Advancing the Science

Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.


Member has chosen to not make this information public.

Posts (13)

Wed, Jan 22 6:00am · What's Next for The Research of the Future

Breakthroughs in medical science rarely burst on the scene. Behind every advance is years of work by dogged researchers who nurtured the seed of idea until it flowered, bore fruit and materialized into a better treatment, device or therapy for patients. Here is where those seeds start: More than a dozen projects related to cancer, cell structures, genetics and epigenetics, immunology and tissue regeneration were funded in this year’s Mayo Clinic Center for Biomedical Discovery 2019 Pilot Grants. The award provides focused, one-time funds for imaginative proof-of-principle studies or model-development needed to lay the foundation for future efforts.


Bone marrow fat (adiposity) is a hallmark of aging bones. Rising levels are correlated with reduction in bone density, which can lead to osteoporosis. Jennifer Westendorf, Ph.D., and team will clarify the role of adipose tissue in bone marrow and discover the pathways that encourage this yellow marrow to form. They will examine the composition of the marrow adipose tissue and a genetic regulator, called histone deacetylase 3, for its role in changing gene expression and cellular composition of bone marrow.

Cellular Antennae and a Rare

With this new funding, Haitao Wang, Ph.D., and Jinghua Hu, Ph.D., will investigate how a cellular “antenna,” or cilium, determine how stem cells differentiate into muscle, connective tissue, or bones. The knowledge will help us to understand many degeneration diseases that currently have no treatment or cure.

Bowel Disease

This team will investigate the interaction between cellular metabolism and intestinal macrophage functions. They are investigating what role, if any, this interaction plays in controlling gut inflammation as seen in inflammatory bowel disease. Study investigator W K Eddie Ip, Ph.D., hopes to use this work to further understand how inflammatory bowel disease begins and what therapeutic targets might be on the horizon.


Fibrosis is a serious disease process characterized by uncontrolled internal scarring. Researchers Daniel Tschumperlin, Ph.D., Christopher Evans, Ph.D., and Robert Vassallo, M.D., are hoping to better understand the biology of fibrosis and how loss of important transcription factors affects the disease process.  The team will investigate the transcription factor CEBPA and develop a new approach to enhancing its expression in lung epithelial cells to reduce fibrosis.

Medical Illustration of the process of fibrosis.
In cell and mouse models, Mayo Clinic researchers and collaborators have identified a way to slow and reverse the process of uncontrolled internal scarring, called fibrosis. The findings were published in Science Translational Medicine.

Liver Regeneration

The researchers on this project are looking at how the liver heals after injury. They hope this knowledge will improve how patients undergoing surgery of the liver recover, and provide ideas on how to support liver regeneration. The researchers on this project are Rory Smoot, M.D., Patrick Starlinger, M.D., Ph.D., and Gregory Gores, M.D.  They report that preliminary data suggests a role for the Yes-associated protein (YAP) and will explore if SHP2 inhibition increases YAP activation in a mouse model and if increased YAP activity results in accelerated liver regeneration in a mouse model.

Mitochondrial Disease

With this project, researchers hope to improve quality of life and life expectancy in Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) by establishing a model system of cardiomyopathy. The researchers on this project — Tamas Kozicz, M.D., Ph.D., Timothy Nelson, M.D., Ph.D., Eva Morava-Kozicz, M.D., Ph.D., — will perform deep phenotyping to improve knowledge of pathology and complete high-throughput drug screening to identify possible therapies.

Illustration of physicians climbing onto a mitochondria designed to mimic a maze and helping a patient out of the shadow of the maze.
Mayo Clinic researchers are pursuing a range of investigative approaches to better understand and predict the impact of mitochondrial malfunctions, with the goal of helping patients. Read more at Discovery’s Edge.

Cancer, Cancer Treatment and Cancer
Treatment Side-Effects

One cancer-related effort will examine cytotoxic T lymphocytes and their role in immunotherapy. Two projects were funded in this area. One will investigate a protein called NKG7, identified by the research team as being associated with a lack of benefit in immunotherapy. Led by Haidong Dong, M.D., Ph.D., and Daniel Billadeau, Ph.D., the team will develop antibodies to detect NKG7 in patient samples and generate cell lines without the genetic ability to produce NKG7. In a second project, Dr. Dong, Roxana Dronca, M.D., and Yiyi Yan, Ph.D., will create a mouse model to examine the role of NKG7 in the ability of CD8-positive T cells to respond during anti-programmed death ligand 1(PD-L1) therapy. The researchers hope that by clarifying the role of mediators to cytotoxicity, they can improve patient response to PD-1 checkpoint blockade immunotherapy.

