pathways. As the cell divides, the virus divides and replicates. Then ultimately the deregulation of gene expression by viral encoded products causes cancer to develop.

“They are essentially using a similar mechanism, p30, to deregulate those pathways from their normal tumor-suppressing function,” Harrod said.

Tumor suppression, DNA damage-repair pathways, begin to fail with age
About 15 percent to 20 percent of all cancers are virus related. Worldwide, about 10 million people are infected with HTLV-1 and, as with other viral-induced cancers, about 3 percent to 5 percent of those infected go on to develop malignant disease.

Cancer is often associated with the process of normal aging, because our tumor suppression and DNA damage-repair pathways begin to break down and fail, explained Harrod. Our pathways don’t as easily repair genetic mutations, which makes us more susceptible to cancers like adult T-cell leukemia and HPV-associated cervical cancers or head-and-neck carcinomas, he said.

The human T-cell leukemia virus is transmitted through blood and body fluid contact, usually infecting infants and children via breastfeeding from their mother. A tropical infectious disease, it’s endemic to Southeast Asia, primarily Japan, Taiwan, China and Malaysia, as well as certain regions in the Middle East, Northern Africa and islands of the Caribbean. In the United States, Hawaii and Florida have the highest incidence of adult T-cell leukemia. HTLV-1 is highly resistant to most modern anticancer therapies, including radiotherapy and bone marrow or matching donor stem cell transplants. The life expectancy of patients with acute or lymphoma-stage disease is about six months to two years after diagnosis.

In the case of HPV, certain high-risk sub-types aren’t inhibited by today’s available HPV vaccines. It’s considered the high-risk HPVs are sexually transmitted through direct contact with the tissues of the virus-producing papillomas or warts. High-risk HPVs can also cause cervical cancers and head and neck carcinomas, many of which are associated with poor clinical outcomes and have high mortality rates.

How do viruses cause cancer?
For both HTLV-1 and HPV, the virus itself does not cause cancer to develop.

“It’s cooperating with oncogenes — cellular genes that become deregulated and have the potential to cause cancer,” Harrod said. “The role of these viruses, it seems, is to induce the proliferation of the cell affected with cancer. We’re trying to understand some of the molecular events that are associated with these cancers. ”

The lab’s three-year NCI grant runs through 2019. Harrod’s two previous grants awarded by the National Institutes of Health were also three-year-grants, for $435,000 and $162,000. Each one has targeted HTLV-1 and the p30 protein.

The lab’s first NCI grant came after the researchers provided the first demonstration that p30 could cooperate with cellular oncogenes, which have the potential to cause cancer, to cause deregulated cell growth leading to normal cells transforming into cancer cells. That original discovery was reported in 2005 in the article “A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions,” in the high-profile journal Molecular and Cellular Biology.

“We find that the p30 protein is involved in maintaining the latency of these viruses. These viruses have to persist in the body for 20 to 40 years before a person develops disease. To do that they have to hide from the immune response,” Harrod explained. “So p30 plays a role in silencing the viral genome so that the affected cells can hide, but at the same time it induces replication of the affected cells. So when the cell divides, the virus divides. We call that pro-viral replication.”

The term “latency maintenance factor” in reference to p30 originated with Harrod’s lab and has gained traction in the HTLV-1 field.

Under the lab’s second NCI grant, the researchers figured out how to block pro-survival pathways to kill tumor cells.

In the current grant proposal, Harrod’s lab demonstrated that by inhibiting specific downstream targets of p53 — essentially blocking pathways regulated by the p53 protein — they could cause infected tumor cells to collapse on themselves and undergo cell death.

“We do that independent of chemotherapy,” Harrod said. “So that was a big find for us.”

Goal is to eliminate cancer cells by inhibiting pathway
Each grant project builds upon the one before it, and the third grant extends the work, to now include high-risk HPVs.

“Now that we’ve shown we can block one or two of these factors to cause cell death, we’re starting to get an eye really on how we can inhibit these cancer cells and what potentially down the road may lead to a therapeutic,” Harrod said. “That’s the ultimate goal.”

One of the biggest challenges will be to inhibit the pathways in the tumor cells without targeting normal cells, he said. The lab’s recent findings indicate the researchers may soon be within reach of identifying a new strategy to eliminate cancer cells by inhibiting pathways key to their survival.

Harrod’s lab collaborates on the research with: Lawrence Banks, Tumor Virology Group Leader, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; Brenda Hernandez, Associate Director, Hawaii Tumor Registry, University of Hawaii Cancer Center, Honolulu; and Patrick Green, Director, Center for Retrovirus Research, The Ohio State University. — Margaret Allen, SMU

Tags Dedman College, Robert Harrod, SMU Department of Biological Sciences

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SMU biochemists, students probe membrane proteins that thwart cancer chemotherapies

Post author By Margaret Allen
Post date August 31, 2016

“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.

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

Tags Center for Drug Discovery Design and Delivery, Dedman College, John Wise, Pia Vogel, SMU Department of Biological Sciences

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

Post author By Margaret Allen
Post date January 8, 2016

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:

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.

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.

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.

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)

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 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)

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.

Tags Alan Humason, Alisa J. WInkler, Annette Caldwell Simmons School of Education and Human Development, Anthony Fiorillo, Beatrice Magnani, Bonnie F. Jacobs, Brian W. Stump, Chris Hayward, Christopher Strganac, Dale A. Winkler, Dani Setlawan, David Meltzer, Dedman College, Diana Vineyard, Diego Román, Dieter Creme, Elfi Kraka, Ernest Jouriles, Fredrick Olness, Gary Johnson, Heather R. DeShon, Jodi Cooley, John F. Graf, John Wise, Kate Andrzejewski, Kurt Ferguson, Lauren Michael, Lorelei Simpson Rowe, Louis L. Jacobs, Marek Freindorf, Matthew Clemens, Matthew J. Hornbach, Michael J. Polcyn, Neil Tabor, Pavel Nadolsky, Pia Vogel, Randy Scalise, Renee McDonald, Robert Gregory, Robert Kalescky, Robert Kehoe, Roy M. Huffington Department of Earth Sciences, Santanu Roy, Simon Dalley, SMU Department of Anthropology, SMU Department of Biological Sciences, SMU Department of Chemistry, SMU Department of Economics, SMU Department of Physics, SMU Department of Psychology, Stephen J. Sekula, Thomas Sexton, Timothy S. Myers, Vytor Oliveira, Wenli Zou

Health & Medicine Videos

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

Post author By Margaret Allen
Post date September 8, 2015

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.”

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.”

Tags Dedman College, James McCormick, John Wise, Pia Vogel, SMU Department of Biological Sciences

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

Post author By Margaret Allen
Post date September 8, 2015

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)

“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.”

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.

