heart Archives - Sanford Burnham Prebys
Institute News

Scientists unite to get to the heart of AFib

AuthorSusan Gammon
Date

August 15, 2023

A collaborative study led by researchers at Sanford Burnham Prebys is paving the way to identifying gene networks that cause atrial fibrillation (AFib), the most common age-related cardiac arrhythmia.

The findings, published in Disease Models & Mechanisms, validate an approach that combines multiple experimental platforms to identify genes linked to an abnormal heart rhythm.

“One of the biggest challenges to solving the AFib genetic puzzle has been the lack of experimental models that are relevant to humans,” says Alex Colas, PhD, co-senior author and assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys. “By working with colleagues who focus on AFib but in different systems, we have created a robust multiplatform model that can accurately pinpoint genes associated with this condition.”

AFib is characterized by an irregular, rapid heartbeat that causes a quivering of the upper chambers of the heart, called the atria. This condition is the result of a malfunction in the heart’s electrical system that can lead to heart failure and other heart-related complications, which include stroke-inducing blood clots.

AFib impacts more than 5.1 million people in the United States, with expectations of 15.9 million by 2050. It is more common in individuals over the age of 60 but can also occur in teenagers and young adults.

“There will never be a one-size-fits-all solution to AFib, since it can be caused by many different genes—and the genes that do cause it vary from person to person,” says Karen Ocorr, PhD, also a co-senior author and assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys. “A better understanding of the gene network(s) that contribute to AFib will help us design tests to predict a person’s risk, and develop individualized approaches to treat this dangerous heart condition.”

To overcome the limitations of current AFib research models, Colas, Ocorr and researchers from UC Davis and Johns Hopkins University combined forces to assemble a multi-model platform that combines:

  • A high-throughput screen using atrial-like cells (derived from human-induced pluripotent stem cells) to measure how a gene mutation alters the strength and duration of a heartbeat.
  • A Drosophila (fruit fly) model—with heart genetics and development remarkably similar to human hearts—that permits analysis of gene mutations in a functioning organ.
  • A well-established computational model that uses computers to simulate the effects of gene mutations on the electrical activity in human atrial cells.

The accuracy of the multi-model platform was confirmed when each screened 20 genes, and all three platforms identified phospholamban, a protein found in the heart muscle with known links to AFib.

“This collaboration has greatly expanded our ability to understand AFib at the genetic level,” says Colas. “Importantly, the high-throughput screening component of the model will also allow us to rapidly and effectively screen for drugs that can restore a heart to its normal rhythm.”

He adds, “Hopefully this is just the beginning. There are many more cardiac diseases to which our system can be applied.”

Institute News

Sanford Burnham Prebys graduate student selected for prestigious Women in Science scholarship

AuthorMiles Martin
Date

June 20, 2023

Katya Marchetti has had her heart set on research since childhood. Today, she’s a bright, confident scientist making her dream a reality at Sanford Burnham Prebys.

Katya Marchetti, a first-year PhD student in the lab of Karen Ocorr, PhD, was recently awarded an Association for Women in Science (AWIS) scholarship. This competitive award encourages outstanding women pursuing degrees in science, technology, engineering and mathematics (STEM) fields at San Diego colleges and universities.

“Receiving this recognition highlights the importance of advocating for women’s empowerment in STEM and fostering an inclusive and diverse scientific community,” says Marchetti.

Marchetti grew up in Bakersfield California and finished her undergraduate degree from UC San Diego in just three years. Last year, she enrolled as a graduate student at 21 years old, making her one of the youngest PhD students to ever join the Institute. For her, the AWIS award is a culmination of a lifelong enthusiasm for science, inspired and encouraged by her family.

“I’m a very curious person,” says Marchetti. “I just inherently have to know how everything works, and my dad is the one got me inspired and interested in exploring things. I am so grateful for the opportunities that he fought for me to have, because he gave me everything that he didn’t.”

With the enthusiastic support of her family, Marchetti began her research career at the ripe age of nine years old. 

“My first-ever science project was heart research,” she says. “My favorite song was “Kickstart My Heart” by Mötley Crüe, and I wanted to see if it would raise blood pressure. I tested myself and my family, and we actually found that it did, obviously.” 