related to immunotherapy, a pilot grant was awarded to Frank
Sinicrope, M.D.
, and Bo Qin, Ph.D., to study the association of the immune
checkpoint protein PD-L1 with a cell-death regulator called BIM in colorectal
cancer cells. They will examine if PD-L1 controls the level of BIM protein via
an enzyme known as an E3 ligase.

was also provided to establish a mouse model that will examine long noncoding
RNA. The researcher leading the project, Wenqian
Hu, Ph.D.
, and his team report that these RNA are important during the
production of red blood cells and regulation of the stem cells that develop
into blood cells. The team will focus on a specific RNA, called Dleu2, and hope
that the mouse model will reveal how it regulates normal blood cell formation
as well as novel insights into the development of chronic lymphocytic leukemia.

Multichannel pipette is filling wells in a lab.
To read more about how advances in lab models will ultimately help the medical treatments, read Mimicking Cancer at Discovery’s Edge.

In another project aimed at blood stem cells, researchers will look at the possibility of predicting the evolutionally trajectories from normal to acute myeloid leukemia and myelodysplastic syndromes, based on variants of a germline zinc finger transcription factor called GATA2. This factor is critical in formation of the stem cells that develop into blood cells. This project will be undertaken by Mrinal Patnaik, M.B.B.S.; Ryan Carr, M.D., Ph.D.; Terra Lasho, Ph.D.; and Moritz Binder, M.D.

pilot grant to examine chemotherapy-induced
nerve damage
was awarded to Christopher Groen, Ph.D., Jewel Podratz, and Anthony
Windebank, M.D.
In a Drosophila model,
the researchers have identified genetic variations in mitochondria genes that
provide resistance to neuropathy (read about their work in Discovery’s
). The award will allow them to examine changes in mitochondria
that confer that resistance novel 3D electron microscopy available through the
Microscopy and Cell Analysis Core Facility. If successful, their work has the
potential to establish a direct link between mitochondrial health and
chemotherapy-induced peripheral neuropathy outcomes.

To study the inherent genetic instability of cancers, a grant was awarded to Larry Pease, Ph.D., and Keith Robertson, Ph.D., who will focus on genetic markers in breast cancer. In their work to date, they’ve detected a form of genetic instability that pervades the genome of breast cancer cells and allows tumors to evade homeostatic cell growth regulation and tumor recognition by the immune system. To look into the nature of genetic changes allowing tumor evolution, the researchers will develop a mouse model of spontaneous breast cancer that can be targeted specifically by tumor suppressing immune cells, enriching for locus-specific modifications in HER2 gene expression in tumor cells escaping from tumoricidal immune attack.

For more information about Mayo’s Center for Biomedical Discovery or past awardees, visit the Center for Biomedical Discovery website.


Jun 20, 2019 · How are Helper T-Cells Made? And Yes, It's Important.

T-cells are having a moment. Well maybe not like Game of Thrones is having a moment, but as stars of the cancer treatment, immunotherapy, T-cells are definitely cool. But what is a T-cell? And how can you get one?

Good news! Your body makes T-cells for you, a lot of them.
All the time.

Wannabe T-cells are born
in bone marrow and migrate to the butterfly-shaped organ called the thymus. Put
your hand on your neck, right where the collar bones meet. There, now you’re
almost touching your thymus, which is in your rib
cage just above your heart. A butterfly is a good metaphor to keep in
mind, too. Like an egg becomes a caterpillar that becomes a pupa which becomes
a butterfly, the T-cell goes through a life cycle to become the powerhouse
protector of the body. As part of that cycle, T-cells in the thymus learn if
they have aptitude for one of two jobs. But the thymus is less job training and
more Hunger Games. The majority never make it out because the body culls any
that aren’t just right.

Red Alert / Chemical

The overall task of a T-cell is to respond to markers, called antigens, left behind by invaders, which stick to cells in our body. T-cells have a port, or receptor, that matches to an antigen. When that happens, the T-cell turns into either a chemical weapon or an alarm bell.

Both are vital, according to Virginia Shapiro, Ph.D., immunologist and co-lead for the immunity platform for Mayo Clinic’s Center for Biomedical Discovery.

Virginia Shapiro, Ph.D.