Tags Center for Drug Discovery, Courtney A. Follit, Dedman College, Frances K. Brewer, John Wise, Pia Vogel, SMU Department of Biological Sciences

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Prevention: Is Organic Food Really Better For You?

Post author By Margaret Allen
Post date August 22, 2013

What you need to know about the safety and health of your food

Health and science reporter Richard Laliberte with Prevention Magazine has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer. The research by Plano, Texas high school student Ria Chhabra is featured in the article, “Is Organic Food Really Better For You?,” published Aug. 21.

Bauer, an assistant professor in SMU’s Department of Biological Sciences, mentored Chhabra in her research to examine whether there would be health differences to fruit flies fed an organic diet or a nonorganic diet. Chhabra’s study found that flies fed an organic diet fared better on important health tests, particularly fertility and longevity.

Read the article.

EXCERPT:

By Richard Laliberte
Prevention Magazine
The Chhabra household of Plano, TX, couldn’t resolve a family dispute. “My husband and I are vegetarian,” says Babita Jain Chhabra. “Our family already eats more fruits and vegetables than most people, and they’re expensive.” Her husband wanted to buy cheap produce at Walmart. Babita said no—the family should buy organic products because their two children needed the healthiest food possible.

“She just assumed organic was healthier,” says Babita’s 16-year-old daughter, Ria, channeling her father’s skepticism. “That’s what sparked my interest.”

Ria, who was only 13 when the organic debate broke out at her dinner table, decided to settle it. She launched a middle school science fair project that bloomed into more than 2 years of research and eventually involved two Southern Methodist University researchers, Santharam Kolli and Johannes H. Bauer. This year, their study, which found that fruit flies that ate organic foods did better in almost every health measure the researchers tracked (living longer, laying more eggs, resisting stress better, and acting livelier) than those that ate conventionally grown food, was published in PLOS One, an online peer-reviewed scientific journal.

For the Chhabras, it was case closed. They are now buying organic. “Because of Ria’s experiment, we know that in the long run, organic food will be better for us than anything else,” Babita says.

Most Americans are dabbling in organics—81% of families buy organic at least some of the time, according to a 2013 survey by the Organic Trade Association. And there are plenty of experts who think everyone should be as decisive as the Chhabras. One of them is Charles Benbrook, PhD, a research professor at Washington State University’s Center for Sustaining Agriculture and Natural Resources.

Last year, when a widely publicized Stanford University study analyzing more than 200 research papers comparing the benefits of eating organic versus conventionally grown food concluded that organic food isn’t any healthier, Dr. Benbrook corrected their math. Utilizing government data on pesticide toxicity, he countered with his own findings that there’s a full 94% reduction in health risks if you eat organic rather than conventional foods. The Stanford researchers had looked at nine old studies about pesticide residue on produce and noted that organics have 30% fewer toxins than conventional crops—but failed to calculate the health benefits based upon the most recent USDA data on actual residues in food.

Read the article.

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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.

Tags Dedman College, Johannes H. Bauer, Ria Chhabra, SMU Department of Biological Sciences

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The Sydney Morning Herald: Flying in the face of the organic debate

Post author By Margaret Allen
Post date April 30, 2013

Unlikely as it may sound, a 16-year-old’s school science project has added weight to the organic versus conventional debate

Life & Style reporter Sarah Berry with The Sydney Morning Herald has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra. The article, “Flying in the face of the organic debate,” published April 25.

Read the article.

EXCERPT:

By Sarah Berry
The Sydney Morning Herald
A 16-year-old’s school science project has added weight to the argument that eating organically has greater health benefits than eating conventionally-grown foods.
Ria Chhabra overheard her parents debating the topic and decided to see if she could find out the answer for herself, the New York Times reports.

To test whether organically grown food provides greater health benefits than its conventionally grown counterpart, Chhabra turned to fruit flies; they have around 75 per cent of the genes that cause disease in humans and have a short life span so a variety of biological factors can be studied in a reasonably short period of time.

Her experiment was conducted over her summer break with the help of an assistant professor and a researcher at Southern Methodist University in Dallas. It won her top honours in a national science competition and has now been published in the respected Plos One journal.

Half of the flies in the experiment were fed an organic diet and the other half a conventional one. She then tested levels of fertility, stress resistance, physical activity and longevity.

They found that eating organically improved levels on virtually all fronts.
“These data suggest that organic foods are more nutritionally balanced than conventional foods, or contain higher levels of nutrients, leading to improved fertility and longevity,” they said.

Similarly, flies on the organic diet were more active and had greater stress resistance.
The main exception to these findings was that the diet had to be balanced. Flies that were fed only one type of organic food had shorter lifespans and were less fertile than those fed a balanced conventional diet.

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New York Times: Is Organic Better? Ask a Fruit Fly

Post author By Margaret Allen
Post date April 18, 2013

New York Times reporter Tara Parker-Pope has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer.

The article on the New York Times Wellness blog covers the research of Bauer and Plano, Texas, high school student Ria Chhabra. “Is Organic Better? Ask a Fruit Fly” appeared April 17.

Read the New York Times article.

EXCERPT:

Tara Parker-Pope
New York Times
When Ria Chhabra, a middle school student near Dallas, heard her parents arguing about the value of organic foods, she was inspired to create a science fair project to try to resolve the debate.

Three years later, Ria’s exploration of fruit flies and organic foods has not only raised some provocative questions about the health benefits of organic eating, it has also earned the 16-year-old top honors in a national science competition, publication in a respected scientific journal and university laboratory privileges normally reserved for graduate students.

The research, titled “Organically Grown Food Provides Health Benefits to Drosophila melanogaster,” tracked the effects of organic and conventional diets on the health of fruit flies. By nearly every measure, including fertility, stress resistance and longevity, flies that fed on organic bananas and potatoes fared better than those who dined on conventionally raised produce.

While the results can’t be directly extrapolated to human health, the research nonetheless paves the way for additional studies on the relative health benefits of organic versus conventionally grown foods. Fruit fly models are often used in research because their short life span allows scientists to evaluate a number of basic biological effects over a relatively brief period of time, and the results provide clues for better understanding disease and biological processes in humans.

Read the New York Times article.

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Le Journal de la Science: Et si manger bio était bel et bien meilleur pour la santé?

Post author By Margaret Allen
Post date April 15, 2013

Le Journal de la Science: And if eating organic was indeed better for your health?

Science journalist Alain Tranet writing in the Paris-based science publication Le Journal de la Science has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra. The article, “Et si manger bio était bel et bien meilleur pour la santé?,” published April 3.

Read the article in French. An English translation follows the French excerpt below.

EXCERPT:

By Alain Tranet
Le Journal de la Science
Manger bio serait-il en définitive meilleur pour la santé ? C’est en tout cas ce que suggère une étude américaine menée… sur la mouche du vinaigre. Un résultat qui contredit plusieurs précédents travaux.

