cancer

Newest Bond LSC faculty addition adds to focus on inflammation

May 22, 2020 By Lauren Hines in #IAmScience Tags: #IAmScience, cancer

#IAmScience Olga Baker — Olga Baker, professor of Otolaryngology, will join Bond LSC June 1, 2020, as our newest principal investigator with a focus on inflammation. | photo by Roger Meissen, Bond LSC

By Lauren Hines | Bond LSC

Olga Baker is the type of person who acts when she sees a problem.

In her home country of Venezuela, Baker worked as a dentist who was part of a team that treated head and neck cancer patients.

“They told me how much they suffered as I used to do their cavities and fix their teeth,” Baker said. “That’s how I became so motivated, because I saw their suffering myself.”

These patients stopped producing saliva due to radiation from their head and neck cancer treatments that destroyed their salivary glands.

“Because they look okay everybody thinks they’re normal and they’re healthy,” Baker said. “Nobody knows the suffering that is ongoing inside them, so this brings a lot of psychological burden for these patients.

That motivated Baker to enroll in a biochemistry Ph.D. program at the Central University of Venezuela which she completed in 2003.

Ever since, Baker has been studying salivary glands, tissue regeneration and Sjögren’s syndrome at multiple universities

That passion led Baker to Mizzou initially as a post-doctoral fellow in 2003.

Baker moved from her post-doctoral fellowship to become a senior researcher at Mizzou but left in 2009 for the State University of New York Buffalo to accept an assistant professor position as an independent investigator to gain more experience. In 2014, she then moved to the University of Utah School of Dentistry as a tenured associate professor.

Baker officially returns to Mizzou on June 1 as a full professor in the departments of otolaryngology-head and neck surgery and biochemistry to collaborate with former colleagues as LSC’s newest principal investigator

“I later on decided that it would be nice to be close to home because my husband is from Missouri,” Baker said. “So, working with many people who helped me to be here, I applied to MU and made my decision to come back after seeing all the possible scientific collaboration with great colleagues.”

This time around, Baker will have her own lab to find ways to treat salivary gland hypofunction and to develop the products that sprung from prior work at the University of Utah where Baker created her own business

She aims to further create and distribute saliva substitutes in her business venture using proteins in saliva called mucins. Baker isolates mucins from plants and animals to be used as a mouth spray to moisturize people’s oral cavity who otherwise can’t produce saliva.

“So then with that they can eat better, they can talk better, and that lasts long in their mouth,” Baker said.

Baker plans to bring it to market while working at Mizzou.

Due to having so much expertise in the salivary field, she’s also studying how to prevent COVID-19 from infecting patients through saliva

“COVID-19 is found in saliva, and that’s very important because we could find ways to prevent transmission if you block the entry into saliva. So that’s a new area of interest for my lab.

Baker will be opening her lab on the fifth floor working on inflammation. She plans on being part of the inflammation group at the LSC with Michael Petris and her former colleague Gary Weisman

“I think it will be very rewarding for us at Bond LSC if she locates a lab there because there are people ready to work in her area of research with her,” said Weisman, Curator’s Distinguished Professor of biochemistry.

Baker and Weisman plan on further studying Sjögren’s syndrome, an autoimmune disease that also causes dry mouth, dry eyes and a number of other systemic symptoms.

When Baker isn’t fighting for a cure, she enjoys her other passion — singing and dancing.

She was a lead singer of a band called, Peña Flamenca, who used to play in the Music Café (now known as Café Berlin) and also appeared on a TV show, Pepper and Friends, as part of Hispanic Heritage Month.

Even though she isn’t part of a band anymore, she still dances.

“I really enjoy that part of my life, being a singer and dancing and bringing joy to people,” Baker said.

Baker’s mission is to solve the oral health problems she encountered, and her journey isn’t over yet.

#IAmScience Michael Petris

May 15, 2020 By Becca Wolf in #IAmScience Tags: cancer, copper

By Becca Wolf | Bond LSC

Growing up more than 9,000 miles away in Melbourne, Australia, Michael Petris never thought he would work at MU, especially since he could not even locate the state of Missouri on a map.

Now a professor of biochemistry, Petris was introduced to science early on in his life by his mother, who was a microbiologist and a high school science teacher, who made sure to immerse her children in the science field. He remembers growing up watching Australian wildlife documentaries and being interested in his science classes at school.

After completing secondary school (the Australian equivalent of high school), Petris obtained his bachelor of science degree in biochemistry and genetics as well as a Ph.D. in genetics from the University of Melbourne.