“One type of T-cell can recognize that the danger is
coming from inside a cell, as in the case of a virus, and will inject it with a
granule of toxic chemicals. Those are the cytotoxic (kills living cells)
T-cells or CD8 T-cells,” she explains. The other type is the CD4, or
helper T-cell, Dr. Shapiro continues. “These are the cells that get the
immune message, become activated, but do not kill the messenger.”

Sometimes T-cells can take care of the problem then and
there, but other times, the immune system needs to coordinate for a larger
clean-up mission. So both types of T-cells are important for a robust immune

But remember: ALL THE THINGS. How can your body create T-cells
with receptors for all the antigens it might encounter?

“How many protein-coding
genes are there in people?” asks Dr. Shapiro. “Twenty-one thousand-ish,” she says, answering her
own question. “But the body has to make antigen receptors to, well, let’s
just say a gazillion things for simplicity.” She explains that the way
that happens is the body takes gene segments, mixes and matches them in a way
that’s, “actually a bit sloppy but that increases diversity even more.”

And what you get is a T-cell with a receptor but no idea
what it might recognize.

“Two thirds of the rearrangements will produce
junk,” says Dr. Shapiro. “So part of the process is to go through
quality control checkpoints so you only keep T-cells with receptors that are
good.” In the thymus, immature T cells are tested. If the response from
the receptor array (signal) does not react to anything, they’re told to die. If
their receptor reacts to the part of the cell that defines “you” (versus
“not-you”) then they’re also culled to prevent damage to your own

“You need the signal through the receptor to be not too
strong, not too weak but just right,” says Dr. Shapiro. “Once it’s in
that goldilocks zone, the T-cell has a choice. Do I become a helper T-cell or a
cytotoxic T-cell?”

Providing a Choice

In a recent paper in eLife, Dr. Shapiro and her team clarified an important part of this process in mice. At the point where surviving T-cells choose what to be, an enzyme called histone deacetylase 3 or HDAC3 helps keep both options open. It is part of a family of enzymes that typically repress gene expression. In this case Dr. Shapiro’s team reports that HDAC3 holds back the expression of genes that push a T-cell to become cytotoxic and allow T-cells down the path of becoming helper cells.

“When it comes to making that decision T-cells have two
fates,” says Dr. Shapiro. “But when HDAC3 is gone, it doesn’t matter
if you were supposed to be a cytotoxic or a helper. The deck is stacked and everybody
becomes cytotoxic.”

That means only T-cell chemical weapons, no T-cell alarms to
coordinate immune response.

In a separate paper, published in The Journal of Immunology, the team expanded on the role of HDAC3. They report that it also suppresses genes for a particular receptor called P2X7.

“P2X7 is a receptor that recognizes the energy molecule
in cells, which they release as they die,” explains Dr. Shapiro.
“With only 10 percent of T-cells in the goldilocks zone, there are lots of
dying cells, meaning the thymus is an environment rich in that molecule, called
ATP. So without HDAC3, you have more P2X7 receptor
expressed on the surface of the T-cells and more cell death, meaning fewer
T-cells in general.”

That means without HDAC3, the body can only produce chemical
weapons and will produce fewer T-cells in general.

And that could be a problem for patients during cancer

T-Cell Development
Informs Cancer Therapies

Some cancer treatments use HDAC-inhibitors. That is, as part
of treatment they block HDAC. Now, if you already have helper T-cells you don’t
need HDAC3.

“But tumors are really good at shutting down an immune
response and exhausting T-cells,” says Dr. Shapiro. “You depend on
having newly generated T-cells coming into the tumor that have not been spoiled
by the tumor. So these inhibitors may have an effect on normal cells and
introduce unintended effects.”

Right now, Dr. Shapiro says, we have the broad picture and
we know HDAC3 is critical, but “the next step is to understand it at a
mechanistic level and ask the molecular questions.”

To improve cancer therapy, we have to understand one of the
body’s best weapons against it, says Dr. Shapiro.

“If you have diseases which disrupt the ability to make
T-cells it has a severe effect on health,” Dr. Shapiro says. “So at the
most basic level we care about how you make a T-cell.”


Feb 26, 2019 · Bone Marrow Stem Cells Stall Out in Chronic Lymphocytic Leukemia

Snow and ice cause cars to stall out on the road to their destination. In patients with CLL, it’s their stem cells that stall out and researchers want to know why.

For patients who have chronic lymphocytic leukemia, fighting off a serious infection can be difficult and often is just not possible. And a team of Mayo researchers is starting to find out why in a paper published recently in the journal Leukemia.

What is Chronic Lymphocytic Leukemia?