Manger bio a-t-il un effet bénéfique sur la santé humaine ? Alors que ce débat fait rage depuis de nombreuses années maintenant, une nouvelle étude menée sur la drosophile met en lumière l’existence d’une influence positive de l’alimentation biologique sur la santé de cette mouche (laquelle est, rappellons-le, un modèle animal abondamment utilisé par les scientifiques pour toutes sortes d’expérimentation, et notamment celles portant sur les mécanismes cellulaires du vieillissement). Ce résultat a été publié par des biologistes américains de la Southern Methodist University (Dallas, États-Unis) dans la revue en accès ouvert PLoS One, sous le titre “Organically Grown Food Provides Health Benefits to Drosophila melanogaster”.

Quelle est la nature exacte du résultat obtenu par le biologiste Johannes H. Bauer et ses collègues ? Ils ont constaté que des mouches drosophiles nourries durant toute leur (courte) existence avec des aliments issus de l’agriculture biologique présentaient une longévité accrue et une plus grande fertilité par rapport à des drosophiles nourries avec des produits issus de l’agriculture conventionnelle.

Plus précisément, les scientifiques ont testé les effets sur la santé de quatre produits issus de l’agriculture biologique : des pommes de terre, du raisin des bananes et du soja. Pour évaluer les effets séparés de ces quatre aliments, quatre groupes de 200 drosophiles ont été constitués, recevant chacun l’un ou l’autre de ces produits durant l’intégralité de leur vie, ainsi que quatre groupes contrôle constitués de 200 drosophiles recevant également durant toute leur existence l’équivalent non biologique de l’un ou l’autre de ces quatre aliments.

TRANSLATION:
Is eating organic ultimately better for our health? That’s what a new U.S. study suggests … for the fruit fly. The result contradicts several previous studies.

Does eating organic have a beneficial effect on human health? While this debate has been raging for many years now, a new study on Drosophila highlights the existence of a positive effect of organic food on the health of the fly (which is, remember, an animal model widely used by scientists for all kinds of experiments, including those on the cellular mechanisms of aging). This result was published by American biologists from Southern Methodist University (Dallas, USA) in the open access journal PLoS One, titled “Organically Grown Food Provides Health Benefits to Drosophila melanogaster.”

What is the exact nature of the result obtained by the biologist Johannes H. Bauer and his colleagues? They found that fruit flies fed throughout their (short) life with organically grown food had increased longevity and higher fertility compared to fruit flies fed with products from conventional farming.

Specifically, the scientists tested the effects on health of four kinds of produce from organic farming: potatoes, grapes, bananas and soybeans. To assess the separate effects of these four foods, 200 fruit flies were sorted into four groups, each receiving either of these products during their entire life, and four control groups consisting of 200 Drosophila also receiving an equivalent non-organic diet.

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Fast Company: Organic Food Will Make You Live Longer And Be More Fertile (If You’re A Fly)

Post author By Margaret Allen
Post date April 5, 2013

Journalist Ariel Schwartz on Fast Company’s Co.Exist web site has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer.

The article, which covers the research of Bauer and Plano, Texas, high school student Ria Chhabra, appeared April 1, “Organic Food Will Make You Live Longer And Be More Fertile (If You’re A Fly).”

Read the Fast Company article.

EXCERPT:

Ariel Schwartz
Fast Company
A new study found that the bugs that ate an organic diet were more healthy and lived longer. So, ask yourself, how much like a fly are you?

Organic food can help you live longer–if you happen to be a fruit fly. A study from researchers at Southern Methodist University found that fruit flies (Drosophila melanogaster) fed on a diet of organic produce experienced increased fertility and longevity. This could have implications for humans, but don’t start using the study as a pro-organic talking point just yet.

The researchers involved in the study (including high school student Ria Chhabra, who was inspired to initiate the study after speaking with her parents about the benefits of organic food) nourished growing fruit flies with produce–bananas, potatoes, raisins, and soy beans bought from a grocery store. Some of the flies received conventional produce, and others ate organic versions.

Ultimately, the researchers found that none of the flies lived that long–as they note in the study, “Drosophila cultured on produce extract diets were generally shorter lived than flies raised on regular lab food, presumably due to limited nutritional balance in diets prepared from a single produce source.” Within the confines of the study, however, the flies who ate on the organic foods fared best (though the flies that gorged themselves on just organic raisins fared worse so, you know, be careful). The flies fed with organic produce also had a longer egg production peak than their counterparts.

At this point, you might be thinking that the study is a major rebuke to another study from 2012 that found organic food to be no more healthy than conventionally grown food. But that study actually looked at humans, not fruit flies. Another problem: The more recent study provides no indications as to why the fruit flies lived longer and more fertile lives. So take any pro-organic conclusions with a grain of natural sea salt.

Read the Fast Company article.

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MNN: Organic food is good for flies, study finds

Post author By Margaret Allen
Post date April 2, 2013

The Mother Nature Network covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “Organic food is good for flies, study finds.”

Read the Mother Nature Network article.

EXCERPT:

By Russell McLendon
Mother Nature Network
Fruit flies live longer and lay more eggs when they eat organic food, according to a study published by university researchers and an ambitious Texas teenager.

After listening to her parents debate the benefits of buying organic food, Ria Chhabra decided to take matters into her own hands. The Texas high-school student — along with biology researchers from Southern Methodist University — began studying how an organic diet affects the health of fruit flies, hoping to shed light on potential benefits for people.

Fruit flies and humans have lots of obvious physiological differences, but the insects are still common test subjects for studying human health, since about 77 percent of known human disease genes have a relevant match in the fruit-fly genome. And based on Chhabra’s research, both species may have a lot to gain by eating more organic food.

“To our surprise, in the majority of our tests of flies on organic foods, the flies fed organic diets did much better on our health tests than the flies fed conventional food,” says SMU biologist Johannes Bauer, who served as Chhabra’s mentor, in a press release. “Longevity and fertility are the two most important aspects of fly life. On both of these tests, flies fed organic diets performed much better than flies fed conventional diets. They lived longer, had higher fertility, and had a much higher lifetime reproductive output.”

That’s a promising result, but as Chhabra points out, it’s still unclear why exactly the organic-fed flies turned out healthier.

“We don’t know why the flies on the organic diet did better,” says Chhabra, a student at Clark High School in Plano, Texas. “That will require further research. But this is a start toward understanding potential health benefits.”

Read the Mother Nature Network article.

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Outside: Eating Organic Helps Flies Live Longer

Post author By Margaret Allen
Post date March 28, 2013

Outside magazine writer Adam Roy has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “Eating organic helps flies live longer.”

Read the Outside article.

EXCERPT:

By Adam Roy
Outside Online
Eating organic food may help you live longer—if you’re a fly, that is. A group of researchers from Southern Methodist University offered fruit flies extracts of different varieties of organic and conventional produce purchased at the same Whole Foods in Texas. They found that flies who fed on organic potatoes, raisins and soy enjoyed a significantly longer lifespan and were more fertile.

