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

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

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

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

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

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

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

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

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

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

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

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

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

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

The molecules that Wise and Vogel discovered stopped the pumps.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Daily Planet: Star Wars come to life in SMU chemist’s invention

Long ago, sort of, scenes from Star Wars triggered a child’s imagination, so that today it’s informed one of his research goals as a chemist.

Discover Canada’s science magazine show Daily Planet reported on the research of SMU organic chemist Alex Lippert, an assistant professor in the Department of Chemistry in SMU’s Dedman College of Humanities and Sciences.

Lippert’s team develops synthetic organic compounds that glow in reaction to certain conditions. He led his lab in developing a new technology that uses photoswitch molecules to craft 3-D light structures — not holograms — that are viewable from 360 degrees. An economical method for shaping light into an infinite number of volumetric objects, the technology will be useful in a variety of fields, from biomedical imaging, education and engineering, to TV, movies, video games and more.

For biomedical imaging, Lippert says the nearest-term application of the technique might be in high-volume pre-clinical animal imaging, but eventually the technique could be applied to provide low-cost internal imaging in the developing world, or less costly imaging in the developed world.

The Daily Planet segment aired Dec. 12, 2017.

Lippert’s lab includes four doctoral students and five undergraduates who assist in his research. He recently received a prestigious National Science Foundation Career Award, expected to total $611,000 over five years, to fund his research into alternative internal imaging techniques.

NSF Career Awards are given to tenure-track faculty members who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research in American colleges and universities.

Lippert joined SMU in 2012. He was previously a postdoctoral researcher at the University of California, Berkeley, and earned his Ph.D. at the University of Pennsylvania, and Bachelor of Science at the California Institute of Technology.

Watch the full Dec. 12 show.

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GAINcast Episode 89: How Speed Happens (with Peter Weyand)

“People recognize the power of science, in terms of testing and numbers. But unless you’re involved in it it’s hard to appreciate the creativity that is also part of the process.” — Peter Weyand

The founder of modern sports performance training, Vern Gambetta, interviewed SMU locomotion researcher Peter Weyand about human speed and performance for his GAINcast show.

The GAINcast name is an acronym for the internationally recognized Gambetta’s self-made sports performance education, outreach and training efforts, Gambetta Athletic Improvement Network.

Gambetta’s 60-minute interview with Weyand posted Nov. 2, 2017, “Gaincast Episode 89: How Speed Happens (with Peter Weyand).”

In it, Weyand touches on the experiences early in his career as a high school and college athlete playing basketball and running track that sparked his pursuit of a research and academic career in sports science and human performance.

As a high school coach, Weyand’s early interest intensified, leading him to pursue advanced degrees and a scientific career exploring the mechanics of human locomotion and speed, including at the University of Georgia and then at Harvard’s Concord Field Station.

During that time, Weyand worked with early pioneers in the biomechanics and human performance field, including renowned researcher Dick Taylor. At the field station in particular, Weyand credits Taylor with mentoring young researchers in aggressively and fearlessly digging into basic science questions surrounding mammalian locomotion.

“It was wide open, anything goes. It wasn’t these reductionist questions …. It was anything under the sun you could cook up. And there was an insistence on good scientific questions, and a real integrative perspective on all of it. Those were my formative scientific experiences. People recognize the power of science, in terms of testing and numbers. But unless you’re involved in it it’s hard to appreciate the creativity that is also part of the process. There’s an art of doing science and Dick was a master of that. And everybody that came through that field station under his training, which is really a who’s who in our field in many respects, learned that art from him.”

Weyand is an expert on human locomotion and the mechanics of running. Research from his SMU Locomotor Performance Laboratory in SMU’s Annette Caldwell Simmons School of Education and Human Development has produced ground-breaking scientific findings about the science of human speed.

The lab focuses on the mechanical basis of human performance and includes physicist and engineer Laurence Ryan, an expert in force and motion analysis.