This disease is cancer of an immune cell called a B lymphocyte. These cells form in bone marrow and migrate out to patrol in the blood stream and lymphoid organs. But in chronic lymphocytic leukemia, the immune system is depleted, a state called immunodeficiency. Because of that, people with this type of leukemia are prone to serious infections and the diseases those may cause. They are also prone to developing other types of cancer.

And it’s those resulting problems that may ultimately contribute to death explains Kay Medina, Ph.D., a Mayo Clinic immunologist. Dr. Medina specializes in how immune cells develop from bone marrow stem cells.

In our bone marrow, stem cells convert to red blood cells, platelets or a variety of immune cells. Those are then sent into the blood stream where they do their job. Red blood cells replace cells that are worn out.

White blood cells patrol the byways of our circulation, chasing down everything from cellular debris to bacteria to virus particles. But not in patients with chronic lymphocytic leukemia.

Joining the Team

Research on chronic lymphocytic leukemia is going on in several labs at Mayo Clinic. Dr. Medina got involved after speaking with colleagues Wei Ding, M.B.B.S, Ph.D., and Neil Kay, M.D., both chronic lymphocytic leukemia physician researchers.

“Mayo has a strong tradition of encouraging physician/basic research collaborations to advance knowledge of disease mechanisms, development, and assessment of new treatment approaches,” says Dr. Medina.

The basic research helps us understand the cause of the disease, in this case the leukemia cell, but it also helps to understand what the disease does to other parts of the body, such as the lymph nodes, spleen, blood and bone marrow, she says.

“Bone marrow is the organ that replenishes all cells in the immune system but has not been evaluated for functional proficiency in CLL patients,” explains Dr. Medina.

Checking out the Cells and their Environment

Kay Medina, Ph.D.

Dr. Medina’s team, with funding from Mayo Clinic’s Center for Biomedical Discovery, decided to look at bone marrow stem cells and their ability to generate all blood cell types. Some of the immune deficiency may be the result of treatment, but untreated patients have the same problem. The chronic nature of the disease itself may also dampen immune activity. But Dr. Medina explains that the leukemia cells may promote an environment that suppresses immune function.

“Our research seeks to add to the discussion by identifying additional ways patients with CLL are unable to fight off tumors and other diseases,” says Dr. Medina.

In a paper published late last year, Dr. Medina and her team, including first author Bryce Manso who is a student in the Mayo Clinic Graduate School of Biomedical Sciences, examined bone marrow and blood samples from chronic lymphocytic leukemia patients and healthy controls to determine the frequency of bone marrow stem cells in each sample and how well they did their job.

Bryce Manso, presenting a poster to a conference attendee.

The authors reported that, in general, samples from patients with chronic lymphocytic leukemia have fewer stem cells in their bone marrow, and those stem cells that remain work less well than stem cells from controls.

Stalled-Out Bone Marrow Stem Cells

As to why this happens, the authors found that it was linked to loosening controls for the on/off switches which regulate this process, proteins called transcription factors. These proteins regulate key functions in the cell, and are out of whack in samples from chronic lymphocytic leukemia patients. They may prevent bone marrow stem cells from pursuing a pathway for development; stalling-out their ability to differentiate, resulting in decreased production of important blood cells that provide the first line of defense against infectious agents.

But, Dr. Medina cautions, there is more to this story.

“This is an emerging area of research in that it’s both a unique explanation for the clinical problem of immune deficiency and it has been minimally studied,” says Dr. Medina. “Future studies are planned to look at specific transcription factors that control stem cell differentiation as well as how the presence of leukemic cells in the bone marrow alter blood cell development.”  They will then relate this information to clinically relevant complications reported in chronic lymphocytic leukemia patients, she says.

Basic Research to Improve Patient Care

Dr. Medina, her team, and their clinical colleagues hope that by understanding how bone marrow function is impaired in chronic lymphocytic leukemia patients, they can develop unique strategies to boost bone marrow function or find alternate treatments that do not block or modify marrow function.

“Through this work we hope to find ways to reduce infections and the incidence of second cancers in chronic lymphocytic leukemia patients. Our research has the potential to improve quality of life as well as extend the lives of these patients” says Dr. Medina.


Related Resources:

SAVOR, SUBSCRIBE, SHARE:  Advancing the Science

  • If you enjoyed this article, you might want to subscribe for regular updates.
  • If you want to share this story with friends, social media links are at the top of the article.
  • And if you want to see other recent stories on the blog, the index page is a great place to start.