The new report follows a study published by Stanford researchers last year which found that organic produce wasn’t significantly more nutritious than conventionally-raised fruits and vegetables, provoking a debate on the merits of chemical-free food. While the new study’s authors stop short of saying that the results are as applicable to humans as to flies, they do suggest that other animals could reap some of the same health benefits.

Read the Outside article.

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Dallas Observer: SMU Researchers Prove that Eating Organic Makes You Live Longer — If You’re a Fly

Post author By Margaret Allen
Post date March 28, 2013

Dallas Observer journalist Eric Nicholson has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “SMU Researchers Prove that Eating Organic Makes You Live Longer — If You’re a Fly.”

Read the Observer article.

EXCERPT:

Eric Nicholson
Dallas Observer
There was a minor furor in the media last year when a study conducted by a researcher at Standford’s medical school concluded that organic fruits and vegetables are no healthier than their conventionally raised counterparts. This wasn’t quite as newsworthy as the headlines made it sound, since the study was looking mainly at vitamin content of produce, not at the chemicals that were or were not sprayed on it. Precious few people buy organic carrots expecting through-the-roof levels of beta carotene.

Then again, maybe they should. A new study by researchers at SMU, which is clearly more definitive than the Stanford one because it’s newer, suggests that eating organic food may cause you to live longer. If you’re a fruit fly.

They chose fruit flies essentially because they’re easier to keep on an all-organic diet, since they can’t sneak off and binge on Twinkies and they don’t object to consuming a single type of liquified produce from Whole Foods (either potatoes, raisins, bananas, or soybeans, depending on the fly) for their entire lives. They also live for about a month, making it easier to parse out the effect of diet on lifespan.

The Atlantic reported this morning on the study’s results:

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The Atlantic: Eating Organic Food Associated With Longer Lives (in Flies)

Post author By Margaret Allen
Post date March 28, 2013

The Atlantic has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “Eating Organic Food Associated With Longer Lives (in Flies).”

Read The Atlantic article.

EXCERPT:

Lindsay Abrams
The Atlantic
Fruit flies fed organic produce from Whole Foods lived longer and laid more eggs than those fed the store’s conventionally grown offerings.

PROBLEM: Last September when Stanford researchers came out with findings that organic food doesn’t confer any additional nutritional value, the world countered: Of course not. While organic fruits and vegetables can claim health benefits in that they lack any number of additives that come included with traditionally farmed foods, calling produce organic doesn’t make it any healthier than it already, by virtue of being a fruit or vegetable, is supposed to be.

Still, that doesn’t mean researchers can’t turn it around and ask if produce containing chemicals, preservatives, and hormones are, comparatively, a little bit less healthy. While we know organic food serves the interests of the environment, public health, and human rights, there’s a lot we still don’t know about its benefits for the individual supermarket shopper deciding between the banana with the “organic” sticker and the one that’s heaped in with the other, conventional foods.

METHODS: At Southern Methodist University, researchers raised fruit flies on extracts of typical grocery store produce. Different groups of flies received either organic or conventional versions of potatoes, soybeans, raisins, or bananas, all purchased from the same Texas Whole Foods.

RESULTS: Despite the relatively poor health exhibited by all — as happens when one lives its entire life consuming only one type of food — the flies who ate organic generally performed better on a number of health measures.

Specifically, diets of organic potatoes, raisins, and soy were all associated with significantly longer lifespans, with no difference seen between organic and conventional bananas. Flies raised on organic versions of all four foods were more fertile.

Read The Atlantic article.

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CBS News: Organic foods linked to better fertility, longevity in fruit flies

Post author By Margaret Allen
Post date March 27, 2013

CBS News has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “Organic foods linked to better fertility, longevity in fruit flies.”

Read the CBS News article.

EXCERPT:

Ryan Jaslow
CBS News
New research shows eating lots of organic food can lead to a healthier life — if you happen to be a fruit fly.

Scientists fed fruit flies extracts from either organic foods or non-organic, conventionally-grown foods, and found the organic group was healthier and lived longer than their counterparts.

“We don’t know why the flies on the organic diet did better. That will require further research. But this is a start toward understanding potential health benefits,” study leader Ria Chhabra, a student at Clark High School in Plano, Texas, said in a written statement.

That’s right, the study was led by a Texas high school student who got the idea from hearing her parents discuss whether or not it was worth it to buy organic foods for health reasons.

So, Chhabra teamed up with her mentor, Dr. Johannes H. Bauer, an assistant professor of biology at Southern Methodist University in Texas.

“It’s rare for a high school student to have such a prominent position in the lab. But Ria has tremendous energy and curiosity, and that convinced me to give this research project a try,” Bauer said.

The fruit fly, or Drosophila melanogaster, is used in Bauer’s lab and other research facilities to study human diseases including diabetes, heart disease and even Alzheimer’s. Fruit flies are widely used in research because they’re cheaper and have a shorter life cycle than other lab animal models.

Read the CBS News article.

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UPI: Some organic food may be healthier

Post author By Margaret Allen
Post date March 27, 2013

The international news wire service UPI has covered research carried out in the fruit fly lab of SMU biologist Johannes H. Bauer by Plano, Texas, high school student Ria Chhabra in its March 27, 2013, article “Some organic food may be healthier.”

Read the UPI article.

EXCERPT:

UPI
Fruit flies fed an organic diet did better on tests of general health and two significant measures of health — fertility and longevity, U.S. researchers say.

Ria Chhabra a student at Clark High School in Plano, Texas; biologist Johannes H. Bauer of the Southern Methodist University in Dallas; and Santharam Kolli, a research associate at SMU, said the data demonstrated fruit flies raised on organic food extracts performed better on the majority of health tests.

“We don’t know why the flies on the organic diet did better. That will require further research. But this is a start toward understanding potential health benefits,” Chhabra said in a statement.

Chhabra said the study was inspired by a conversation her parents had on the merits of buying organic food.

Bauer said his laboratory utilized one of the most widely used model systems, the fruit fly Drosophila melanogaster, often used to study human diseases such as diabetes, heart function and Alzheimer’s disease because of the fruit fly’s short life cycle and low cost.

The study, published in PLoS One, also found some negative or neutral results using diets prepared from organic raisins, which might suggest the beneficial health effects of organic diets might be dependent on specific food items, Bauer said.

Read the UPI article.

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Fruit flies fed organic diets are healthier than flies fed nonorganic diets, study finds

Post author By Margaret Allen
Post date March 25, 2013

Fruit flies raised on diets based on organic foods performed better on a variety of health tests, including fertility and longevity

A new study looking at the potential health benefits of organic versus non-organic food found that fruit flies fed an organic diet recorded better health outcomes than flies fed a nonorganic diet.