“I was studying the molecular biology of metal nutrition, which is the study of genes and biochemical processes that regulate metal nutrients in the body and how they’re important in disease processes,” Petris said.

A fax led Petris to Mizzou. While working on research as a post-doctoral student, a fax about a job opening at MU arrived in the lab. Petris decided to apply.

“I thought that I’ve got nothing to lose. It’s a tremendous experience to work in another country and to start a lab, and if I’m successful, terrific. If not, I can always go back to Australia and get a job,” Petris said, “This to me represented a once in a lifetime opportunity.”

It is safe to say it was good he took that chance back in 1999.

After his interview, Petris went back to Australia where he later found out he got the position, and he has been at MU ever since.

Adjusting to the American lifestyle was both difficult and easy. There were a lot of things we take for granted that took some getting used to, such as driving on the right side of the road, different types of food, the reverse of seasons, and even being able to understand one another.

“I used to get a lot of people in the community having trouble understanding my accent, which was much stronger back then,” Petris said, despite English being the first language in both the United States and Australia.

Luckily for him, adjusting to the United States workwise was pretty seamless.

“The science side of it is universal. So that was easy,” he said.

Once Petris got his lab set up and running, he began focusing on the biology of the micronutrient copper and how it relates to cancer and infectious diseases. Currently, his lab is interested in developing a drug that can block the transport and delivery of copper to cancer tumors, thus reducing cancer growth.

Petris’ lab looks specifically at the function of copper in a family of enzymes called lysyl oxidases, which have well-documented roles in cancer. These enzymes make the tissue surrounding tumors denser, which encourages the growth and the spread of tumor cells. In diseases such as breast cancer, mammograms are used to detect this increased density in the tissue.

“The drug we’re developing blocks the movement of the copper into that class of enzymes so that we can block the potential for breast cancer and other types of cancer,” Petris said.

While a certain amount of copper is needed in order to stay healthy, Petris explained that by limiting the amount in cancer patients, “Their chances of relapse and the cancer returning are diminished.”

By focusing on regulating copper as a way to prevent cancer long term, Petris’ lab has developed a novel compound that blocks the transporter that takes the copper into the body.

“We’re hopeful that we can develop this small molecule into a drug that could be used therapeutically first in cancer, and, ultimately, for other types of diseases,” Petris said.

In fact, Petris and his Bond LSC collaborators, Dr. Kamal Singh and Dr. Vinit Shanbhag, have submitted a patent application for this compound so that it could be developed for clinical use.

Expanding his research even further, he recently began focusing on ophthalmology and the role copper has on eye diseases as well.

After living in the United States for over 20 years, Petris’ Australian accent is a little less obvious and he does not have to think twice about what is the correct side of the road to drive on. He is happy where he is at.

“Now my research is becoming more applied and translational, I’m becoming even more gratified with the science that I’m doing.”

A NEET Connection

March 2, 2020 By Becca Wolf in Research Tags: Arabidopsis, cancer, reactive oxygen species

Protein is important in balancing iron and reactive oxygen in plant and cancer cells

Arabidopsis growing in Ron Mittler’s lab. | photo by Becca Wolf, Bond LSC

By Becca Wolf | Bond LSC

You might tend to think durability is more of an issue in building a car or engineering a building, but environmental stress makes resilience vital for plants, too.

In the world of understanding and engineering more durable crops, scientists recently identified a protein that’s key to some of that resilience in a neat way. Actually, it’s literally a NEET protein.

Ron Mittler, a Bond Life Sciences Center principal investigator and professor of plant sciences and surgery, is probing the use of the NEET protein to balance iron and reactive oxygen species (ROS) in the chloroplast to make plants stronger and healthier, and it plays a similar role in cancer cells. These proteins belong to a unique family of iron-sulfur (Fe-S) proteins ideally maintaining the proper balance of the heavy metal in and outside of plant cells. Along with several other scientists, Mittler published his most recent plant findings in The Plant Journal last October.

Since NEET proteins regulate both iron and ROS, Mittler teamed up with heavy metal expert David Mendoza, fellow Bond LSC primary investigator and associate professor of plant sciences. Through a Bond LSC Grant for Innovative Collaborative Research, the two started work at the intersection of two labs.

“The main philosophy of Bond LSC is to establish collaborations between researchers to advance the field of whatever sciences that you do,” Mendoza said.

Mittler and Mendoza looked at how NEET impacts iron and ROS, working together to figure out how to make plants more durable. Doing so, they have made a lot of progress in the field and believe that their collaboration has been a good one. Says Mendoza, “It is a very productive collaboration.”