Feb 18, 2019 · Head to the Lab for the Treatments of Tomorrow

Top: Paul Galardy, M.D.; Saad Kenderian, M.B., Ch.B.; Hu Li, Ph.D.
Bottom: Aleksey Matveyenko, Ph.D.; Christina Pabelick, M.D.; Hu Zeng, Ph.D.

Medical breakthroughs start in the lab with a phase of research called discovery science. It helps to understand how the body functions and how disease begins at the most basic level. That in turn provides insight into how whatever has gone wrong can be fixed.

To kick off the medical treatments of tomorrow, the Center for Biomedical Discovery is proud to support the following Discovery Science Award projects for 2019. These projects all promote innovative, cutting-edge discovery science teams that focus on understand the biological processes that contribute to human disease.

Investigating the role of a Gene in how a normal immune process goes bad

When we encounter infectious agents – either naturally or by vaccination – our immune system generates a highly selective defense against that particular danger. While essential for healthy life, this ability comes at a price: lymphomas. These cancers arise when immune cells edit their genetic material to customize and optimize the reaction to infections. Our work will uncover how the gene UCHL1 regulates the building of proteins in normal and cancerous immune cells in hopes of gaining a better understanding of how we might harness these events to enhance immunity – and fight cancer.

Primary Investigator:  Paul Galardy, M.D., Department of Pediatric and Adolescent Medicine;

Co-investigators:  Wenqian Hu, Ph.D., Department of Biochemistry and Molecular Biology; James Cerhan, M.D., PhD., Department of Health Science Research


Can a form of cellular communication hamstring the newest immunotherapy treatment?

This project will investigate the idea that small particles, called extracellular vesicles, produced by chronic lymphocytic leukemia B cells and secreted into the circulation can bind to chimeric antigen receptor T-cells (CAR T-cells) and blunt their ability to recognize tumor cells. We have identified a specific receptor on the extracellular vesicles as the trigger signal responsible for this impairment of function. This may unveil a unique functional role of leukemic extracellular vesicles. It is also meaningful to see if this mechanism is applicable to other disease states where we know that CAR T-cells also do not work, including solid tumors.

Primary Investigator:  Saad Kenderian, M.B.,Ch.B, Division of  Hematology

Co-investigators:  Neil Kay, M.D., Division of Hematology; Fabrice Lucien-Matteoni, Ph.D., Department of Urology


Studying colon cancer to clarify metastasis and identify new treatments

Using patient-derived tumors grown in 3-D vessels (organoids) and artificial intelligence-based approaches we will: Identify potential targets for colon cancer therapy, improve understanding of what causes tumor metastasis, detect patients with tumors at high risk of progression, and identify new treatment methods targeted at slowing or halting tumor progression. We will characterize how a protein associated with epigenetic processes in cells, HP1α, alters cell signaling in colon cancer. We will also characterize how loss of HP1α impacts mitotic fidelity in colon cancer, and we will identify targetable changes in tumor cells caused by disruption of HP1α.

Primary Investigator:  Hu Li, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics

Co-investigators:  Martin Fernandez-Zapico, M.D., Department of Medical Oncology; Steven Offer, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics.


Obese or not, there’s more to the Type 2 diabetes story

Although obesity is a risk factor for type 2 diabetes mellitus, most people who are obese do not develop diabetes. Their β-cells are able to increase insulin output and maintain normal blood glucose. However, in a subset of people β-cells fail leading to development of the disease. Our group will test whether increased expression of a specific gene/protein (SLC4A4/NBCe1) is the main culprit in leading to failure of β-cells to produce enough insulin in type 2 diabetes mellitus. The ultimate goal of these studies is to provide novel information into how the disease develops, and identify novel therapeutic strategies to treat/prevent this disease.

Primary Investigator:  Aleksey Matveyenko, Ph.D., Department of Physiology and Biomedical Engineering

Co-investigators:  Michael Romero, Ph.D., Department of Physiology and Biomedical Engineering; Taro Hitosugi, Ph.D., Department of Molecular Pharmacology and Experimental Therapeutics.


Premature Babies may benefit from more than oxygen

We are testing the hypothesis that prematurity and high oxygen suppress hydrogen sulfide expression and function in the airway, thus blunting the beneficial effects of the gas. We will use cell and mouse models of asthma exposed to moderate hyperoxia and test the efficacy of hydrogen sulfide gas we well as novel hydrogen sulfide donors in inducing bronchodilation and preventing cell proliferation and fibrosis. The results of these novel studies will provide significant insight into the mechanisms of hydrogen sulfide generation and action in developing airways, and conversely the benefit of using the gas as a therapeutic target to treat airway diseases in premature babies.

