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McArdle News

2019

Paul Alquist in video screenshot

Paul Ahlquist speaking in the video on broad-spectrum antivirals and the Morgridge Institute for Research.

Dr. Paul Ahlquist speaks about our constant fight against emerging viruses in a video and article originally posted by the Morgridge Institute for Research. 

“Viruses evolve at phenomenal rates,” noted Ahlquist, adding that “the viruses are winning, but in an environment that values fundamental research, we have a much better chance of shifting the balance in our direction.”

Broad-spectrum antivirals are a promising solution to ensure our safety. The broad spectrum approach targets multiple dangerous viruses with one treatment type. 

See the full article and video here.

 

 

By Dominique Barthel (dbarthel@wisc.edu)

Howard Temin, photo from the Nobel Foundation archive

“Throughout the 1970s, a biologist named Howard Temin became convinced that something wasn’t right in science’s understanding of viruses. His colleagues dismissed him as a heretic. He turned out to be right.” – Malcolm Gladwell

Revisionist History Season 4, Episode 10 podcast “The Obscure Virus Club”exposes listeners to Howard Temin’s remarkable early contributions as a scholar and citizen and how he endured harsh criticism and many frustrations over the course of his ultimately groundbreaking work on retroviruses. The podcast is hosted by Malcolm Gladwell, the New York Times bestselling author and journalist who calls “Revisionist History” his “journey through the overlooked and the misunderstood.”

Howard Temin carried out research over four decades at the McArdle Laboratory, initially focused on understanding the basis for virus-induced cancer caused by a chicken retrovirus, Rous sarcoma virus, and later made major contributions to our understanding of HIV/AIDS.

In 1970, his group and that of David Baltimore’s independently discovered a remarkably retroviral enzyme capable of converting DNA to RNA; reverse transcriptase. The discovery of reverse transcriptase was revolutionary in that it directly challenged the central dogma of molecular biology, provided powerful tools for biotechnology, laid the groundwork for understanding the origins of oncogenesis and, ultimately, set the table for understanding HIV/AIDS and developing potent antiretroviral drugs.

In 1975, Temin was awarded the Nobel Prize in Physiology or Medicine for “discoveries concerning the interaction between tumor and the genetic material of the cell.”

Temin passed away in 1994 due to lung cancer. He was also well-known as a charismatic teacher, mentor, and public citizen whose impacts will long endure at UW-Madison and throughout the field of cancer virology and HIV/AIDS.

Left to right: Don Fechner, Karen Schwarz, and Richard Burgess at Don’s 90th birthday celebration on Sunday, August 18, 2019.

Don Fechner turned 90 years on September 11, 2019. McArdlites who shared any time at the lab with Don agree that he is incredibly kind and was an invaluable member of the McArdle team. He began working at McArdle in 1957 and stayed for 61 years. 

 

On Sunday, August 18th, friends, family, and some McArdlites gathered to celebrate Don’s 90th birthday. 

 

Don’s time at McArdle began with an undergraduate lab position in the Mueller lab. Soon, his mechanical talents were discovered, in particular his skills as a centrifuge repairman. He remained a long-term member of the lab working as a technician. 

 

Dr. Richard (Dick) Burgess met Don when Dick was first hired as an assistant professor in 1971 and has been inspired by him since.

 

“Don is a remarkable individual who devoted most of his professional life to help make McArdle work better,” said Burgess.

 

Many McArdlites shared memories of Don in his “machine shop” on the tenth floor of the old McArdle Cancer Research Building located at 1400 University Avenue. Don was known for a workspace crammed with repair tools and gadgets. While crowded, Don knew exactly where every item belonged and he maximized use of his machine shop resources. 

 

“It was amazing. Don was an instrumental member of the department,” said Burgess. 

 

Further, Don shared his craftsman talents graciously. It was always “done with a generous, gentle attitude,” said Burgess. “He always had help to offer, and he never turned away a project.”

 

Dr. Norman Drinkwater, who was Director of McArdle from 1992 to 2008 and recently stepped down from his interim position as Vice Chancellor for Graduate Research and Education, has known Don for more than 40 years.  