Today, Marchetti’s heart research is a bit more sophisticated. She studies hypoplastic left heart syndrome (HLHS), a rare disease in which the left side of the heart is underdeveloped and unable to effectively pump oxygenated blood to the rest of the body. HLHS is a congenital disease that is nearly always fatal without heart surgery. Marchetti’s research focuses on uncovering the genetics that underpin this disease to find new ways to prevent and treat it.

“Researching heart disease is very rewarding in and of itself, but it’s also really motivating to work on a disease that occurs in one of the most vulnerable populations,” says Marchetti. 

Marchetti is also heavily involved on campus at the Institute, as one of just two graduate students to serve on the Institute’s Education and Training committee, part of the Institute’s Diversity Equity and Inclusion Council. She has also mentored interns for the Institute’s CIRM-sponsored SPARK program, which provides research experiences to high school students from underrepresented backgrounds.

“I really love mentoring people who don’t have a lot of lab experience,” says Marchetti. “It’s my favorite thing I’ve done in graduate school so far. I think that’s kind of my way of paying forward the opportunities that I’ve had.” 

Marchetti will use the funds from the AWIS scholarship to further support her HLHS research. She also maintains that even after finishing her PhD, her long-term goal is to continue working in the San Diego research community. 

“If were to describe myself as a city, it would be San Diego,” she says. “It’s really the perfect place for me.” 

Institute News

Our top 10 discoveries of 2020

AuthorMonica May
Date

December 14, 2020

This year required dedication, patience and perseverance as we all adjusted to a new normal—and we’re proud that our scientists more than rose to the occasion.

Despite the challenges presented by staggered-shift work and remote communications, our researchers continued to produce scientific insights that lay the foundation for achieving cures.

Read on to learn more about our top 10 discoveries of the year—which includes progress in the fight against COVID-19, insights into treating deadly cancers, research that may help children born with a rare condition, and more.

  1. Nature study identifies 21 existing drugs that could treat COVID-19

    Sumit Chanda, PhD, and his team screened one of the world’s largest drug collections to find compounds that can stop the replication of SARS-CoV-2. This heroic effort was documented by the New York Times, the New York Times Magazine, TIME, NPR and additional outlets—and his team continues to work around the clock to advance these potential treatment options for COVID-19 patients.

  2. Fruit flies reveal new insights into space travel’s effect on the heart

    Wife-and-husband team Karen Ocorr, PhD, and Rolf Bodmer, PhD, shared insights that hold implications for NASA’s plan to build a moon colony by 2024 and send astronauts to Mars.

  3. Personalized drug screens could guide treatment for children with brain cancer

    Robert Wechsler-Reya, PhD, and Jessica Rusert, PhD, demonstrated the power of personalized drug screens for medulloblastoma, the most common malignant brain cancer in children.

  4. Preventing pancreatic cancer metastasis by keeping cells “sheltered in place”

    Cosimo Commisso, PhD, identified druggable targets that hold promise as treatments that stop pancreatic cancer’s deadly spread.

  5. Prebiotics help mice fight melanoma by activating anti-tumor immunity

    Ze’ev Ronai, PhD, showed that two prebiotics, mucin and inulin, slowed the growth of melanoma in mice by boosting the immune system’s ability to fight cancer.

  6. New test for rare disease identifies children who may benefit from a simple supplement

    Hudson Freeze, PhD, helped create a test that determines which children with CAD deficiency—a rare metabolic disease—are likely to benefit from receiving a nutritional supplement that has dramatically improved the lives of other children with the condition.

  7. Drug guides stem cells to desired location, improving their ability to heal

    Evan Snyder, MD, PhD, created the first drug that can lure stem cells to damaged tissue and improve treatment efficacy—a major advance for regenerative medicine.

  8. Scientists identify a new drug target for dry age-related macular degeneration (AMD)

    Francesca Marassi, PhD, showed that the blood protein vitronectin is a promising drug target for dry age-related macular degeneration (AMD), a leading cause of vision loss in Americans 60 years of age and older.

  9. Scientists uncover a novel approach to treating Duchenne muscular dystrophy

    Pier Lorenzo Puri, MD, PhD, collaborated with scientists at Fondazione Santa Lucia IRCCS and Università Cattolica del Sacro Cuore in Rome to show that pharmacological (drug) correction of the content of extracellular vesicles released within dystrophic muscles can restore their ability to regenerate muscle and prevent muscle scarring.

