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.


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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.

Mar 28, 2018 · Are we breathing wrong?

Exercise researcher Mike Joyner’s latest quest started with llamas and bar-headed geese. It may end up revising a basic principle of medicine and addressing unmet needs for patients with diseases such as asthma or COPD.

Michael Joyner, M.D., has a cold. But it doesn’t decrease his obvious excitement for a project that really started over two decades ago. And like everything he’s studied since his undergraduate days, it has to do with oxygen.

“One of the things that has bothered me for about the last 20 or 25 years is that birds [bar-headed geese] flying over Mount Everest have left-shifted hemoglobin,” he says.

Hemoglobin is a protein that gives red blood cells their color. It carries oxygen throughout the body, and different conditions affect the amount of oxygen that can attach to the hemoglobin. When oxygen saturation is measured the normal value is expressed as an s-shaped curve, but that curve can shift to the left or right depending on health conditions or other factors. Currently, medical textbooks say a shift to the right means hemoglobin gives up oxygen to tissues more easily and protects the body against low oxygen levels, while a left-shift means less oxygen is released.

“It’s literally the first thing they teach you in medical school,” says Dr. Joyner.

Textbooks or Evolution

But that doesn’t square with the left-shifted geese. They fly at altitudes over 20,000 feet through high mountain passes where oxygen is scarce. So, Dr. Joyner wondered, why wouldn’t the geese be right-shifted to maximize what little oxygen was present? When he started to look further, the oddities increased.

“And it turns out llamas are left-shifted, as are a bunch of other animals that live at very high altitudes,” says Dr. Joyner. “This bothered me for a while and I started wondering, okay, why would evolution pick a different solution than the biochemistry textbooks tell us is correct?”

Now, Dr. Joyner, his lab and collaborators get to find out.

He recently received the National Heart Lung and Blood Institute’s Outstanding Investigator Award to study this question. The award provides support for, “projects of unusual potential,” by providing more money than a typical grant for a longer period of time. The goal is to give researchers more time and flexibility to pursue a risky scientific question that could pay off big.

Michael Joyner, M.D.

Geese, Llamas… Humans?

Dr. Joyner started his investigation by looking for any humans who might be naturally left-shifted.

“Left-shifted people sometimes have a high blood count,” explains Dr. Joyner. “It’s sort of an incidental finding and it’s a very small fraction of the population.”

Prior to getting the award, Dr. Joyner pulled in colleagues and scoured medical journals. Ultimately, they found a large family to take part, and they began to determine how they might find answers. Fortunately, Mayo has a specialized area for studying just these kinds of complex questions, says Dr. Joyner. Called the Clinical Research and Trials Unit, this area provides expertly trained staff and tools that allow researchers to collect a range of data. It is part of Mayo Clinic’s Center for Clinical and Translational Science, says Dr. Joyner, explaining that the CRTU allows researchers to undertake detailed studies of key aspects of physiology.

“We are one of the few institutions left that have something like the CRTU,” says Dr. Joyner. “We have developed capabilities where we can measure how air gets into the lungs; how it gets across the lungs into circulation, how much blood the heart actually pumps, how much blood goes to each organ and how each organ is using that blood.”

The CRTU was built for just these sorts of investigations and has contributed to significant findings in heart failure, aging and exercise benefits.

“We can also start to understand the other adaptations these people have made and start thinking about how we can intervene in patients with disorders,” says Dr. Joyner. For example, he says, in people who have trouble oxygenating their blood due to lung disease or an acute lung injury, might a drug that left-shifted hemoglobin help their lungs pick up more oxygen, provided it can be off-loaded at the tissue level? Or on the other hand, for people without sufficient blood flow, a right-shift might help.

“I’m attempting to keep pushing the envelope a bit,” says Dr. Joyner. “And hopefully we’ll make some discoveries about oxygen transport in humans that will be of general interest to the whole field and that may provide insights into patient care.”


Jul 13, 2017 · The curious link between tall men, small babies and kidney disease

We are born with a lifetime supply of something you may not think about every day: Nephrons.