 

In the era when lab equipment lasted, Don made it last longer. There was nothing he couldn't fix. When you needed an odd piece of equipment or a device to do your next experiment, Don was able to turn your crude Sharpie drawing on a paper towel into something that really worked. Everyone visiting him in his machine shop on the 10th floor of old McArdle got a smile, a kind word, and all the help they needed. Don was truly a treasure through all his years as part of the McArdle family,” said Drinkwater.

 

McArdle wishes Don Fechner a happy birthday and thanks him for his years of maintenance and support. 

 

Don Fechner (top row, second from the right) and Dick Burgess (top row, first from right) played on the same graduate student intramural basketball team in 1974.

 

Don Fechner and his wife, Wanda, at the McArdle Symposium in November 2008, honoring Gerry Mueller and Roz Boutwell. 

 

 

 

By Dominique Barthel (dbarthel@wisc.edu)

 

 

Left to right: : Stuart Fogarty, Amada Loke, Dongwhan (Heron) Jeon, Katie K.,  Alejandro Casco, Santina Snow 

Last fall, six new graduate students joined the Cancer Biology program. During their fall semester, they had a chance to rotate between several labs. Then, in December, the students choose their home labs at which they will study in throughout the rest of their graduate program. Now that they’ve had a year under their belt, we checked in to find out about some of their Madison favorites and current research projects. 

Alejandro Casco

1. Research project title and lab

Dynamics of Epstein-Barr Virus Lytic Transcription; Johannsen lab

2. Research statement—or summary of current project

Elucidating the spatial and temporal organization of EBV lytic transcription.

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

Be open minded when picking your rotations. Some of us come here with a specific research area we are interested in, but choosing one or two rotations focused on other research affords you not only the opportunity to find a different interest, but also learn different molecular and bioinformatic techniques you may not be exposed to.

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?

The Polar Vortex was definitely my favorite since I’ve never experienced anything remotely that cold before.

5. New favorite Madison cuisine? 

Ian’s Mac N Cheese Pizza is my favorite.

6. Favorite off-campus WI attraction?

The Terrace during the summer. Great times and somehow there are never mosquitos there.

7. What surprised you the most about living in WI?

The outdoor culture here is great, there is always something to do and someone doing it.

 

Stuart Fogarty

1. Research project title and lab

The role of PIPKIα in stabilizing p53, both mutant and stress-induced wildtype; Cryns lab

2. Research statement—or summary of current project

We have recently demonstrated that both mutant and stress-induced wildtype p53 are stabilized by the activity of the enzyme PIPKIα and the small heat shock proteins αB-crystalin and Hsp27. Phosphatidylinositol phosphate kinases (PIPKs) phosphorylate PI(4)P and PI(5)P to produce PI4,5P2, also known as PIP2. PIPKIα is a type I PIPK that converts PI(4)P to PIP2. We demonstrated that PIP2 is then associated with a polybasic motif in the C-terminal regulatory domain of p53, and then recruits the small heat shock proteins αB-crystalin and HSP27. Both PIP2 and small heat shock proteins were demonstrated to be required for the stabilization of nuclear p53. Additionally, since phosphoinositides are small molecules and kinases are typically druggable, the development of an inhibitor of PIPKIa may prove to be a feasible and specific strategy to target mutant p53 for destruction and kill tumor cells driven by this oncoprotein.

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

When choosing a lab, the science is important, but the people in a lab you are choosing are arguably even more important, as they will be the ones supporting you and forming the environment in which you will work for your graduate career. 

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?

Fall

5. New favorite Madison cuisine?

Bartaco in Hilldale 

6. Favorite off-campus WI attraction?

Milwaukee County Zoo

7. What surprised you the most about living in WI?

How healthy and active people in Madison are.

 

Dongwhan (Heron) Jeon

1. Research project title and lab
Potential of Toll-like receptors in cancer immunotherapy; McNeel lab

2. Research statement—or summary of current project

McNeel lab has recently found that the stimulation of Toll-like receptors increases the efficacy of anti-tumor immunity of CD8+ T cells. This was mediated through IL-12 secretion by professional antigen presenting cells, specifically dendritic cells, and led to suppression of PD-1 expression on CD8+ T cells. Following on these preliminary results, my project is to determine whether the combination of TLR agonists with different immune stimulants, including other TLR agonists or T-cell checkpoint blockade affects CD8+ T cell function.