The study from the lab of SMU biologist Johannes H. Bauer, Southern Methodist University, Dallas, found that fruit flies raised on diets of organic foods performed better on several tests for general health.

“While these findings are certainly intriguing, what we now need to determine is why the flies on the organic diets did better, especially since not all the organic diets we tested provided the same positive health outcomes,” said Bauer, principal investigator for the study.

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Fruit flies on organic diets showed improvements on the most significant measures of health, namely fertility and longevity, said high school student researcher Ria Chhabra.

“We don’t know why the flies on the organic diet did better. That will require further research. But this is a start toward understanding potential health benefits,” said Chhabra, a student at Clark High School in Plano, Texas, who led the experiment.

Chhabra sought to conduct the experiments after hearing her parents discuss whether it’s worth it to buy organic foods to achieve possible health benefits.

Bauer, an assistant professor in SMU’s Department of Biological Sciences, mentored Chhabra by helping guide and design her research experiments. The research focus of Bauer’s fruit fly lab is nutrition and its relationship to longevity, health and diabetes.

“It’s rare for a high school student to have such a prominent position in the lab. But Ria has tremendous energy and curiosity, and that convinced me to give this research project a try,” Bauer said.

The findings, “Organically grown food provides health benefits to Drosophila melanogaster,” have been published in the open access journal PLOS One. Buaer and Chhabra co-authored the paper with Santharam Kolli, a research associate at SMU. The article is available from PLOS One online at http://bit.ly/RGB8LJ.

Flies on organic food performed better on some health tests
“The data demonstrated that flies raised on organic food extracts by-and-large performed better on the majority of health tests,” reported the researchers.

It remains unclear why organic diets delivered better health, the researchers said.

The Bauer lab results come at a time when the health effects of organic food are widely debated.

Prior studies by other researchers have found conflicting results when reviewing the scientific literature for data. While several studies have shown elevated nutrient content and lower pesticide contamination levels in organic food, a recent publication reporting a large-scale analysis of all available studies concluded no clear trend was apparent.

Fruit flies were fed extracts from produce purchased at a grocery store
In order to investigate whether organic foods are healthier for consumers, the lab utilized one of the most widely used model systems, the fruit fly Drosophila melanogaster. Because of the low costs associated with fly research and the fly’s short life cycle, researchers use fruit flies to study human diseases, from diabetes to heart function to Alzheimer’s disease.

The Bauer lab fruit flies were fed organic and nonorganic produce purchased from a leading national grocery retailer of organic and conventional foods. The flies were fed extracts made from organic and conventional potatoes, soybeans, raisins and bananas. They were not fed any additional nutritional supplements. The researchers tested the effects of each food type independently and avoided any confounding effects of a mixed diet.

The health tests measured longevity, fertility, stress and starvation resistance.

Findings suggest beneficial health effects dependent on specific foods
Some negative or neutral results were obtained using diets prepared from organic raisins, which suggests the beneficial health effects of organic diets are dependent on the specific food item, Bauer said. That might explain some of the inconsistent results in the published studies in the scientific literature, he said, noting some studies suggest there is a nutritional benefit from organic food, while others suggest there is not.

“To our surprise, in the majority of our tests of flies on organic foods, the flies fed organic diets did much better on our health tests than the flies fed conventional food,” Bauer said. “Longevity and fertility are the two most important aspects of fly life. On both of these tests, flies fed organic diets performed much better than flies fed conventional diets. They lived longer, had higher fertility, and had a much higher lifetime reproductive output.”

Factors such as soil condition and latitude where the produce was grown weren’t considered, mimicking a typical grocery store shopping experience. — Margaret Allen

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Discover blog “80 beats”: Newly Unearthed Papers From Fossil Hunters Include An Ode to Bones

Post author By Margaret Allen
Post date October 5, 2012

The science magazine Discover has covered the research of SMU vertebrate paleontologist Louis L. Jacobs and the infamous Bone Wars of the late 1800s.

In a post on Discover’s “80 beats” blog, the magazine reprinted the translation of a poem written by frontier naturalist and fossil hunter Jacob Boll.

Jacobs came across the poem at the American Museum of Natural History on a label on the back of Eryops specimen No. AMNH 4183.

SMU biology professor Pia Vogel translated the poem. Vogel and Jacobs worked with SMU English professor John M. Lewis to retain the essence of the poem in English.

The Bone Wars was a flurry of fossil speculation across the American West that escalated into a high-profile national feud. Drawn into the spectacle were two scientists from the Lone Star State, geologist Robert T. Hill, now acclaimed as the Father of Texas Geology, and Boll, who made many of the state’s earliest fossil discoveries.

Hill and Boll had supporting roles in the Bone Wars through their work for one of the feud’s antagonists, Edward Drinker Cope, according to Jacobs’ new study.

A professor in Dedman College‘s Roy M. Huffington Department of Earth Sciences, Jacobs joined SMU’s faculty in 1983.

Currently his field projects include work in Mongolia and Angola. His book, “Lone Star Dinosaurs” (1999, Texas A&M University Press) was the basis of an exhibit at the Fort Worth Museum of Science and History that traveled the state. He consulted on the new exhibit, Mysteries of the Texas Dinosaurs, which opened in 2009.

Read the full story.

EXCERPT:

Discover
This poem in praise of the Permian amphibian Eryops was scrawled on the back of a label now in the American Museum of Natural History by Jacob Boll, a Swiss-German fossil hunter involved in a tumultuous 19th-century paleontology feud.

Graduate students and post-docs do a lot of important work in science these days, in the names of their more eminent supervisors, and there was a similar set-up in the early days of American paleontology. Many of the fossils named by and attributed to E.D. Cope and O.C. Marsh, archenemies and the era’s most prominent paleontologists, were collected in the field by hired hunters like Boll and his contemporary Robert T. Hill, who both worked for Cope.

Paleontologists sifting through papers in the library of Southern Methodist University recently came across letters between Hill and Cope and, while examining specimens at AMNH, happened on Boll’s little poem.

Read the full story.

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Frontburner: Texas’ Bone Wars Studied by SMU Professor

Post author By Margaret Allen
Post date September 10, 2012

Jason Heid, an editor with D Magazine’s popular Frontburner blog, covered the research of SMU vertebrate paleontologist Louis L. Jacobs and the infamous Bone Wars of the late 1800s.

The Bone Wars refers to a flurry of fossil speculation across the American West that escalated into a high-profile national feud. Drawn into the spectacle were two scientists from the Lone Star State, geologist Robert T. Hill, now acclaimed as the Father of Texas Geology, and naturalist Jacob Boll, who made many of the state’s earliest fossil discoveries.

Hill and Boll had supporting roles in the Bone Wars through their work for one of the feud’s antagonists, Edward Drinker Cope, according to Jacobs’ new study.

A professor in Dedman College‘s Roy M. Huffington Department of Earth Sciences, Jacobs joined SMU’s faculty in 1983.

