Toshihiko Ezashi

#IAmScience Teka Khan

April 9, 2021 By Becca Wolf in #IAmScience Tags: placentas, YEWOM

By Becca Wolf | Bond LSC

Growing up in the countryside of Pakistan, Teka Khan did not have a science class in high school. In fact, his first science class was in college and it was in English — a language he did not know at the time.

“First I had to understand the word meaning. So, what I did for physics, chemistry, and biology is I bought a dictionary,” Khan said. “I had to translate each and every word, and then I had to understand them, so I wrote down the meaning of each word. Sometimes I look back and think, ‘how did I do that?’”

Now a postdoctoral fellow in the Michael Roberts’ lab, Khan knows his stuff, and wants to give back to his community in Pakistan.

To do so, he helps with the Youth Educational & Welfare Organization in Mattani, Peshawar, Pakistan (YEWOM).

YEWOM promotes educational and welfare activities in hopes of improving the community and making students productive people in society.

“We usually have different types of activities,” Khan said. “We visit different schools to observe if there are any deficiencies in quality of learning, if there’s water or if there aren’t any toilets for the kids. Depending on the cost, we try to fix it. If the cost is beyond our limit, we try to find a funding agency or consult NGOs in the government organization.”

Khan was president of YEWOM for two years and still helps out even though he now lives over 7,000 miles away.

“From here, I usually give them suggestions,” Khan said. “So right now I’m contributing by sharing my own experiences, because I’m one of the senior most in the organization. We always promote the young people so they can learn how to lead the community. We provide them the platform to grow.”

Khan has always had a passion for helping others. To him, it is the best way to become a good person.

“It is necessary for each and every human being to do some work to live,” Khan said. “I’m a researcher, somebody will be a teacher, somebody will be a businessman, and so on. The ultimate goal is to get the resources for life, which we are doing for ourselves. But it doesn’t matter how much I’m a good scientist or how rich a businessman is, what matters is if we are good human beings, to me, that is most important. Everyone should be firstly a good human being then you can do other things.”

Toshi Ezashi, research professor in the Roberts lab, has witnessed this positive attitude firsthand.

“He spent a long time to come here but he never gave up and eventually came here in March [2020],” Ezashi said. “He tried to invite his family here around June, but then the pandemic happened. I think it was hard to him because he couldn’t see them for such an extended time. I don’t think they were able to join him until last November, but he didn’t complain. He just put all of his time and energy into the science and research. Even after his family joined him, he’s still passionate about his work.”

In the lab, Khan is working on developing trophoblasts in the early stages of the human placenta using embryonic stem cells.

“Sometimes experiments don’t work, but he doesn’t get upset,” Ezashi said. “He might be feeling bad, but he doesn’t project that onto others and never gets discouraged by failure. He just keeps pressing forward and tries to improve.”

This tenacity has paid off for Khan. He has developed protocol for isolating nuclei from trophoblast cells and is publishing that work soon.

Now that Khan has settled down here at Bond LSC, he plans on continuing to help others and promote educational opportunities.

“I like to say that as a biologist we can understand the nature of almost all animals,” Khan said. “We can understand if you are just doing things for yourself because every animal is doing things for themselves. As a social animal, humans give back to others. You have to try to give back to other people and help out.”

#IAmScience Shrikesh Sachdev

February 5, 2021 By Lauren Hines in #IAmScience Tags: cancer, stem cells, virology

By Lauren Hines | Bond LSC

Science is a pyramid. Every breakthrough and discovery are reached through incremental steps that build off the previous level.

Shrikesh Sachdev, a senior research associate in the Michael Roberts lab, thoroughly understands this.

“It takes many small steps to get to a treatment or a cure,” Sachdev said. “It very often takes decades, but it’s nice to be able to put in your little piece of the puzzle that might help lead to the discovery, if not a cure.”

Sachdev began his path to Bond Life Sciences Center when he left his home country of Canada in 1991 to earn his master’s degree in fisheries and wildlife from Mizzou.

Once he graduated in 1993, he felt his heart being pulled towards another field — disease and disease-related processes. That led him to conduct his Ph.D. in biochemistry doing cancer research with Mark Hannink lab in the Biochemistry Department at Mizzou.

After receiving his Ph.D. in 1998, Sachdev went to Munich, Germany as a Leukemia and Lymphoma Society Fellow for his postdoctoral research in Rudi Grosschedl’s lab, where he researched a developmental signaling pathway that has been implicated in cancer.

“Every scientist thinks, ‘I want to cure cancer, or I want to cure HIV,’” Sachdev said. “You always want to contribute to that, but I think the pursuit of knowledge should be our primary goal. Once we can understand the basics of how things work, then we can try and understand what is causing the diseases.”