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

I think rotation during the first semester is really really really (really) important for your entire graduate study, even more than coursework. You should find the lab that fits perfectly for you.

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?
Hot/Humid Summer ( I don't prefer humid but..)

5. New favorite Madison cuisine?
Cheese Curds!!!!!!!!

6. Favorite off-campus WI attraction?

Devil's Lake, Wisconsin Dells

7. What surprised you the most about living in WI?

Incredibly safe (even at night), low living cost, perfect neighbors, awesome bike trails

 

Katie Knutdtson

1. Research project title and lab

Investigating Mutation-Dependent Interactions with Subclonal and Extratumoral Cell Populations; Deming lab

2. Research statement—or summary of current project

My research focuses on understanding how different molecular profiles of colorectal cancer (CRC) direct interactions with the tumor and tumor environment. CRC is the second-leading cause of cancer related deaths in the United States and is now being understood as a collection of diseases determined by the molecular profiles of the tumors. Many proto-oncogenes and tumor suppressors are deeply involved in a number of cellular processes, such that their mutations could uniquely impact cellular metabolism and extracellular signaling. Cancer-associated fibroblasts (CAFs) are developed by signaling with cancerous cells and are known to support cancer. My research aims to evaluate the metabolic and growth dynamics across molecular profiles with and without treatment using novel 3D mouse and patient-derived organotypic cancer spheroids combined with optical metabolic imaging (OMI), which takes advantage of the inherent autofluoresence of metabolic coenzymes NADH and FAD. Further, I aim to use these tools to investigate how the molecular profile affects cancer cells’ interactions with subclonal populations and cancer-associated fibroblasts in order to have a more complete understanding of how different mutational profiles signal to their environment, with the goal of finding targetable pathways to improve treatment selection and efficacy.

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

There’s a lot of great things to do in Madison. It may be tempting to stay in when you get a break from the lab, but it’s a lot more fun to go out and experience what the Madison area has to offer.

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?

Summer

5. New favorite Madison cuisine?

New Orleans Take Out

6. Favorite off-campus WI attraction?

Nearby, Wisconsin Brewing Company in Verona is a good hangout. For longer trips, Door County is highly recommended.

7. What surprised you the most about living in WI?

There’s no BBQ here.

 

Amanda Loke

1. Research project title and lab

Elucidating the role of transcription factor Atoh1 in development of Merkel Cell Polyomavirus Positive (MCPyV+) Merkel Cell Carcinoma using in vitro and in vivo methods; Lambert lab

2. Research statement—or summary of current project

The focus of my primary, current project is to study the potential role of the transcription factor Atoh1 in inducing Merkel Cell Carcinoma (MCC) in the presence of Merkel polyomavirus viral proteins (MCPyV). Atoh1 is a transcription factor that is involved in Merkel cell fate determination. Published in vivo evidence indicates that overexpression of Atoh1 in transgenic mice expressing the Merkel cell polyomavirus T antigen expression produce a MCC-like disease phenotype in the skin. I plan to approach this research topic using in vitro and in vivo experiments to study development of MCC. My studies will use tissue culture and transgenic mouse model systems established in the Lambert laboratory

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

Keep an open mind; you'll learn and get so much more out of your graduate school experience!

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?

Neither. I like a happy medium- fall is my favorite season. (If I had to chose between summer or winter, I'll probably choose summer)

5. New favorite Madison cuisine? 

Morris Ramen on King Street - I love a bowl of Japanese ramen and green tea combo.

6. Favorite off-campus WI attraction?

Lakeshore Path - it has the great view of the lake as well as a place to relax. The commemorative rock dedicated to Howard Temin is also a great source of motivation!

7. What surprised you the most about living in WI?

How accessible everything is here - I was not expecting the ease of getting around the city with just public transport. 