Nephrons act as filters within the kidneys. They fine tune blood composition which in turn maintains our blood’s pressure, volume, and cleanliness. During pregnancy nephron development ends as a fetus reaches the last weeks in the womb. But unlike our standard ten fingers and toes, nephron numbers vary widely—from 200,000 to 2.5 million according to researchers. Genetic influence, maternal diet and health, as well as exposures to certain substances (antibiotics, alcohol, non-steroidal anti-inflammatory drugs) contribute to variation in nephron numbers, as does preterm birth. For this reason, birth weight is linked to nephron number.

Who cares about nephrons?

Nephrons do not often trouble my mind, but I came across an interesting statement in a recent New England Journal of Medicine paper. The senior author is Andrew Rule, M.D., a physician scientist within the division of nephrology and Hypertension at Mayo Clinic. The paper presents the case for assessing kidney health using two methods: total function of all the nephrons in the kidney or the average function of individual nephrons. The authors conclude that while they have similarities, the single nephron assessment (not standard of care) provides additional information on risks for kidney disease. But in the discussion there was another statement. It said, “… tall stature in a person who had a low birth weight (and for whom there may be low nephron endowment) has been linked to hypertension, which is risk factor for chronic kidney disease.”

Low birth weight in a baby can equal low nephron numbers and if that baby becomes a tall adult, possibly a higher risk for hypertension and chronic kidney disease? How does that work, I wondered.

Dr. Rule and coauthors cite two population-comparison studies in Sweden and Finland. In the Finland study, the highest hypertension risk was linked to low-birth-weight babies with continued accelerated growth past age seven. The Swedish paper found that males born at less than 7.2 pounds who were above 5’7” at age 50 had particularly high blood pressure compared to the other participants in the study. They add, however, that it was only problematic for those in the upper 1/3rd of body mass index (in this case, with BMI of 26 or higher).

The idea is this: In low birth weight babies the growth potential of the fetus was not reached. But as these infants catch up to their peers and attain full growth, those who grow taller or heavier (or both) than the norm may eventually outstrip their kidney’s innate filtering capacity. The result? Higher risk for chronic kidney disease and cardiovascular disease.

We should all care about nephrons.

So there you have it.

But what if you were a normal weight baby who has grown into an average height adult? Well, considering the kidney’s filtering ability seems to decline naturally after age 40, you’re not off the hook. For you, the National Kidney Foundation has a six step guide to kidney health and of course, you should always talk to your doctor for accurate assessment of your health, kidneys and otherwise.

Not sure about you, but I’m off to drink a nice glass of water in solute (chemistry joke!) to my hard working nephrons.

Sep 13, 2016 · Mayo Clinic Investigator Pushes for more Research on Osteoporosis Treatment


Osteoporotic bone

Crumbling infrastructure puts us at risk, especially if it’s our own internal, bony frame.

But patients dealing with thinning bone in hips and spine have a choice to make.

They can accept the inevitable slumping spine and eventual hip fracture with all its associated disability that is quite likely to occur, or roll the dice with complications from osteoporosis medications.

“Many, many patients who really need treatment are not taking it because of those concerns,” says Sundeep Khosla, M.D., practicing endocrinologist at Mayo Clinic.

Dr. Khosla is one of the top osteoporosis experts in the world and a past president of the American Society for Bone and Mineral Research and he is the society’s Louis V. Avioli lecturer this year at the groups annual conference.

Dr. Khosla has spent the last 28 years translating clinical need into discovery, and discovery into clinical therapy to meet the needs of patients experiencing bone loss. If there’s one thing he knows, it’s the progression of therapeutic options for osteoporosis patients.

Osteoporosis Treatment: Research Success, Patient Concern

Sundeep Khosla, M.D.

Sundeep Khosla, M.D.

“When I joined Mayo in 1988, I could offer calcium, vitamin D, estrogen, and that was pretty much it,” says Dr. Khosla.

But through collaboration and explorations of the fundamental nature of bone biology, Dr. Khosla has witnessed a blossoming of therapeutic options. From examining the spiral of spine and hip fractures leading to immobility, loss of independence, and premature death; came a host of options to turn off the cells that breakdown bone, slow bone loss and help prevent those first debilitating fractures.