While in Munich, Sachdev found a new type of SUMO E3 ligase enzyme that modulates a developmental signal transduction pathway. That was one of those underappreciated incremental steps.

“Science is incremental, but those ‘aha moments’ are what you live for,” Sachdev said. “I was thinking to myself, ‘I am the only person in the world that knows this right now…And it’s going to help people understand other things.’”

Currently, Sachdev works with research professor Toshi Ezashi to characterize and analyze induced pluripotent stem cells from patients with Smith-Magenis neurodevelopmental syndrome.

A mutation in the Retinoic Acid-Induced one (RAI1) causes the Smith-Magenis syndrome. Sachdev and Ezashi convert fibroblasts — skin tissue cells — into pluripotent stem cells which can turn into certain different types of tissue cells. Researchers use this method to understand the effects of the disease on a molecular level.

“Dr. Ezashi had a huge impact on introducing me to stem cells and really igniting a passion within me,” Sachdev said.

Ezashi has known Sachdev for more than eighteen years. The two started collaborating while Sachdev was near the end of his time in Munich.

“He’s very friendly and kind,” Ezashi said. “Whenever I need help, he never rejects me. He tries to help every time, which I do appreciate.”

While Ezashi has been working with pluripotent stem cells since 2003, Sachdev brings biochemistry and molecular biology expertise to the project.

“We have complementary backgrounds,” Ezashi said. “He has strengths that I don’t have, so we complement each other. We can cover each other’s deficiencies.”

The induced pluripotent stem cells will help the researchers do more since they won’t have to use embryo-derived materials that are restricting and complicated. However, both researchers have a long way to go in their study.

With a little luck, Sachdev’s multiple ongoing collaborations will each have their own set of incremental steps waiting to be found.

#IAmScience Toshi Ezashi

December 4, 2020 By Lauren Hines in #IAmScience Tags: placentas, stem cells

By Lauren Hines | Bond LSC

Despite his quiet demeanor, Toshi Ezashi leaves an impression on those who meet him in the halls of Bond LSC through his quiet intensity and constant courtesy.

The research professor was here before the “Joy of Discovery” sculpture in the atrium was built or the living plant wall was hung, calmly making progress with stem cells as part of the Mike Roberts lab team.

“I’m mainly doing research on trophoblast that compose the main component of the placenta tissue,” said Ezashi, who first came to Mizzou in 1995. “Using stem cell technology, we try to understand the pregnancy disease which happens in the placenta.”

Stem cells can be considered the ultimate source. They turn into all different types of the adult cells that make up the many tissues, organs and parts of a living thing. Induced pluripotent stem cells, on the other hand, are a little different. They start out as adult skin or blood cells but are pushed to revert back to an embryonic-like stage where they can once again turn into about any type of cell and self-renew.

Induced pluripotent stem cells were first discovered in a paper that appeared in Cell in 2006, and Ezashi excitedly presented it to his lab mates that same day.

“He knew instantly how important that was going to be,” said Laura Schulz, associate professor of Obstetrics, Gynecology and Women’s Health who works with the Roberts lab. “That’s just him. I think he really sees those things.”

Schulz has worked with Ezashi for the past 15 years.

“He’s just an incredibly kind person, but also a really very thoughtful, thorough and creative scientist,” Schulz said. “So, together those have made him a great collaborator.”

Currently, Schulz and Ezashi are studying trophoblast cells — stem cells from the placenta of early pregnancies. Ezashi is using these trophoblast cells to try to eventually understand preeclampsia, which results in dangerously high blood pressure and almost a rejection of the placenta. It is a potentially fatal complication that is only cured by the premature delivery of the baby.

Studying the placenta is difficult due to ethical issues and its ephemeral nature in relation to pregnancy. However, Ezashi generates placental cells that derive from umbilical cords left over after pregnancy to study the early stage of the placenta. This way, Ezashi and other researchers can figure out what causes the pregnancy complication.

“Right now, we don’t have any way to cure this disease,” Ezashi said. “The only option is to deliver the baby prematurely. Because of this issue being rooted in our lack of information of the time of the period, how the placenta works, we are expecting this study to provide important information to understand why this disease develops in this case.”

Ezashi has seen attitudes towards this kind of research shift in his many years working with stem cells.

“It was 2002,” Ezashi said. “We had this type of way of thinking that was just application. In those days, there was some understanding or social acceptance of stem cells, but we stepped forward to using stem cells in this field. I look back more than 17 or 18 years ago, but I still think it was the right move and decision to get into this field.”

Ezashi has grown along with attitudes and Bond LSC.

“He’s gained confidence and leadership skills I think over those 15 years, but actually he seems very similar to the person I met 15 years ago,” Schulz said. “He’s really just kind of a down-to-earth, quiet guy and the same careful scientist he’s always been.”