Jacobs co-leads Projecto PaleoAngola, a collaborative international scientific research program focused on the ancient life of Angola.

Besides the discovery of the first dinosaur of Angola, the team has uncovered mosasaurs, plesiosaurs, turtles and other Cretaceous marine animals, but the aim is also to create a strong and lasting institutional and scientific collaboration that has a multiplier effect in Angolan academia.

In the laboratory, Jacobs’ research utilizes advanced imaging and stable isotope techniques to investigate paleoenvironmental, biogeographic and phylogenetic issues of the Mesozoic and Cenozoic eras.

Jacobs is featured by National Geographic on its Explorers web site, which acknowledges the work of the world’s scientists whose research is made possible in part through funding from National Geographic.

Read the full blog entry.

EXCERPT:

By Jason Heid
Frontburner
SMU paleontologist Louis Jacobs has been studying the role of two Texas fossil collectors in the 19th century Bone Wars, which played out across the American frontier as rivals competed fiercely to uncover new fossils (and thus discover new extinct species.) In doing so he found a poem written by one of the men, Dallas naturalist Jacob Boll, whose Swiss family was among those that founded the utopian La Reunion colony here.

During a break in his field labors, Boll’s fascination with ancient bones prompted him to write in his native German an ode to fossils. Jacobs found the poem in the American Museum of Natural History on a label on the back of Eryops specimen No. AMNH 4183.

SMU biology professor Pia Vogel translated the poem. Vogel and Jacobs worked with SMU English professor John M. Lewis to retain the essence of the poem in English.

Read the full blog entry.

Tags Dedman College, Institute for the Study of Earth and Man, John Lewis, Louis L. Jacobs, Pia Vogel, Roy M. Huffington Department of Earth Sciences, SMU Department of Biological Sciences, SMU Department of English

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Texas frontier scientists who uncovered state’s fossil history had role in epic Bone Wars

Post author By Margaret Allen
Post date September 5, 2012

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Treasure trove of archived letters discovered at SMU; Permian hunter’s German ode to a fossil is translated into English

In the late 1800s, a flurry of fossil speculation across the American West escalated into a high-profile national feud called the Bone Wars.

Drawn into the spectacle were two scientists from the Lone Star State, geologist Robert T. Hill, now acclaimed as the Father of Texas Geology, and naturalist Jacob Boll, who made many of the state’s earliest fossil discoveries.

Hill and Boll had supporting roles in the Bone Wars through their work for one of the feud’s antagonists, Edward Drinker Cope, according to a new study by vertebrate paleontologist Louis L. Jacobs, Southern Methodist University, Dallas.

The study by Jacobs expands knowledge about Cope’s work with Hill and Boll.

It also unveils new details about the Bone Wars in Texas that Jacobs deciphered from 13 letters written by Cope to Hill. Jacobs discovered the letters in an archive of Hill’s papers at SMU’s DeGolyer Library. The letters span seven years, from 1887 to 1894.

Hill, who worked for the U.S. Geological Survey, not only provided Cope with fossils of interest but also shared geological information about fossil locales.

Boll, who was a paid collector for Cope — as was the practice at the time — supplied the well-known paleontologist with many fossils from Texas. More than 30 of the taxa ultimately named by Cope were fossils collected by Boll.

“Fossils collected by Boll and studied by Cope have become some of the most significant icons in paleontology,” said Jacobs, an SMU professor of earth sciences and president of SMU’s Institute for the Study of Earth and Man.

Robert T. Hill USGS survey party — The survey party of USGS geologist Robert T. Hill explored Texas during the 1800s to report on the geology and resources to open the West to agriculture. (Credit: USGS)

Jacobs’ study, “Jacob Boll, Robert T. Hill, and the Early History of Vertebrate Paleontology in Texas,” is published in the journal Historical Biology as part of the conference volume of the 12th International Symposium on Early Vertebrates/Lower Vertebrates.

Rush to find fossils explodes during opening of the American West
Jacobs describes the late 1800s as a period of intense fossil collecting. The Bone Wars were financed and driven by Cope and his archenemy, Othniel Charles Marsh. The two were giants of paleontology whose public feud brought the discovery of dinosaur fossils to the forefront of the American psyche.

Cope, from Philadelphia, and Marsh, from Yale University, began their scientific quests as a friendly endeavor to discover fossils. They each prospected the American frontier and also hired collectors to supply them with specimens. Cope and Marsh identified and named hundreds of discoveries, publishing their results in scientific journals.

Over the course of nearly three decades, however, their competition evolved into a costly, self-destructive, vicious all-out war to see who could outdo the other. Despite their aggressive and sometimes unethical tactics to outwit one another and steal each other’s hired collectors, Cope and Marsh made major contributions to the field of paleontology, Jacobs said.

Hill first to identify and map the Cretaceous geology in North Texas
Born in 1858, Hill was a teenager when he left Tennessee as an orphan and arrived on the Texas frontier in 1874, says Jacobs’ study. Hill settled in Comanche, southwest of Fort Worth, where he went to work for his brother’s newspaper, the Chief. After earning a Bachelor of Science in geology from Cornell, Hill was hired as a field geologist for the USGS.

Hill is noted for being the first to identify and map the distinct rock formations in North Texas that correspond to the Earth’s Cretaceous geologic period from 146 million years ago to 65 million years ago, Jacobs said. For much of the Cretaceous, a shallow sea cut North America in half from the Arctic to the Gulf of Mexico. Dinosaurs roamed the coastal shoreline and huge reptiles swam the waters, an environment that preserved plants and animals as fossils for posterity millions of years later.

Through his reading of the letters, Jacobs found that Cope disagreed with the way Hill named the Cretaceous rock units, and told him so. Cope counseled Hill: “You mustn’t mind criticism. We all get it and get used to it; but it isn’t comfortable at first.”

In subsequent letters, said Jacobs, it’s apparent Hill had changed his approach, for which Cope offered him high praise: “I wish to say definitely that your discovery of the lower Cretaceous series in this country is the most important addition to our geology that has been heard for a long time.”

Hill contributed one of 1,000 species of backboned animals named by Cope
Jacobs’ research found that numerous letters reveal that Cope was persistent in trying to buy a Cretaceous fish fossil that Hill had collected. In various letters, Cope expresses a desire to view the fossil, each time stating his request in a different way. Hill ultimately sold Cope the fossil for $15. Cope named the specimen Macrepistius arenatus. It is housed at the American Museum of Natural History in New York City.

Hill’s fish specimen was one of 1,000 species of backboned animals, from fish to dinosaurs, that Cope described and named in his lifetime.

Also evident in the correspondence is a glimpse into the battle intrigue between Cope and Marsh, Jacobs said. In one letter, Cope angles to learn from Hill details about a new director of the USGS, to judge whether “our ? friend O.C.M.” would have an advantage.