Primary Investigator:  Christina Pabelick, M.D., Department of Physiology and Biomedical Engineering

Co-investigators:  David Linden, Ph.D., Department of Physiology and Biomedical Engineering; Y.S. Prakash, M.D., Ph.D., Department of Physiology and Biomedical Engineering.



Lupus, the immune system and Fatty acid processing in the body

The humoral immunity is essential but abnormal B cell activation contributes to autoimmune disorders, including systemic lupus erythematosus, which has no cure and lack new effective treatment. Our preliminary results show that B-cell function relies on fatty acid synthesis mediated by an enzyme, stearoyl-CoA deasaturase. Inhibition of that enzyme alleviates disease pathology in a mouse model of systemic lupus erythematosus. This proposal aims to investigate how stearoyl-CoA deasaturase-mediated fatty acid metabolism modulates B-cell differentiation and autoimmune diseases. We will also examine whether this mechanism is involved in human autoimmune diseases.

Primary Investigator:  Hu Zeng, Ph.D., Division of Rheumatology

Co-investigators:  John Copland III, Ph.D., Department of Cancer Biology; Ian Lanza, Ph.D., Division of Endocrinology, Diabetes, Metabolism, Nutrition; Uma Thanarajasingam, M.D., Ph.D., Division of Rheumatology; Mariam Alexander, M.D., Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology.

More information
Read more about previous CBD awardees on the Center for Biomedical Discovery website.



SAVOR, SUBSCRIBE, SHARE:  Advancing the Science

  • If you enjoyed this article, you might want to subscribe for regular updates.
  • If you want to share this story with friends, social media links are at the top of the article.
  • And if you want to see other recent stories on the blog, the index page is a great place to start.

Dec 24, 2018 · Our gift to you this holiday season

Your holiday gift list may include model planes or model rockets, but I hope it also includes the Mayo Model of Research.

Haven’t you heard of it? It isn’t new but it is pretty amazing.

It’s based around Mayo’s core value, the needs of the patient come first, as that value applies to research.  Right out of the box it allows you to see how Mayo transforms medicine.

It comes with:

  • People (+3,800!) – Teams of both scientists and clinicians who work together to solve patients’ most serious complex and rare conditions.
  • Blue Glue (lots, figuratively) – A focus on collaboration is the glue binding these teams together so working as a team just comes naturally.

With the people and the glue, and the focus on the patient, you can make:

You can read more about it in this brochure.

With this model, Mayo has made progress in studies that use electrical stimulation to address paralysis and investigate stem cells for use in medical care. It supports the NIH All of Us Research Program aimed at advancing individualized care, helps understand disease where it starts at the level of the cell, and examine the role of senescent cells in aging and diseases of aging.

If you are a human who ages, or one who would like to see better treatments for disease, consider adding the Mayo Model of Research to your gift list today.

It’s an easy one to give: Tell someone you love how research at Mayo is helping save lives, or share stories about Mayo Clinic research that you find on this blog, Discovery’s Edge or other Mayo Clinic sources like Facebook or Twitter. That’s it. A share here, a retweet there and you’re done.

It could help someone in your social network now, and it will help patients in the future.

Nov 29, 2018 · The right diet for you... or for your gut microbes?

This article originally appeared on the Center for Individualized Medicine blog on Oct. 10, 2018.

The right diet, obesity and gut health are topics patients, clinicians and scientists wrestle with every day. We want to eat a good diet and lose weight or avoid weight gain, so our health span matches our life span.

But statistics suggest we struggle.

To help, scientists are examining how food, our gut, and our weight are related. Purna Kashyap, M.B.B.S. moderated a break out session on personalized nutrition at the Individualizing Medicine Conference 2018, during which those examinations led to three conclusions that may change the way we look at our food, our gut and our weight loss plans:

The environment inside our gut is governed by the same rules as the environment outside the body.
The rules that ecologists have discovered in the natural world hold sway in our gut, too. According to Jens Walter, Ph.D., of the University of Alberta in Canada, while our gut microbes can change, the pattern of change is predictable. For example, where microbes roam (dispersal) and how they win their territory (selection) in the gut, follow the same rules as seeds dispersing from a plant or two seed-eating birds competing for a common food source. This knowledge can help researchers cut through the variation between individuals to understand the underlying similarities in our gut ecosystem.