The Weyand lab’s most recent research found that the world’s fastest sprinter, Usain Bolt, has an asymmetrical running gait, contrary to the common notions about coaching and training for speed. Bolt’s asymmetry was discovered using the lab’s two-mass model tool, which the researchers have described in the Journal of Experimental Biology, “A general relationship links gait mechanics and running ground reaction forces.” The model can assess the crucial early portion of foot-ground contact — the impact-phase force and time relationships — from motion data only.

Weyand is Glenn Simmons Professor of Applied Physiology and professor of biomechanics in the Department of Applied Physiology & Wellness.

Listen to the podcast.

EXCERPT:

By Martin Bingisser
GAINcast

There are some basic questions out there that are difficult to answer, such as what limits human running speed. As technology advances, scientists can better study and start to answer this and other simple questions like what makes one athlete faster than another.

Dr. Peter Weyand has spent decades researching locomotion on both animals and humans. His work with elite sprinters has brought some interesting conclusions and is driving the field forward. On this episode of the GAINcast he joins us to discuss his research and its practical implications.

Listen to the podcast.

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Study: New simple method determines rate at which we burn calories walking uphill, downhill, and on level ground

New method uses three variables of speed, load carried and slope to improve on the accuracy of existing standards for predicting how much energy people require for walking — a method beneficial to many, including military strategists to model mission success

When military strategists plan a mission, one of many factors is the toll it takes on the Army’s foot soldiers.

A long march and heavy load drains energy. So military strategists are often concerned with the calories a soldier will burn, and the effect of metabolic stress on their overall physiological status, including body temperature, fuel needs and fatigue.

Now scientists at Southern Methodist University, Dallas, have discovered a new more accurate way to predict how much energy a soldier uses walking.

The method was developed with funding from the U.S. military. It significantly improves on two existing standards currently in use, and relies on just three readily available variables.

An accurate quantitative assessment tool is important because the rate at which people burn calories while walking can vary tenfold depending on how fast they walk, if they carry a load, and whether the walk is uphill, downhill or level.

“Our new method improves on the accuracy of the two leading standards that have been in use for nearly 50 years,” said exercise physiologist Lindsay W. Ludlow, an SMU post-doctoral fellow and lead author on the study. “Our model is fairly simple and improves predictions.”

The research is part of a larger load carriage initiative undertaken by the U.S. Army Medical Research and Materiel Command. The average load carried by light infantry foot soldiers in Afghanistan in April and May 2003 was 132 pounds, according to a U.S. Army Borden Institute report.

“Soldiers carry heavy loads, so quantitative information on the consequences of load is critical for many reasons, from planning a route to evaluating the likelihood of mission success,” said SMU biomechanist and physiologist Peter Weyand, @Dr_Weyand.

“The military uses a variety of approaches to model, predict and monitor foot-soldier status and performance, including having soldiers outfitted with wearable devices,” Weyand said. “There is a critical need with modern foot soldiers to understand performance from the perspective of how big a load they are carrying.”

Weyand is senior author on the research and directs the Locomotor Performance Laboratory in the SMU Simmons School of Education, where subjects for the study were tested.

The researchers call their new method the “Minimum Mechanics Model” to reflect that it requires only three basic and readily available inputs to deliver broad accurate predictions. They report their findings in “Walking economy is predictably determined by speed, grade and gravitational load” in the Journal of Applied Physiology.

The necessary variables are the walker’s speed, the grade or slope of the walking surface, and the total weight of the body plus any load the walker is carrying.

“That’s all it takes to accurately predict how much energy a walker burns,” Ludlow said.

While the measurement is a critical one for foot soldiers, it’s also useful for hikers, backpackers, mall-walkers and others who are calorie conscious and may rely on wearable electronic gadgets to track the calories they burn, she said.

Muscle and gait mechanics tightly coupled across speed, grade, load
Existing standards now in use rely on the same three variables, but differently, and with less accuracy and breadth.

The new theory is a departure from the prevailing view that the mechanics of walking are too complex to be both simple and accurate.

“Ultimately, we found that three remarkably simple mechanical variables can provide predictive accuracy across a broad range of conditions,” Ludlow said. “The accuracy achieved provides strong indirect evidence that the muscular activity determining calorie-burn rates during walking is tightly coupled to the speed, surface inclination and total weight terms in our model.”