 

Santina Snow

1. Research project title and lab

Identification of Molecular Features Impacting Polyp Growth and Progression; Halberg lab

2. Research statement—or summary of current project

In the Halberg Laboratory, we study colon cancer. Polyps can form in the colon, however, only 5% of polyps become cancerous. We are curious as to why this small percentage of polyps become malignant while the vast majority remain static or even regress in size. My project focuses on identifying the underlying molecular differences between polyps of known growth fates (growing, remaining static or shrinking). It is important to know what causes the various growth progressions in order to better predict a patient's risk of developing colon cancer in the future. A patient's risk assessment could be used to develop a more personalized surveillance regime and prevent interval cancer deaths. 

3. What piece of advice would you give to first year graduate students in Cancer Biology, after a full academic year under your belt?

Make finding a work/life balance a priority now while you're still figuring out your new life routine rather than later when your routine is already set. Incorporate activities into your daily life that allow you to decompress in order to remain physically and mentally healthy to prevent feeling burnt out. 

4. Favorite season in WI --Polar Vortex vs Hot/Humid Summer?

My favorite season is fall when I can hike amongst the fall foliage, go apple picking, carve a pumpkin or get lost in a corn maze. If I had to choose between Polar Vortex or a hot/humid summer, then I would definitely choose long, sunny summer days! 

5. New favorite Madison cuisine? 

That would be a tie between frozen custard and cheese curds (squeaky fresh or deep fried- both are delicious!). 

6. Favorite off-campus WI attraction?

CrossFit Madtown!!! I also find up north in the woods just glorious and deeply relaxing. I really enjoy hiking and snowshoeing in the state parks particularly Mirror Lake, Devil's Lake, Governor Dodge and Blue Mounds. 

7. What surprised you the most about living in WI?

I'm not from the Midwest and I had only heard about 'midwestern nice'. Now that I live here, I understand why it is a phrase since the people are just so friendly and kind.

 

 

 

By Dominique Barthel (dbarthel@wisc.edu)

Cell Division Images

Unequal segregation of chromosomes during cell division is called aneuploidy and can contribute to cancer (left). Aussie Suzuki uses his optimized microscopy method to map out the kinetochore proteins that have an important role in the dividing process (right). 

 

Dr. Aussie Suzuki, a new faculty member in the McArdle Laboratory, is utilizing an optimized method of microscopy known as 3-dimensional (3D) fluorescence co-localization that allows accurate measurement at the scale of 10 nanometers.

 

Suzuki, who came to the McArdle lab in August, created this method during his postdoctoral studies and recently published the method in the journal eLife.

 

This novel method of microscopy allows for measurements in the x, y, and z planes, making it three dimensional and extremely helpful in studying cell division errors that lead to cancers. Moreover, the technique has broad research applications for studying any subcellular structure within the cell, he said.

 

His research primarily focuses on understanding the molecular mechanisms that ensure faithful chromosome segregation. Cancer can be caused by errors during chromosome segregation in mitosis, a process of cell division. 

 

An unequal division of chromosomes in mitosis is known as aneuploidy, and roughly 90% of solid tumors and 50% of blood tumors contain aneuploid cells. Additionally, aneuploidy is one of the main causes of developmental diseases such as trisomy 21, also known as Down syndrome, and miscarriages.

 

Correct separation of replicated sister chromatids requires long protein filaments known as microtubules to attach to each kinetochore. A kinetochore is the mega-protein complex built at the primary constriction of each sister chromatid.

 

The microtubules attach to individual kinetochores and pull the sister chromatids to opposite sides of the cell to undergo accurate division. If microtubules from opposite spindle poles attach to a single kinetochore, the chromosome lags, resulting in an uneven split of genetic material between daughter cells.

 

Fluorescence microscopy is one of the most powerful tools in biological and biomedical research, said Suzuki. However, the optical limitation of many fluorescence  microscopes is on the scale of only ~250 nm laterally and ~500 nm axially without applying special techniques and mathematical image processing.

 

A kinetochore is made up of at least 25 different core-structural proteins and each protein has 70~250 copies. So, despite being only about 200 nm wide, it is an intricate structure and can not be studied using traditional fluorescence microscopy techniques alone, said Suzuki. 

 

“It is surprising that this tiny protein architecture (the kinetochore) on each chromosome is responsible for proper chromosome segregation machinery including microtubule assembly, monitoring errors, repairing errors, and generating force for chromosome movements,” he added.

 

It is a daunting challenge to study kinetochore deformation since the kinetochore is smaller than the diffraction limit of microscopy, said Suzuki. 