Trays of Arabidopsis in Ron Mittler’s lab. | photo by Becca Wolf, Bond LSC

A Balancing Act

But the work doesn’t stop with plants. Mittler found NEET proteins also play a similar role in cancer cells, regulating the level of iron and potentially toxic ROS compounds. Humans and plants need iron and ROS, but too much of either can be destructive. NEET proteins allow cells to grow and spread quickly which is beneficial for plants, but detrimental for humans when cancers grow out of control. In humans, NEET proteins also play a significant role metabolism related to diabetes and progression of neurodegenerative diseases.

Despite needing both iron and ROS to function, there can be too much of a good thing. To keep iron levels balanced, oxygen is needed. While oxygen on its own is a fairly stable molecule, adding electrons or exciting the present electrons can make the molecule want to react with things around it creating oxidants. Electrons are the negatively charged particles of an atom that keep balance within the cell. When balanced, iron and ROS helps cells grow, but when placed together, the iron turns ROS into hydroxyl radical, an ion that reacts with anything and destroys everything. If not controlled, this desire to bond with things nearby can damage cells and lead to cancer.

Cancer cells like ROS and iron because it enables them to spread quickly and take over more of the body. To stay balanced, NEET proteins are needed.

“These proteins apparently enable the cells to keep high levels of both iron and ROS and to survive,” says Mittler, “So it looks like cancer needs these proteins because if you suppress these proteins or if you target them with drugs, the cancer cells die.”

Sara Zandalinas holding a dying Arabidopsis seedling and a living seedling in Ron Mittler’s lab. | photo by Becca Wolf, Bond LSC

Poisoning the cell

Knowing NEET proteins make cancer and plant cells stronger, Mittler wanted to look at “what happens if they’re not functioning well,” in hopes to understand their function. To test this, Mittler and his collaborators found a way to make the NEET proteins not function. Mittler called this “poisoning the cell.”

“If there is no protein, there’s no life,” he states. “We were able to control when we introduce this protein, and being able to introduce this protein enabled us to actually find out what happened to the cell if this protein goes bad.”

It was found that if the function of this protein is disrupted, the chloroplast is destroyed. Mittler described it as “completely blown to pieces.” The destruction of the chloroplast is caused by too much iron due to a broken NEET protein. Similarly in cancer cells, if there are no NEET proteins, the cells do not spread as quickly and die.

Mittler elaborated, “What we found is that we can target those proteins in cancer, so then we basically destroy the cancer cells.” Currently, NEET proteins are used as markers in the cancer field. Doctors and scientists look for them in order to help diagnose patients and to figure out life expectancy rates. But in the future, doctors hope to use targets these proteins to kill off cancer cells, a treatment that would be less toxic than chemotherapy.

In plants, Mittler has concluded that the NEET protein would make them grow bigger and faster, leading plants to be “more tolerant to stresses because it has the ability to modulate the levels of iron and reactive oxygen.” Findings like these may one day help plants deal with stress like drought and temperature extremes. With humans continuing to contaminate the environment and climate change escalating conditions, Mittler hopes his findings on iron, ROS, and NEET proteins will make plants able to withstand changes better.

“If I can improve the way plants balance reactive oxygen and iron, I can make plants tolerate much more of these bad combinations of stresses even, and maybe even make bigger, stronger, healthier plants.”

Read more about this research in the October 2019 edition of The Plant Journal article “Expression of a dominant‐negative AtNEET‐H89C protein disrupts iron–sulfur metabolism and iron homeostasis in Arabidopsis.”

The Bond LSC Grant for Innovative Collaborative Research program aims to foster inter-laboratory collaboration to make pilot projects that have potential for later federal funding.

Art of balance

February 17, 2017 By Jinghong Chen in Research Tags: biochemistry, cancer, copper

Vinit Shanbhag mixes the CRISPR plasmid DNA with cells. The lab will test whether the gene of interest has been knocked out of the cells later. | photo by Jinghong Chen, Bond LSC

Jinghong Chen | Bond Life Sciences Center

It might be strange to say, but in a way the Australian soil led scientist Michael Petris to where he is now.

In certain areas of Australia, soils suffer from extremely low level of copper bioavailability, resulting in poor growth and neurological problems on sheep.

Petris, a Bond LSC investigator and professor of biochemistry who was born in Australia, now spends his time studying how copper, an essential mineral in human body, works in cells to build and maintain essential functions.