Some patients and physicians, however, are concerned about these medications because of the relatively rare risks of jawbone deterioration, leg fracture, or abnormal heart rhythm.  Just when the future of osteoporosis therapy seemed bright, uncertainty has led to under-utilization of these therapies.

“I’ve been pushing to address this head on,” says Dr. Khosla, “because it has the potential to completely undo all of the wonderful research and translation that’s been done in the field.”

[Read Dr. Khosla’s editorial, “Crisis in the Treatment of Osteoporosis” in the Journal of Bone and Mineral Research.]

Researcher and Physician: The Patient’s Best Resource

Although research duties take up much of Dr. Khosla’s time, he is a clinician and actively sees patients. This allows him to identify the unmet patient needs and push his research team, and the field of endocrinology, to find solutions. It also allows him to separate likely findings from unlikely ones published in his field.

“The cross talk between what I’m doing in my research versus what I do in my clinical activities is important,” says Dr. Khosla. “It both helps to guide the research in new directions but also shuts off directions that don’t make sense from my understanding of what’s happening in the clinic.”

It’s this ability to see both his patients’ concerns and the clarity of the research that has led Dr. Khosla to push for more research on the subset of patients who will develop complications from osteoporosis treatment.

“I think the field has to be more proactive,” says Dr. Khosla, “and listen to what patients are saying and directly address the concerns they have.”

New Therapies on the Horizon

Some areas of research Dr. Khosla is investigating include better monitoring or adaptation of current bone density imaging to pick up the earliest signs of complications. Pharmacogenomics approaches may also help identify patients who may be at risk for complications. New bone remodeling pathways and new therapeutics in the drug discovery pipeline may also offer options for patients dealing with bone loss.

So while alleviating concerns over treatment complications poses a huge challenge for physicians, Dr. Khosla has high hopes for the field and its ability to get the answers patients need.

“The osteoporosis field over the past 25 plus years is really a great example of how a better understanding of the fundamental biology can drive new therapeutics,” says Dr. Khosla, “and it continues today.”

Sep 2, 2016 · Looking Back to Move Forward: Medical Surveys are Worth Your Time

Surveys can be a pain when you’re buying coffee or shoes, or surfing the web. Or maybe you find them fun—what color or literary character are you anyway?

But is the current survey deluge training us to ignore the ones that actually matter? Ask Ann Harris, associate director of Mayo Clinic’s Survey Research Center, and she’ll nod.

“Now everyone has a survey,” she says. “I think we’ve just over-surveyed people and our challenge coming up is how do we do this?”

Survey Says…

Mayo Clinic sends thousands of surveys a year to patients.

They flow out over the internet of course, but also by phone and (snail) mail. But the surveys don’t flow back in like they used to.

Ann Harris, associate director of Mayo Clinic's Survey Research Center

Ann Harris

“When I first started here,” says Harris, 25 years ago, “our response rates were 90 to 86 percent and they’re now closer to 50 to 60 percent depending on what the subject matter is.”

But regardless of the subject matter, health and health care-related surveys do matter. They help answer clinical questions that make a real difference in patients’ lives. For example:

  • After following high-risk patients who chose to have prophylactic mastectomies, investigators concluded that the risk of breast cancer is substantially reduced with this procedure.
  • Gelatin was added to the list of vaccine allergens after a case study led to a survey investigating the prevalence of this reaction.
  • Surveys of patients with congenital heart defects helped researchers find that it was important to intervene early, and plan subsequent operations over the patient’s lifetime, to decrease the total number of operations to increase survival. While a number of papers have been published using this survey data, the most recent publication is on heart transplant after Fontan procedure.
  • Lymphedema (swelling) in the lower body was more common than expected following surgery for endometrial (uterine) cancer. This finding contributed to practice changes aimed at reducing the risk of lymphedema in future patients.

…Your Responses are Important

So when if you get a survey request from Mayo Clinic, think about the people you help with your responses.

And thanks in advance for taking the time to respond.

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