Yo-Yo dieting may be due to a memory of famine in our gut microbes.
While science often examines what leads to obesity, patients are often already there. We typically need to lose weight and keep it off for health reasons. But keeping weight off is difficult and researcher Christoph Thaiss, Ph.D., of the University of Pennsylvania wanted to know why. In a series of mouse experiments he and his team replicated yo-yo dieting and discovered that the microbiome remembers feast and famine, and adjusts accordingly. After weight loss, when mice were given a high-fat diet, they regained more weight faster than they had in the first round of weight gain.

The researchers then delved into the specifics of what changed in a post-obesity mouse gut and identified two molecules that were lost: apigenin and naringenin. These plant-derived flavonoids are associated with the tendency to maintain a low weight over time, says Dr. Thaiss, and when mice were supplemented with both in their diet, the mice were able to “forget” the period of obesity and avoid regaining weight. Dr. Thaiss explained that one theory is that this mechanism might be an evolutionary response to fluctuating environmental conditions. In forthcoming research, Dr. Thaiss is examining this effect in humans.

Eating food your gut microbes want can help keep blood glucose levels stable.
Humans have been in pursuit of the best diet ever since we had a choice in the matter. But despite a long and vigorous effort, the best diet eludes researchers, said Tali Raveh-Sadka, Ph.D., director of research at DayTwo. The company is one of a few new ventures that gather data from consumers, digest it in a computer algorithm, and report back personalized food recommendations.

When participants in one trial were fitted with a continuous glucose monitor, the variety of responses was high. One person’s blood sugar spiked when consuming a banana but not a cookie, explained Dr. Raveh-Sadka, but another participant had the opposite response. The researchers found that when participants ate the “good for their microbiome” diet, their microbiome shifted and their blood sugar readings remained stable.

Mayo Clinic Center for Individualized Medicine sponsored the conference, which was held Sept. 12-13 in Rochester.

More conference-related highlights

Join the conversation
For more information on the Mayo Clinic Center for Individualized Medicine, visit our blogFacebookLinkedIn or Twitter at @MayoClinicCIM.


Oct 1, 2018 · How Bread Yeast and Book Damage Help Clarify Epigenetics

Genes don’t change, but how they are used by the body can.  That shift in use (which is called epigenetics) can mean the difference between illness and health. To better understand how that happens Mayo researchers are examining how genes are activated (used) and copied. With a recent publication in the journal Science, a team of basic scientists at Mayo have clarified a key piece of the puzzle; one they hope may lead to better cancer therapy.

The Basics 

Think of the human genome, the collection of our genes coded into DNA, like the book of life. Hopefully it comes from the printer in perfect condition, all pages crisp and perfectly bound.  Think of the sentences as our DNA, printed on paper. The equivalent to paper in the cell is chromatin.

But the point of a book is to read it, right? Over and over if it’s a good one. But maybe you read in the bath and the paper gets a bit wrinkly. Or horrors, you drop the book in the water (this has happened to me). Or maybe you’re reading while camping and the book is singed by the fire (this has also happened to me). Or you just read it over and over for years, dog-earing pages and stuffing the book in backpacks and totes (again, me). It can end up looking like this:

The same thing sort of happens to your DNA. In a cell, damage and multiple reads can affect both the actual words (genes), but also the paper (the chromatin that organizes DNA). Changes to the chromatin can affect our health by exposing some genes for “reading” and hiding others.

“Mutations or abnormal regulation of proteins involved in chromatin replication have been directly linked to different human cancers,” says Mayo Clinic research scientist Chuanhe Yu, Ph.D., lead author on the new study published in Science. “Our work provides insight into the fundamental process of epigenetic inheritance and may create new opportunities for human cancer therapy.”

Can I change the margins? Make the font bigger? No!
Just as changing the words in the book would change the meaning, so changing the size of the paper or the line spacing would change the experience of reading the book. Similarly, when DNA is copied, it should be packaged in chromatin as it was on the original strands of DNA – not any looser or tighter than the original strand. To accomplish this, part of the chromatin called histones are copied along with the DNA strand. These histones are called parental histone tetramers because they are from the original DNA strand (parental) and have a tetramer chemical structure.


But when DNA is copied, each strand of the helix is copied separately. One new strand is manufactured all at once (the leading strand) and the other is made in small pieces (lagging strand). It helps to see it so here’s a video: DNA Replication.

Based on that difference, researchers wondered if the chromatin (including the parental histone tetramers) copied from old to new differs between the strand. That, Dr. Yu says, is a fundamental question of epigenetics — if the parental histone tetramers are randomly and equally distributed on DNA strands to be replicated.