By using two different sets of research subjects, the researchers independently evaluated their model’s ability to accurately predict the amount of energy burned.

“If muscle and gait mechanics were not tightly coupled across speed, grade and load, the level of predictive accuracy we achieved is unlikely,” Weyand said.

First generalized equation developed directly from a single, large database
The two existing equations that have been the working standards for nearly 50 years were necessarily based on just a few subjects and a limited number of data points.

One standard from the American College of Sports Medicine tested only speed and uphill grades, with its first formulation being based on data from only three individuals.

The other standard, commonly referred to as the Pandolf equation is used more frequently by the military and relies heavily on data from six soldiers combined with earlier experimental results.

In contrast, the generalized equation from SMU was derived from what is believed to be the largest database available for human walking metabolism.

The SMU study tested 32 adult subjects individually under 90 different speed-grade and load conditions on treadmills at the SMU Locomotor Performance Laboratory, @LocomotorLabSMU.

“The leading standardized equations included only level and uphill inclinations,” Weyand said. “We felt it was important to also provide downhill capabilities since soldiers in the field will encounter negative inclines as frequently as positive ones.”

Subjects fast prior to measuring their resting metabolic rates
Another key element of the SMU lab’s Minimum Mechanics Model is the quantitative treatment of resting metabolic rate.

“To obtain true resting metabolic rate, we had subjects fast for 8 to 12 hours prior to measuring their resting metabolic rates in the early morning,” Ludlow said. “Once at the lab, they laid down for an hour while the researchers measured their resting metabolic rate.”

In separate test sessions, the subjects walked on the treadmill for dozens of trials lasting five minutes each, wearing a mouthpiece and nose clip. In the last two minutes of each trial, the researchers measured steady-state rates of oxygen uptake to determine the rate at which each subject was burning energy.

Adults in one group of 20 subjects were each measured walking without a load at speeds of 0.4 meters per second, 0.7 meters per second, 1 meter per second, 1.3 meters per second and 1.6 meters per second on six different gradients: downhill grades of minus six degrees and minus three degrees; level ground; and uphill at inclines of three degrees, six degrees and nine degrees.

Adults in a second group of 20 were each tested at speeds of 0.6 meters per second, 1 meter per second and 1.4 meters per second on the same six gradients, but they carried loads that were 18 percent of body weight, and 31 percent of body weight.

Walking metabolic rates increased in proportion to increased load
As expected, walking metabolic rates increased in direct proportion to the increase in load, and largely in accordance with support force requirements across both speed and grade, said Weyand and Ludlow.

Weyand is Glenn Simmons Professor of Applied Physiology and professor of biomechanics in the Department of Applied Physiology and Wellness in SMU’s Annette Caldwell Simmons School of Education and Human Development. He also is lead scientist for the biomechanics and modeling portion of the Sub-2-Hour marathon project, an international research consortium based in the United Kingdom. — Margaret Allen, SMU

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Sapiens: Can Medical Anthropology Solve the Diabetes Dilemma?

As the number of sufferers continues to rise, some researchers are moving in new directions to figure out how culture and lifestyle shape disease outcomes.

Sapiens reporter Kate Ruder covered the research of SMU anthropologist Carolyn Smith-Morris, who has studied diabetes among Arizona’s Pima Indians for more than 15 years.

Smith-Morris wrote about what she learned from her research in her 2006 book, “Diabetes Among the Pima: Stories of Survival.”

The Pima have the highest prevalence of diabetes ever recorded, although the disease is alarmingly on the increase throughout the United States. In an effort to understand the rise of the disease, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) from 1965 to 2007 focused on the Pima to carry out the largest continuous study of diabetes in Native Americans. Researchers examined the environmental and genetic triggers of the disorder, management of the disease, and the treatment of thousands of Pimas.

Smith-Morris is a medical anthropologist and associate professor in the SMU Anthropology Department in Dedman College. Her research addresses chronic disease, particularly diabetes, through ethnographic and mixed methodologies. She has conducted ethnographic research among the Gila River (Akimel O’odham) Indian Community of Southern Arizona, Mexicans and Mexican immigrants to the U.S. and veterans with spinal cord injuries.