 

The kinetochore protein architecture can deform during mitosis and this structural change is thought to be important for proper chromosome segregation. 

 

Another limitation of fluorescence microscopy is chromatic aberration, which means if someone is trying to assess two or more structures in the cell using multiple fluorescent labels, the colors are sometimes shifted due to optical reasons. This shift makes is difficult to obtain precise measurements. Specifically, each color has a different wavelength, and the microscope lens alters what color the viewer sees because each wavelength has a different focal point through the lens. 

 

Therefore, to measure the separation between green and red fluorescently labeled proteins, chromatic aberrations must be corrected for. Chromatic aberration is not uniform, which makes optimizing a method a challenge, said Suzuki.

 

To solve this issue and obtain accurate measurements of subcellular structures, such as the kinetochore, Suzuki developed the optimized 3D fluorescence localization method. 

 

The 3D fluorescence co-localization method “is an amazing technique due to the 5 nm resolution for 2D measurements and ~10 nm accuracy for 3D measurements, which is better than any expensive super-resolution microscopes,” said Suzuki. With his optimized method, Suzuki has mapped ~25 different core-kinetochore protein’s 3D positions at metaphase, a stage of mitosis. 

 

“We now have a tool to study the mechanisms of how the kinetochore architecture is deformed, and what the function of this deformation is in mitotic checkpoint control and proper chromosome segregation.” 

 

The loss of kinetochore structural integrity may be involved in carcinogenesis. He is excited to further examine kinetochore function and move research forward in understanding the cancer-causing process, he added.

 

 

By Dominique Barthel (dbarthel@wisc.edu)

Aurelia Faure holding cell cultures

Aurélia Faure, the paper’s first author, holding cell cultures. 

Primary Effusion Lymphomas (PELs) are a highly aggressive blood cancer found in immunosuppressed individuals, such as people living with HIV, that researchers have long struggled to study due to the difficulty of developing similar cells in the lab. The lymphomas kill patients within six months of diagnosis on average in the United States.

Dr. Bill Sugden of the McArdle Laboratory for Cancer Research and his team recently broke this barrier of studying the debilitating cancer by discovering how to transform a type of white blood cell, known as B cells, into PEL-like cells by infecting the cells with two viruses.

The paper was published this week in the Proceedings of the National Academy of Sciences journal. 

“It’s exciting because it finally gives us a handle to begin to understand this lymphoma. It is the only lymphoma we know that has two distinct tumor viruses,” said Sugden. 

The lymphoma has long been known to occur with a cancer-causing virus known as Kaposi’s sarcoma-associated herpesvirus (KSHV), and several KSHV genes have been shown to be significant in the maintenance of PELs.

Moreover, 86% of PELs are also infected with another herpesvirus known as Epstein-Barr Virus, which also causes its own type of cancer in some cases.

In this study, Sugden, Aurélia Faure, and Mitch Hayes demonstrate for the first time that infecting B cells with KSHV and EBV within 24 hours of each other is an optimal method to yield cells in the lab with some properties of PELs.

There are three major components that make the dually infected cells so similar to PELs.

  1. The cells contain both viruses (EBV and KSHV).

  2. Both PELs and KSHV infected B cells express a peculiar antibody molecule. Most B cells in the body have a light chain that is kappa. PELs tend to have lambda, and the dually infected cells also express lambda light chain.

  3. In one subset of the dually infected cells, the cells inhibit cellular genes as do PELs.

Of 100 infected B cells, only two cells will take up both of the viruses, and only two percent of these dually infected cells form the most PEL-like cells, which also gives insight to the rarity of the cancer. The doubling time of these dually infected cells is somewhere between 48 and 72 hours. For comparison, bacterial contamination doubles every 30 minutes, and a yeast contamination doubles every four hours, underscoring the need to grow these cells sterilely.

The researchers identified a subset of the dually infected cells that overgrew the other cells in the culture. This “fast” cell line shares multiple properties with PELs and seems to be the best model of the cancer. 

Primary effusion lymphomas make up only three percent of the types of lymphomas found in HIV patients, but it is important to remember that there are currently 38 million people living with HIV worldwide. About half of these people do not receive antiretroviral therapy, so 17 million people living with HIV are particularly vulnerable. 