Recently published work from his lab focuses on how the ATP7A protein, one of the major proteins, cycles within the cell.

“Copper is solely acquired from diet. The absorption of copper from the intestine in the blood needs ATP7A,” Vinit Shanbhag, a Ph.D. biochemistry student at Petris’ lab and an author of the study, said. “It transports copper to different copper dependent enzymes and exports free copper from the cell to the outside.”

After exporting copper at the cell membrane, ATP7A needs to come back to its steady-state location within the Golgi apparatus of cells – via a process called retrograde trafficking. But one question baffled scientists: what are the key elements that lead ATP7A coming back?

Back in the late 90s, Petris discovered the importance of one single di-leucine in retrograde trafficking of ATP7A. For those of you wondering, leucine is an amino acid that forms the building blocks of proteins like ATP7A, while di-leucine consists of two of them connected via a peptide bond.

His team wished to identify other signals for retrograde trafficking, but one technical hurdle stood in the way— the ATP7A gene is unstable when grown in bacterial plasmids, the traditional way of amplifying genes in the lab.

Commercial DNA synthesis was the answer. This method could create artificial genes in the laboratory.

“We reasoned that if we introduced enough silent mutations into a DNA sequence, we could avoid or change the region of instability in the native sequence without affecting the encoded protein,” Petris said.

To stabilize the gene, they changed more than 1,000 nucleotides within a 3,000 nucleotides segment, and thus solving the problem of instability of the ATP7A gene. In doing so, they subsequently found that in fact multiple di-leucines that are required for retrograde trafficking of ATP7A. This approach could be used by other laboratories whose gene of interest is also unstable.

An overlooked mineral

“If you ask [people], is it important to understand iron nutrition? Is it important to understand calcium nutrition? Most people would say of course! … But, perhaps you would not get the same answer for copper, despite the fact there is a little dispute that copper is important,” Petris said.

As an essential micronutrient, copper performs central functions to develop and maintain human skin, bones, brains and other organs.

“If you don’t have enough copper in your body, you cannot use oxygen to make energy,” Petris said. “If you don’t have copper, you would not survive.”

Pregnant women who carry a mutated ATP7A gene on their X chromosome can pass it on to their children in the form of Menkes disease.

Menkes disease is a genetic disorder that results in poor uptake and distribution of copper to cells. The incidence of this disease is estimated to be one in 100,000 newborns, according to U.S. National Library of Medicine.

Infants with Menkes disease typically begin to develop symptoms during infancy and rarely live past the first few years of life. Abnormally high accumulation of copper in kidneys and low-level accumulation in the liver and brain, cause visible symptoms like sparse hair, loose skin and failure to grow.

Despite copper’s importance, it also can be a potentially toxic nutrient.

“Copper deficiency can be a problem but too much copper is also a problem. There should be a balance,” Shanbhag explained.

The liver normally stores excessive copper and excretes it into bile to release it out of the body. Yet people with genetic disorders that preventing copper excretion might suffer Wilson’s disease, leading to life-threatening organ damage.

Shanbhag said people with Wilson’s disease accumulate toxic amounts of copper in liver and other organs, causing Kayser–Fleischer rings that encircle the pigmented regions of the eye, a hue caused by copper deposits in the cornea.

Its clinical consequences differ from chornic liver failure to neurological sysmptoms like tremors, dystonia, ataxia and cognitive deteriortation.

About one in 30,000 people have Wilson disease, according to National Institute of Diabetes and Digestive and Kidney Diseases.

Starving tumors

In 2013, Petris’ lab published the first direct evidence suggesting ATP7A is essential for the dietary absorption of copper. Since then they have dug deeper into this copper transporter, and his lab now sets their sights on a greater enemy of human health — cancer.

Tumor growth requires access to large amounts of nutrients. Without an adequate supply of oxygen and nutrients, tumors fail to grow and survive. Scientists have identified that by preventing access to nutrients—for example by blocking the growth of new blood vessels—they could starve the tumor of nutrients.

Copper is a key nutrient for tumor growth. With the new-introduced system CRISPR-Cas9 — a genome editing tool to knock out specfic genes — his lab has explored how to exploit understanding of copper metabolic pathways to withhold copper from cancer cells.

“Copper starvation might be a good approach as an anti-cancer strategy,” Petris said.