Even with 25 years under his belt, Ezashi isn’t leaving Bond LSC anytime soon.

“I know I have a different background, but by staying here to do something, I can uniquely contribute to society,” Ezashi said. “That means something. I can be a part of some message to the work, ‘How much can we achieve?’”

How does Zika move from mother to child?

July 19, 2016 By Roger Meissen in Research Tags: stem cells, Zika

Scientists use placental cells in lab to study virus

Megan Sheridan, an MU grad student, removes the base solution from a demonstrated sample of stem cells that will be grown into placental cells for study of Zika virus. Within four days of exposure to the correct hormones, the stem cells express genes of placental cells, and within another day start producing placental hormones. The cells are infected with Zika at day four to ensure maximum measurable interaction, as the stem cells naturally die in culture after about ten days. | photo by Phillip Sitter, Bond LSC

By Phillip Sitter | MU Bond Life Sciences Center

Scientists believe they have a better way to study how Zika virus can spread from a pregnant mother to her fetus — and their technique doesn’t even involve observations of babies in the womb or post-natal examinations.

“As soon as we heard about Zika, everybody’s light bulbs turned on,” said Megan Sheridan, a graduate student at the University of Missouri Bond Life Sciences Center.

Sheridan works in the lab of Toshihiko Ezashi at Bond LSC, and she, in turn, is part of a cross-campus team researching Zika with R. Michael Roberts, Alexander Franz, Danny Schust and Ezashi.

Roberts’ lab studies pluripotent stem cells — progenitor cells which can develop into any other type of cell in the body.

“We use the proper signals to drive stem cells to become like placental cells,” Sheridan explained. With this capability to stimulate stem cells with growth hormones and inhibitors at opportune moments, Roberts’ researchers realized they could create enough placental cells to create an environment similar to that of a womb in very early stages of pregnancy.

Megan Sheridan sits in front of a demonstration of her work with pluripotent stem cells. Sheridan is a graduate student who works in Toshihiko Ezashi’s lab, where she produces cells with placental characteristics from the stem cells in order to study placenta interaction with Zika virus. | photo by Phillip Sitter, Bond LSC

This is something which Sheridan thinks hasn’t been done before in regards to studying placental interaction with Zika. Their technique could give a look into the first trimester, when epidemiological studies say a fetus is most susceptible to infection.

Roberts’ lab is trying to understand the placental barrier’s vulnerability to Zika virus in its early stage of pregnancy. During this time, an infection could occur even before the mother is aware she is pregnant.

If the lab uses their technique to understand how Zika virus enters placental cells, then potentially they could also learn how to strengthen the placenta as a barrier to Zika and make it a first line of defense against infection of the fetus in the womb. If developing babies don’t get infected with Zika, then they won’t suffer the consequences of birth defects.

One such defect is microcephaly where a baby is born with a smaller than expected head, which may in turn be a sign that their brain has not fully developed. While infection with Zika virus is rarely fatal or otherwise severe in itself — many people don’t even develop symptoms — birth defects like microcephaly could cause further developmental problems like delays in learning how to speak and walk, intellectual disabilities, difficulty swallowing and problems with hearing and vision, according to global health organizations.

Microcephaly only became a widely documented effect of Zika after a particular strain surged across South and Central America with the infected mosquitoes that carry it, Sheridan explained, but this may be in part because previous Zika infections and outbreaks were themselves poorly documented.

While birth defects caused by Zika have drawn much media attention as the disease has spread northward through our hemisphere from Brazil, studies focusing on infection in the womb have only used placental material that has come to term. This may not be the most accurate way to see how the placenta gets infected in the first place early in pregnancy.

The pathway of Zika virus infection in lab mice isn’t really comparable to human infection, because mice aren’t infected with this virus naturally. Only lab mice that have had their genomes altered to be able to acquire the virus have susceptibility to the infection that can be modeled.

Roberts’ lab is currently working with the African strain of Zika and obtained strains from Southeast Asia and Central America recently. There’s about a 99 percent genetic similarity across strains, Sheridan said.

Zika virus was first discovered in Africa in Uganda in 1947, according to the Centers for Disease Control and Prevention. The first human case was documented in 1952, and subsequent outbreaks also occurred in Southeast Asia and the Pacific Islands. The Pan American Health Organization issued an alert about the confirmed arrival of the virus in Brazil in May 2015.

The lab has completed Zika infections of some of their stem cell-produced placental cells. Sheridan reassured that even though the lab works with live viruses, Zika is not airborne, and none of their work involves mosquitoes.