The discovery will help Sudgen, his team, and other researchers around the world to learn how this blood cancer develops and, eventually, how it can be eliminated.  

Sugden is eager to move this research forward and wants to share additional knowledge and all the cell lines with others to help do so. 

This approach for developing PEL-like cells outside of the body opens the door to understanding what each virus contributes to the lymphoma and to then “identify viral gene targets for intervention,” said Sugden. 

 

By Dominique Barthel (dbarthel@wisc.edu)

Janesville Summer Research Institute students at the McArdle Laboratory for Cancer research (7/25).

Last Thursday, students from the Janesville Summer Research Institute visited the McArdle Laboratory. 

The six-week program is headed by Dr. Zach Pratt, a researcher and former graduate student at McArdle. Throughout the course, the students learned about bacteria, viral infections, and genetics. Their work also included hands-on experimental techniques. 

The visit to McArdle allowed the students to see real-life applications of their new knowledge. 

Janesville’s local newspaper, the GazetteXtra, covered the visit. Read the full story here

 

The program project grant team (left to right): Nathan Sherer, PhD, Shannon C. Kenney, MD, Paul F. Lambert, PhD ’85, Janet E. Mertz, PhD, Eric C. Johannsen, MD, Paul Ahlquist, PhD ’81, Daniel Loeb, PhD, and Bill Sugden, PhD.

2018-19 was a banner year for McArdle’s Cancer Virology program. 

First, the program renewed a ~$10 million NIH program grant, “Molecular Biology and Genetics of Human Tumor Viruses," funded by the National Cancer Institute, to continue to study how viruses cause 15-20% of all human cancers (Professor Paul Lambert, Principal Investigator; Paul Ahlquist, Eric Johannsen, Shannon Kenney, Daniel Loeb, Janet Mertz, Nate Sherer, and Bill Sugden). This program project grant (P01) was first envisioned by the late Howard Temin (Nobel Prize, 1975) and has been continually funded groundbreaking cancer virus research at McArdle for more than 40 years. 

Second, UW-Madison hosted at two major international cancer virology conferences held in back-to-back weeks; the International Conference on Epstein-Barr Virus and Kaposi’s Sarcoma Herpesvirus (organized, in part, by McArdle Professors Eric Johannsen, Shannon Kenney, and Janet Mertz) and the annual DNA Tumor Virus Meeting (organized, in part, by Professor Paul Lambert). McArdlites contributed to the more than 200 projects at these meetings (~120 oral presentations and >140 scientific posters).  

A recent article in SMPH’s Quarterly magazine summarizes these achievements.

Cell division

Errors in cell division can cause cancer. Here, chromosomes in blue are being pulled in the wrong directions by the microtubules in red which will result in aneuploidy. Photo by Ryan A. Denu of the UW Carbone Cancer Center and the National Cancer Institute

Dr. Aussie Suzuki is studying the fundamental mechanisms of cell division to better understand how cancer develops from aneuploidy, a deadly error in the dividing process. UW News covers how he and Dr. Beth Weaver of McArdle along with Dr. Mark Burkard are paving the way to clarity with technological advances. Read the full article on the UW News website.

 

 

  

Dr. Yongna Xing and Jordan Lang, March 2019 In front of angel’s wings made by patient families.

Dr. Yongna Xing and Jordan Lang, March 2019 in front of angel’s wings made by patient families.

Jordan’s parents spent years visiting doctors to find out why their baby girl wasn’t meeting developmental milestones. After getting a diagnosis in 2016 by whole-exome sequencing, they began connecting researchers and patient families to collaborate and learn more about their daughter’s genetic mutation, which is now known as Jordan’s Syndrome.

Dr. Yongna Xing is a part of that research team.

The patient families are amazed that all of their kids’ symptoms are caused by a single nucleotide alteration in the PPP2R5D gene, said Xing.

“The mutation leads to a wide range of neurological symptoms, including intellectual disabilities, loss of or reduced verbal skills, autism, mild seizures, and hypotonia, which means that their muscles do not function properly.” she said.