Weapon of the immune system

Michael Petris and lab — Michael Petris, a professor of biochemistry at MU, stands with his lab. From left to right: Vinit Shanbhag, Nikita Gudekar, Michael Petris, Kimberly Jasmer-McDonald, Aslam Khan. | photo by Jinghong Chen, Bond LSC

Currently, four members study in Petris’ lab to tackle the relationship between copper and various diseases. Petris plans to expand his research to another area: the role of copper in innate immunity against bacterial pathogens.

This is the topic of Petris’ next grant. Nutritional immunity, which describes how the mammalian host withholds nutrients from the invading bacteria during infection, is very well-described for iron and zinc.

Yet copper performs differently.

During infection, the level of copper in blood actually goes up instead of going down. The immune system concentrates copper at sites of infection and within regions where the bacteria are engulfed.

“We speculate that copper is being used as weapon by the host to kill the bacteria,” Petris said. “That is the area we are trying to develop further.”

Michael Petris is a Bond LSC investigator and a professor of biochemistry. The study “Multiple di-leucines in the ATP7A copper transporter are required for retrograde trafficking to the trans-Golgi network” was published by The Royal Society of Chemistry in September 2016.

Scientists dig into the epigenetics of cancer

March 31, 2015 By Caleb O'Brien in Research Tags: cancer, epigenetics

Joya Chandra, associate professor of pediatrics at The University of Texas MD Anderson Cancer Center, explains the epigenetics of pediatric cancers at the 2015 MU LSSP Symposium on epigenetics on Sunday, March 15.//photo by Caleb O'Brien/Bond LSC — Joya Chandra, associate professor of pediatrics at The University of Texas MD Anderson Cancer Center, explains the epigenetics of pediatric cancers at the 2015 MU LSSP Symposium on epigenetics on Sunday, March 15.//photo by Caleb O’Brien/Bond LSC

The evolving science of epigenetics is shaking up how scientists and doctors think about cancer.

At the 11^th annual University of Missouri Life Sciences & Society Program symposium, scientists, historians and philosophers explored the epigenetic theme. On its final day, two researchers spoke about how cancer and epigenetics intersect.

Epigenetics involves changes to how genes work that do not occur within DNA. Epigenetic changes can, in effect, turn genes on or off, and those changes can then be passed from generation to generation. Because cancer involves cells that grow uncontrollably, don’t die and can travel throughout the body, it makes sense to look for epigenetic changes that could account for cancer’s unusual attributes.

Shuk-mei Ho, director of the University of Cincinnati Cancer Center and Chair of the Department of Environmental Health, discussed the developmental origins of health and disease (DOHaD) hypothesis, which suggests that problems early in development or during other key periods such as puberty and pregnancy can have wide-ranging implications later in life.

She centered on whether early exposure to a high fat diet and endocrine disruptors such as bisphenol A can affect an offspring’s risk of developing certain types of cancer.

“These studies are really important because they help us identify some early warning signs that may be related to epigenetics,” she said “They allow us to devise measures that we can use to interfere with and prevent development of cancer.”

A proactive approach to cancer could harness science’s newfound understanding of epigenetics and target cancers before they start.

“It is much more effective to have prevention rather than have the cancer and devise ways to treat it,” she said. “This will minimize a lot of suffering and also reduce the cost of the health care.”

Prevention is especially important because epigenetic effects can arise quickly and persist for multiple generations. For example, breast cancer rates in immigrant populations can increase within one generation of arrival. In mice, scientists have detected the lingering effects of a high fat diet after three generations.

Epigenetics and childhood cancer

Pediatric oncology is especially apt for integration with epigenetics.

Joya Chandra, associate professor of pediatrics at the University of Texas MD Anderson Cancer Center, studies therapies for childhood cancers. She said developments in epigenetics have helped researchers better understand childhood cancers and the ways they differ from adult cancers.

“The field of epigenetics has just exploded in terms of giving us insight into how pediatric cancers are different from adult cancers.” Chandra said. “Just in the past 2-3 years we’ve learned a lot about cancers that are present in adults and children that have really different epigenetic profiles. This presents an opportunity for pediatric cancer oncologists to treat these cancers differently, and increasing knowledge about epigenetics will help serve that goal.”

leukemia, for example, is the most common pediatric cancer but only the sixth most common among adults. And about 70 percent of infants with leukemia exhibit epigenetic changes associated with their cancer.

Children with glioblastoma, a type of brain cancer, exhibit epigenetic traces that are distinct from the same kind of cancer in adults.

A deeper understanding of epigenetics and of how cancer in children differs from adult cancer could allow for the development of new medicines, novel therapies and powerful strategies for proactively protecting patients from certain types of cancers.

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