Cope wrote to Hill, “Possibly you can find out how the land lies?”

Cope’s other Texas connection was through Jacob Boll
Boll was a much larger supplier to Cope and ultimately made significant contributions to the field of paleontology. Boll “is mentioned, usually in passing, in virtually every history of the subject,” according to Jacobs.

Born in 1828 in Switzerland, Boll was the first to discover vertebrate fossils in the Permian red beds along the drainages of the Wichita and Red rivers and their tributaries.

“The discoveries opened up an entirely new chapter in vertebrate evolution some 280 million years old,” Jacobs said. “Boll’s finds include some of the oldest close relatives of mammals whose evolution eventually led to humans.”

Boll belonged to one of the Swiss families that founded the mid-19th century utopian society La Reunion in Dallas, Jacobs said. Boll made Dallas his home sometime after 1874. He died in the field in the Permian red beds in 1880 from a snake bite.

At least one scholar has asserted that Cope — to keep the identity of his collectors secret from Marsh — never credited Boll for the Texan’s many fossil discoveries. Jacobs, however, found evidence that in 1878 Cope, in fact, did acknowledge Boll’s contribution, at least for the big-headed, semi-acquatic amphibian Eryops. Cope wrote that the fossil was “found … by my friend Jacob Boll.”

Boll’s fossil fascination erupted into a poem for Eryops
During a break in his field labors, Boll’s fascination with ancient bones prompted him to write in his native German an ode to fossils. Jacobs came across the poem in the American Museum of Natural History on a label on the back of Eryops specimen No. AMNH 4183.

SMU biology professor Pia Vogel translated the poem. Vogel and Jacobs worked with SMU English professor John M. Lewis to retain the essence of the poem in English.

“Now you will with some few others
Trek to the professor’s seat.
Awakened through his careful thought,
Be reassembled from your fragments,
To tell to others yet to come
From the sculpting of your teeth
How you lived and disappeared,
Name you he will, and what he found.”

While Hill and Boll were linked by their relationship to Cope, it isn’t known whether the two of them ever met, according to Jacobs.

”Hill and Boll both made major contributions to frontier science at an important time in American history,” Jacobs said. “They may have been nearly forgotten, but their lives have influenced much that came later.” — Margaret Allen

Tags Dedman College, Institute for the Study of Earth and Man, John Lewis, Louis L. Jacobs, Pia Vogel, Roy M. Huffington Department of Earth Sciences, SMU Department of Biological Sciences, SMU Department of English

Health & Medicine Technology Videos

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

Post author By Margaret Allen
Post date June 19, 2012

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

Tags Center for Drug Discovery Design and Delivery, Dedman College, John Wise, Pia Vogel, SMU Department of Biological Sciences

Health & Medicine Plants & Animals Videos

Human diabetes has new research tool: Overfed fruit flies that develop insulin resistance

Post author By Margaret Allen
Post date June 4, 2012

Researchers find that fruit flies overloading on carbs and protein not only gain weight but have shortened life spans — and develop insulin resistance, a hallmark of Type 2 human diabetes

With Type 2 human diabetes climbing at alarming rates in the United States, researchers are seeking treatments for the disease, which has been linked to obesity and poor diet.

Now biologists at Southern Methodist University, Dallas, report they have developed a new tool that will help researchers better understand this deadly disease.

By manipulating the diets of healthy adult fruit flies, the researchers developed flies that are insulin-resistant, a hallmark of Type 2 diabetes.

Until now, researchers largely have relied on rats, mice and other animals as model systems for exploring the metabolic and genetic changes that take place in diabetics.

A dye test in fruit flies uncovers whether fat cells are responding to insulin. On the left, insulin signaling is active. On the right, insulin signaling is inactive. (Credit: Bauer, SMU)

The fruit fly Drosophila melanogaster has been widely deployed in labs to investigate a wide range of human diseases, from Alzheimer’s to cancer. But the scientific literature hasn’t documented use of the adult fruit fly for studying the metabolic disruptions that are the hallmark of Type 2 diabetes. The fruit fly’s advantages include its low cost and a very short lifespan, both of which enable scientists to undertake rapid screenings in their search for new genetic and drug treatments.

The insulin-resistant fruit fly was developed in the lab of SMU biologist Johannes H. Bauer, principal investigator for the study. It was accomplished by feeding fruit flies a diet high in nutrients, said Bauer, an assistant professor in SMU’s Department of Biological Sciences. That process mimics one of the ways insulin resistance develops in humans — overeating to the point of obesity.

The lab’s insulin-resistant fruit flies now can serve as a highly relevant and efficient model for studying Type 2 diabetes.

“We learned that by manipulating the nutrients of fruit flies, we can make them insulin resistant,” Bauer said. “With this insulin-resistant model we can now go in with pinpoint precision and study the molecular mechanisms of insulin resistance, as well as drug treatments for the condition, as well as how to treat obesity, how to block insulin resistance and how metabolic changes from a specific diet develop. The possibilities are endless.”

The researchers reported their findings in the article “Development of diet-induced insulin resistance in adult Drosophila melanogaster,” published in Biochimica et Biophysica Acta – Molecular Basis of Disease.

Two overfeeding diets, carb and protein, both result in insulin resistance
Insulin, produced by the pancreas, is the hormone that tells our cells to absorb glucose, a necessary sugar molecule that provides our body, particularly the brain, with the energy to function, make repairs, move and grow.

In Type 2 diabetes, a person is insulin-resistant because his or her cells fail to respond to insulin’s signal to absorb glucose. The disregulation of glucose upsets the body’s delicate internal equilibrium, causing massive disruptions in normal cellular processes. These interruptions manifest in multiple disease symptoms, making Type 2 diabetes difficult to characterize, treat and cure.

To provide a good base model organism to study aspects of this complex disease, researchers in the Bauer lab wanted to determine whether flies develop diabetes-like metabolic changes when fed different diets. The researchers developed the insulin-resistant flies in two different ways: One group of fruit flies was overfed a carbohydrate-loaded diet; a second group of flies was overfed a protein-loaded diet. In both cases, the disruption had a profoundly detrimental effect on the flies’ health and physiology.

SMU biologist Siti Nur Sarah Morris, lead author on the study, said the results the researchers observed were both expected and unexpected. The researchers expected the flies to gain weight, which they did. Carb-loaded flies gained excessive weight and got fat, just like humans who overeat sweets, french fries, pasta and ice cream. Protein-loaded flies also gained weight, but upon extreme overfeeding they lost weight, just like humans who follow the popular Atkins Diet, a weight loss program in which participants eat only meat, seafood and eggs.

The researchers expected the carb-loaded fruit flies to develop insulin resistance, which they did.

In a surprising result, however, the fruit flies that overate protein also developed insulin resistance, but at a quicker and more severe rate.