Very few patients get diagnosed because so little is known about the syndrome, and molecular diagnosis by whole-exome sequencing is not widely used. Jordan wasn’t diagnosed until she was 9 years old after a whole exome sequencing test. The test allowed doctors to search her whole genome for mutations leading them to the diagnosis that left them with very few answers.

Jordan’s parents started a foundation to do as much as they could to increase resources for their daughter and help other affected families.

The Jordan’s Guardian Angels Foundation connects families affected by Jordan’s Syndrome, raises awareness and research support, and compiles PPP2R5D research from around the world.

Today, the PPP2R5D intellectual disability (ID) mutations have been found in more than 100 children from 21 months to 25 years old in 19 countries across the globe, with more children being diagnosed each month. It is estimated that 250,000 cases are undiagnosed.

“The patient’s family is very motivated, and they are very good at getting experts together,” said Xing.

Dr. Xing has been conducting multidisciplinary research mainly focused on structural biology, biochemistry, and system biology to understand protein phosphatase 2A regulation and disease mutations.

PP2A is critical for many cellular and physiological functions by the formation of ~100 heterotrimeric holoenzymes that belong to four major families. Multiple types of cancer and diverse neurological disorders are linked to the deregulation of PP2A.

The PP2R5D gene encodes one member of the regulatory subunits in the B’ family, known as B’d, making it an important part of the PP2A system. Her group initiated PPP2R5D research in 2017 under grant support from the Jordan’s Guardian Angels Foundation.

There are 12 different research groups across the United States and Europe that Jordan’s parents connected. All 12 research groups and Jordan’s parents attend bimonthly web meeting to discuss new progress and collaborations.

Jordan’s Guardian Angels Foundation has granted $1 million to the Xing lab since 2017 till 2021. They have raised money by fundraising and received support from the state of California, which works with UC Davis to distribute the grants to the different research groups.

The 12 research groups are studying the mutation from several angles such as stem cell research, animal models, cell biology, biochemistry, structural biology, and clinical work.

“The progress has been exceptional,” said Xing.

There can be several different ID mutations to PPP2R5D. The most common and most severe mutation is E198K and has been identified in the majority of patients with Jordan’s syndrome. More than 10 other PPP2R5D ID mutations have also been identified.

All mutations, except the mildest one that can be inherited, predominantly occur during spermatogenesis. Intriguingly, the same somatic mutations were found in the tumor tissue of cancer patients.

Each variation has similarities and shared symptoms with differences in severity. A deceased patient recently known to have a mild version of Jordan’s syndrome had been misdiagnosed for Parkinson’s disease for 20 years.

Using x-ray crystallography and single particle cryo-electron microscopy, the Xing lab is working to understand the unique conformation and structure of the wild type PP2A- B’d holoenzyme to ultimately understand how ID mutation in PPP2R5D changes the holoenzyme conformation.

“Our preliminary structural modeling suggests that mutations could alter enzyme conformation as well as substrate entry, a hypothesis under testing right now," said Xing.

Building knowledge gained on substrate recognition, Xing’s lab has also built bioinformatic tools to predict PP2A substrates potentially affected by PPP2R5D ID mutations. For example, those in brain tissues such as the hippocampus, caudate nucleus, and cerebellum might contribute to the symptoms in learning, sleep, language, and sensor motor association.

“Built on structural understanding, we are also trying to understand how to restore the conformation of the mutant holoenzyme, and if we do that, hopefully we find a treatment for patients where we can identify small molecules that modulate the holoenzyme conformation,” said Xing.

The collaboration with the other research groups has been advantageous in moving forward with personalized medicine plans, and Dr. Xing is especially motivated by the potential to create effective treatment for the children living with Jordan’s Syndrome.

The foundation laid out a highway for personalized medicine for Jordan’s Syndrome, she said. Any potential therapeutic strategies could be rapidly tested and assessed in animal models and in vitro mini-brain of the disease established by other research groups.

Communicating with patient families and research teams has been exciting. “It is a good example for people to see how what you do in the lab can directly affect clinical practice and personalized medicine,” she said, “and the research on Jordan’s Syndrome also set up a great working model for tackling other phosphatase diseases that the lab research is involved.”

 

By Dominique Barthel (dbarthel@wisc.edu)

 

 

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