“People tried to answer this question for about 40 years but no suitable method was available,” he says.

That is until his team developed one.

Their method is called eSPAN, short for ‘enrichment and Sequencing of Protein-Associated Nascent DNA’. With eSPAN, Dr. Yu explains, the researchers can tell the difference between the parental tetramers on the two new DNA strands.

Batch Copying and a Surprise Assist
Using bread yeast as the model, they determined that parental tetramers are reused on both strands of DNA, but that they have a slight preference for the lagging strand. So to put that in book terms, the small batch books may have more differences in the number of words printed on each page than books printed in a large batch.

They also report that different proteins help, or chaperone that transfer.

“One surprise point is that DNA polymerase is not only involved in DNA replication, it also serves as a chaperone for the transfer of parental histones during DNA replication,” says Dr. Yu. “And our results indicate that other unknown factors may help transfer histone to lagging strands.”

The next steps, according to Dr. Yu, are to explore the other protein regulators involved in this process and evaluate the mechanisms in human cell lines. Other authors on the study from Columbia University, Chinese Academy of Sciences, University of Chinese Academy of Sciences, and Umeå University can be found listed on the report. The authors declare no conflict of interest.

For more information about Mayo Clinic’s epigenetics research efforts take a look at our Center for Individualized Medicine Epigenetics Program page.

Aug 8, 2018 · New pathway in prostate cancer cells suggests possible therapy

Expanding on previous findings, a group of Mayo researchers continue using discovery research in cells to find options for treating cancers. In their most recent paper, published in Molecular Cell, the team’s research suggest that a drug used for breast cancer may be helpful in some types of prostate cancers.

“In the current study we show that in prostate cells, an overexpressed enzyme called DUB3 causes [drug] resistance due to the increased levels of a protein called BRD4,” says senior author and Mayo Clinic molecular biologist Haojie Huang, Ph.D.

Bromodomain and extra-terminal domain inhibitors are drugs that prevent the action of BET proteins, an important task because these proteins help fuel cancer cells. BRD4 is a BET protein and enzymes like DUB3 fuel the protein’s action. Dr. Huang explains that researchers already knew that DUB3 required the action of another group of enzymes called cyclin-dependent kinases, or CDKs.

In this paper, the scientists report that blocking CDK4 and CDK6 needed by the enzyme DUB3, decreases BRD4 protein levels in prostate cancer cells.

“Given that CDK4/6 inhibitor is already in clinical use, our findings could lead to immediate clinical trials for treatment of DUB3-overexpressed prostate cancer by combined use of BET and CDK4/6 inhibitors,” says Dr. Huang.

This research also presents a mystery.

In their article published last year in Nature Medicine, Dr. Huang and team reported on a new biomarker that could be used to improve outcomes in some prostate cancers. The researchers explained how resistance to one class of drug can develop from mutations within the SPOP gene, which is frequently altered in primary prostate cancer and often causes resistance to drugs called BET-inhibitors.

“Based on our findings, SPOP gene mutation or elevated BET protein expression can now be used as biomarkers to improve outcome of BET inhibitor-oriented therapy of prostate cancer with SPOP mutation or BET protein overexpression,” says Dr. Huang.

In the current study, the researchers had expected that in SPOP mutated cells, blocking DUB3 would not increase the sensitivity of the cells to BET inhibitors and decrease the levels of BDR4 in cells. However, Dr. Huang says, that was actually what they found.

“It is very exciting because it not only highlights the existence of another enzyme that can cause BRD4 protein destruction, but also emphasizes that inhibition of DUB3 by CDK4/6 inhibitors can be harnessed to overcome BET inhibitor resistance in SPOP-mutated prostate cancer, which was the major finding of our study published previously,” explains Dr. Huang.

As for next steps, this effort produced a clear horizon.

“In the current study we provide evidence that there exists an unidentified enzyme mediating BRD4 protein destruction in a manner independent of SPOP and that warrants further investigation,” says Dr. Huang.

In addition to Dr. Huang, other authors are: Xi Jin, M.D., Ph.D.; Yuqian Yan, Ph.D; Dejie Wang, Ph.D.; Donglin Ding, Ph.D.; Tao Ma; Zhenqing Ye, Ph.D.; Rafael Jimenez, M.D.; Liguo Wang, Ph.D.; and Heshui Wu, M.D.

Funding for this work was provided by the National Institutes of Health and the National Natural Science Foundation of China.

Contact Us · Privacy Policy