“Carb-loaded flies gain weight. Protein-loaded flies gain and then lose weight. So the two diets have exactly opposite effects on metabolism,” Bauer said. “But too much of either one of them causes insulin resistance. That surprised us.”

Overfed flies had shortened lifespans, differences in fertility
In other findings, carb-loaded flies experienced a profound decline in egg-laying, a measurement of fertility. In contrast, protein-loaded flies first experienced increased egg-laying, but the extreme diet led to decreased egg laying. Both diets led to shortened longevity, the scientists reported.

“The high-protein flies looked frail and unhealthy. They moved less, almost as if sedated,” Morris said. “The fatter flies on the high-carb diet had massively decreased fertility; they flew less but still tried to move.”

While both diets resulted in insulin resistance, differences were remarkable.

“The carb data imply a linear relationship between carb levels and health. The more carbs, the more weight, the more sugar storage and fat, the more insulin resistance and the less fertility,” Bauer said. “But with protein, this relationship becomes parabolic, meaning all readouts go up, then come down again. The decreased storage we liken to a catabolic state that is primarily destructive for the body’s optimum metabolic functioning, such as the ketosis typically seen in people eating Atkins-type diets.”

Besides Morris and Bauer, other authors on the study were SMU students Claire Coogan, Khalil Chamseddin and Santharam Kolli. Other co-authors, from Pennington Biomedical Research Center, Baton Rouge, La., are Jeffrey N. Keller, director, Institute of Dementia Research & Prevention, and Sun Ok Fernandez-Kim. The research was funded by the National Institute on Aging. — Margaret Allen

Tags Dedman College, Johannes H. Bauer, Siti Nur Sarah Morris, SMU Department of Biological Sciences

Health & Medicine Researcher news

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

Post author By Margaret Allen
Post date March 27, 2012

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

Tags Center for Drug Discovery Design and Delivery, Dedman College, John Wise, Pia Vogel, SMU Department of Biological Sciences

Health & Medicine

Blocking enzyme may prove novel way to thwart HIV

Post author By Margaret Allen
Post date November 21, 2008

In 1996 the introduction of “triple cocktail” drug therapy transformed AIDS from a death sentence into a manageable chronic disease. The drug regimen, also known as HAART for highly active antiretroviral treatment, involved treating patients with three or more classes of antiviral medicines.

But the virus fought back. It mutates easily, and the mutations caused resistance to first one and then another drug making up the cocktail. Unsettling reports of newly infected patients with the drug-resistant virus meant researchers needed to find new ways to fight HIV infection.

That could be what is happening in the Dedman Life Sciences Building at SMU, where a young assistant professor of biological sciences is conducting research that may lead to a novel way of combating HIV-1.

Harrod%2CRobert%20lab4.jpg
In his office in Dedman College’s Department of Biological Sciences, Assistant Professor Robert Harrod talks about an exciting discovery his research team made last year. The discovery involves the way viruses replicate and the disease Werner syndrome, a rare genetic disorder that causes premature aging.

The HIV-1 virus infects white cells involved in fighting infection, inserting itself into the genetic material of the cells, commonly known as T-cells, to cause AIDS. Once the virus is integrated into the host cell, Harrod explains, it is dependent on “human cellular transcription factors” to replicate. The researchers have shown that the Werner syndrome enzyme is an essential factor in that transcription process. They reasoned if they could inhibit the enzyme function, they could block the transcription.

Using cells developed by researchers at the University of Washington who are studying Werner syndrome, the SMU researchers were able to insert the enzyme defect that causes Werner syndrome into HIV-infected T-cells, blocking 95 percent of retroviral transcription. If the HIV/AIDS virus can’t be transcribed, it can’t replicate.

The one in 1,000 people in Japan who are Werner syndrome carriers (without developing the syndrome) have not been observed to develop AIDS, Harrod points out, suggesting that affecting the functioning of the enzyme that causes Werner syndrome is a plausible way to fight HIV/AIDS.

The beauty of the Werner syndrome-enzyme approach to HIV/AIDS treatment is that the virus can’t mutate to defeat treatment, Harrod says.

The HIV-inhibition research was published in the April 20, 2007 issue of “The Journal of Biological Chemistry.”

Harrod’s research group, which includes Master’s degree student Madhu Sukumar and three biological sciences undergraduates, now is searching for molecules that will inhibit the function of the Werner syndrome enzyme, and thus, viral replication.

Harrod’s work also is an example of the international collaboration that is occurring to find solutions to global health issues. He is collaborating on the research with Antonito Panganiban from the University of New Mexico-Health Sciences Center, Carine Van Lint from the Universite Libre de Bruxelles and two clinical researchers, Dennis Burns and Daniel Skiest, from UT Southwestern Medical Center at Dallas.

According to the World Health Organization, 33 million people are living with HIV/AIDS worldwide. That is why Professor William Orr, chair of Biological Sciences at SMU, calls Harrod’s research exciting.

“It’s going to provide an alternative way in which one might be able to deactivate or slow down this scourge,” Orr says.

Harrod joined SMU in 2002 and teaches undergraduate and graduate students. He earned his Ph.D. at the University of Maryland in 1996, and received postdoctoral training at the National Institutes of Health and the Naval Medical Center. — Cathy Frisinger

Tags Madhu Sukumar, Robert Harrod, SMU Department of Biological Sciences, William Orr

Energy & Matter Health & Medicine Plants & Animals Student researchers

Aids, cancer targeted by biology researchers

Post author By Margaret Allen
Post date June 1, 2008

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.

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.

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.

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.

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.

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.

Although 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

Tags Christina Paulson, Jim Waddle, John Wise, Pia Vogel, Robert Harrod, SMU Department of Biological Sciences

Researcher news

Vik named 2008 SMU Ford Research Fellow

Post author By Margaret Allen
Post date May 30, 2008

Steven Vik, in the Department of Biological Sciences of Dedman College, has received an SMU 2008 Ford Research Fellowship.

A professor in the Department of Biological Sciences, Vik’s research interests include protein structure and function, and the biochemistry of membrane-bound enzymes. His work focuses on key mechanisms of bioenergetics, the study of how living systems get and use the energy sources required to sustain life.

Vik has made significant contributions to the understanding of the key enzyme in these processes, the ATP synthase.

He was the first to correctly deduce the internal mechanisms of how the movement of charged ions across a biological membrane coupled with the ATP synthase’s rotary mechanism produce adenosine triphosphate, ATP, which is essential for nerve functioning, muscular and molecular movement and other vital cellular processes.

Vik is a member of the editorial board of the “Journal of Biological Chemistry.”

Established in 2002 through a $1 million pledge from Gerald Ford, chair of SMU’s Board of Trustees, the fellowships help the University retain and reward outstanding scholars. Each recipient receives a cash prize for research support during the year.

The new Ford Fellows were honored by the SMU Board of Trustees at its May meeting.

Tags SMU Department of Biological Sciences, Steven Vik

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