Roberts’ lab submitted one grant application earlier this year to the National Institutes of Health for funding for their research. While that application was denied, Sheridan said that they have a lot more preliminary data now and are hoping to submit a revised grant soon.

She said that their original work was “highly scored, but the funding level is still low,” meaning that obtaining funds for research into Zika virus is highly competitive nationally.

Legislation to fund more efforts into studying and preventing transmission of Zika virus is caught in congressional gridlock, according to The New York Times and other media outlets.

In the mean time, as the Roberts lab prepares its next grant application submission, Sheridan said of her efforts that she is “working hard to make progress on the project as quickly as possible.”

Please visit the CDC’s dedicated page for more information on Zika virus — including advice for travellers and pregnant women, description of symptoms and treatment, steps you can take to control mosquitoes and prevent other means of transmission of the virus and more background on the history and effects of the disease.

Bond LSC researchers search for causes of complex pregnancy disorder

January 13, 2014 By Roger Meissen in Research Tags: Pregnancy Disorder

Toshihiko Ezashi, Danny Schust, Laura Schulz and Michael Roberts collaborate on new research to discover the causes of preeclampsia. — Toshihiko Ezashi (left), Danny Schust (middle), Laura Schulz (middle) and Michael Roberts (right) collaborate on new research to discover the causes of preeclampsia. Roger Meissen/ Bond LSC

You can’t see the resemblance, but cells in Michael Roberts’ lab share a family tree with some newborns.

Their common genetics may help explain severe, early-onset preeclampsia, an inherited disorder that leads to a placenta that is often small and inefficient and possibly due to the mother’s body not fully welcoming her pregnancy.

University of Missouri Health Center scientists such as Danny Schust and Laura Schulz, work with Roberts and Toshihiko Ezashi, both Bond Life Sciences Center reproductive biologists, to search for its complex cause.

That starts in the delivery room. OBGYN’s Danny Schust and his residents save small pieces of umbilical cord from preeclampsia pregnancies, allowing Roberts and Ezashi to grow cells with the disease.

“We’re essentially recreating the previous pregnancy, going back in time as far as that baby is concerned,” Roberts said. “That allows us to look at the disease in a Petri dish, look at the properties of these cells to try and figure out what’s wrong with them.”

Preeclampsia affects 3-7 percent of births worldwide, and leads to around 50,000 deaths annually. Symptoms like high blood pressure and protein in the urine tip off doctors to the disorder, but it can go unnoticed until late in the pregnancy unless the symptoms are severe. Left unchecked the disease can lead to seizures and death. The only cure for the serious early-onset form of the disease is to deliver the baby prematurely, usually between 28-33 weeks. This leaves the newborn underweight and with complications like underdeveloped lungs.

Creating useful cells from the collected umbilical cords takes a little bit of work. Cells grown from the umbilical cords are converted into induced pluripotent stem cells, with potential to become any type of cell in the body. Researchers then use a series of hormones, growth factors and other conditions to create placental cells mirroring the previous pregnancy.

Normally the placenta – containing genes from both mother and father – grows into the wall of the uterus to establish a supply of blood, nutrients and oxygen to support the embryo. But in preeclampsia, those cells encounter problems.

Roberts and Schulz focus on extravillous trophoblasts, placental cells that invade the wall of the womb, while collaborators Toshihiko Ezashi and Danny Schust study synctiotrophoblasts, placental cells responsible for uptake of oxygen and nutrients from the mother’s blood.

“The question becomes do these placental cells grow too much or too little, and it appears that in preeclampsia they don’t grow enough,” Roberts said. “We’re just beginning to look at their ability to move and grow through a jelly-like substance that impedes a cell’s mobility and ability to pass through small pores on a membrane. We’re also comparing the gene expression of the cells from preeclamptic patients with those from normal births..”

The Roberts/Ezashi/Schulz/Schust team still has several years left on two five-year National Institutes of Health grants and hopes to narrow the search for genes linked to preeclampsia. If they pinpoint the culprit genes, scientists could one day potentially correct the problem by developing drugs that restore normality to the placental cells or even by using an induced pluripotent stem cell approach.

“It might mean you could go back to correct the defect in those cells or take that patient’s cells, make some normal cells and perhaps substitute them back in to effect a cure,” Roberts said. “My own feelings are that we’re a very long way from doing that, but that is the thought.”

Michael Roberts is a Curators’ Professor of Animal Science, Biochemistry and Veterinary Pathobiology in the College of Agriculture, Food and Natural Resources (CAFNR) and the College of Veterinary Medicine, respectively. Toshihiko Ezashi is a research associate professor in CAFNR. Danny Schust is an associate professor and Laura Schulz an assistant professorof Obstetrics, Gynecology, & Women’s Health, at MU’s School of Medicine.