The Sapiens article, “Can Medical Anthropology Solve the Diabetes Dilemma?” published Aug. 22, 2017.

Read the full story.

EXCERPT:

By Kate Ruder
Sapiens

Mary (a pseudonym) was 18 years old and halfway through her second pregnancy when anthropologist Carolyn Smith-Morris met her 10 years ago. Mary, a Pima Indian, was living with her boyfriend, brother, parents, and 9-month-old baby in southern Arizona. She had been diagnosed with gestational diabetes during both of her pregnancies, but she didn’t consider herself diabetic because her diabetes had gone away after her first birth. Perhaps her diagnosis was even a mistake, she felt. Mary often missed her prenatal appointments, because she didn’t have a ride to the hospital from her remote home on the reservation. She considered diabetes testing a “personal thing,” so she didn’t discuss it with her family.

As Smith-Morris’ research revealed, Mary’s story was not unique among Pima women. Many had diabetes, but they didn’t understand the risks. These women’s narratives have helped to explain, in part, why diabetes has been so prevalent in this corner of the world. An astonishing half of all adult Pimas have diabetes.

Medical anthropologists like Smith-Morris are helping the biomedical community untangle the social roots of diabetes and understand how and why the disease is exploding in the United States. Smith-Morris, based out of Southern Methodist University in Dallas, Texas, has been working on this cause for over 15 years—from a decade spent among the Pimas, to a new study sponsored by Google aiming to prevent diabetes-related blindness. Anthropology, she says, provides the most holistic perspective of this complex problem: “Anthropology seems to me the only discipline that allows you to look both closely at disease … and from the bird’s eye perspective.”

More than 30 million people in the United States are estimated to have diabetes, and it’s on the rise. If trends continue, 1 out of every 3 American adults could have diabetes by 2050, according to the Centers for Disease Control and Prevention.

The condition involves insulin, a hormone that regulates the way the body uses food for energy. In type 1 diabetes, the body stops making insulin entirely; those affected need daily insulin injections to survive. In type 2 diabetes, which accounts for the vast majority of cases, change is more gradual.The body slowly makes less insulin and becomes less sensitive to it over the years. Gestational diabetes, which strikes during pregnancy, can give mothers a dangerous condition called preeclampsia, which is related to high blood pressure and can harm both mothers and babies. Women with gestational diabetes are more than seven times likelier to later develop type 2 diabetes than women who do not have the condition in pregnancy, and their children are at higher risk of obesity and diabetes. If left untreated, diabetes can cause heart disease, kidney failure, foot problems that can lead to amputation, and blindness.

The preventative measures for type 2 and gestational diabetes are seemingly straightforward: eat healthy foods, lose weight, and exercise. Treatment for both can include taking medications. Yet prevention, lifestyle, and treatment cannot entirely solve the problem; family history, ethnicity, and other factors play a critical role in a person’s susceptibility to type 2 and gestational diabetes. Both forms of diabetes continue to plague Americans, particularly certain groups, including Native Americans. “My interest in diabetes grew out of an interest in Indigenous groups,” says Smith-Morris. “I took on diabetes because it was important to them.”

From 1965 to 2007, the Pimas of Arizona were the focus of the largest continuous study of diabetes in Native Americans. Conducted by researchers from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), it examined the environmental and genetic triggers of the disorder, management of the disease, and the treatment of thousands of Pimas. It also documented that they had the highest prevalence of diabetes ever recorded. The pivotal work told researchers much of what they know about diabetes today, including that obesity is a significant risk factor, and that a mother’s diabetes during pregnancy can pass risk along to her children.

The political and economic contributors to the Pima people’s health problems have long been well-known: Their traditional farming practices collapsed during the late 1800s and early 1900s when non-Native settlers upstream diverted essential water resources, contributing to poverty, sedentariness, and a lack of fresh food. Yet Smith-Morris felt something integral was missing from this picture: the Pimas’ stories.

Read the full story.