  10. New drug candidate reawakens sleeping HIV in the hopes of a functional cure

    Sumit Chanda, PhD, Nicholas Cosford, PhD, and Lars Pache, PhD, created a next-generation drug called Ciapavir (SBI-0953294) that is effective at reactivating dormant human immunodeficiency virus (HIV)—an approach called “shock and kill.”

Institute News

5 facts you need to know about atrial fibrillation (AFib)

AuthorMonica May
Date

February 14, 2019

It’s one of the most common heart rhythm disorders and a leading risk factor for stroke, but most people haven’t heard of it—that is, atrial fibrillation, also known as AFib or AF. Below are five facts everyone should know about AFib. 

  1. Nearly 10 percent of people over the age of 65 develop AFib, and it can be deadly. According to the Centers for Disease Control, it is estimated that 12.1 million people in the United States will have AFib in 2030. In 2019, AFib was mentioned on 183,321 death certificates and was the underlying cause of death in 26,535 of those deaths.
  2. There is no cure. Current treatments include surgery to remove the malfunctioning heart tissue; medications that reduce the risk of stroke by thinning the blood, such as warfarin or other anticoagulants; or medications that slow the heart rate or rhythm. But scientists currently don’t know the cause of AFib. There is no cure.
  3. Increased stroke risk makes AFib lethal. The irregular heartbeats that characterize AFib can cause blood to pool in the heart, and clot. If a blood clot travels to the brain, stroke may occur. About 15 to 20 percent of strokes are due to AFib, according to the American Heart Association.
  4. The Apple Watch can detect—but not diagnose—the condition. The Apple Watch can take an electrocardiogram and send a notification if an irregular heart rhythm is identified. However, only a doctor can diagnosis AFib. Apple has teamed up with Johnson & Johnson to determine if the wearable technology’s ability to detect AFib earlier improves diagnosis and patient outcomes.
  5. Fruit flies could unlock new AFib treatments. Believe it or not, the heart of a fruit fly—which is a tube—models early heart development. In a human, this tube folds into the four chambers of the heart. Combined with their short life cycle and simple genome, fruit flies are an excellent model of heart disease that could unlock new treatments, including those for AFib. Listen to how SBP scientists are using fruit flies to study AFib.

Additional AFib resources: 

Institute News

Nobel laureate Michael Rosbash presents his latest fruit-fly research at Sanford Burnham Prebys

AuthorMonica May
Date

February 8, 2019

You may want to reconsider swatting that pesky fruit fly: Despite appearances, we share more than half of our genes with the tiny insect. For this reason—and their shorter life span and simpler genome—researchers often use the flies as models for human health and disease. 

Nobel laureate Michael Rosbash, PhD, is one such scientist. A self-described “fly chauvinist,” this month he visited SBP to present his latest research on the circadian rhythm of fruit flies. The event quickly became standing room only. 

Rosbash received the 2017 Nobel Prize in Physiology or Medicine, along with Jeffrey Hall and Michael Young, for their work uncovering the molecular timekeepers behind circadian rhythm. Their work was conducted in fruit flies, but has since unlocked new discoveries in animals and plants. 

Rolf Bodmer, PhD (pictured left), who introduced Rosbash (pictured right), is using fruit flies to uncover how our heart develops and ages, with a particular focus on a heart rhythm disorder called AFib. Nearly 10 percent of people over the age of 65 develop the condition, a leading cause of stroke, but we don’t know its cause, and there is no cure. By studying AFib in fruit flies, Bodmer and his team, which includes a cardiologist at Scripps Clinic, are hoping to learn the cause of the disorder and find effective treatment(s). 

While he has all the reason in the world to have an ego, Rosbash remains humble and down-to-earth. He ended his presentation by thanking his lab, without whom he would “not have a job and such prizes.” 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

American Heart Association awards postdoctoral fellowship to SBP scientist

AuthorMonica May
Date

January 23, 2019

It’s no surprise that muscles are important to our metabolism: it’s why building muscle at the gym can accelerate weight loss. 

Scientists are particularly interested in how muscle metabolism affects the heart, arguably the most important muscle in the body. With heart disease remaining the number-one killer of men and women in the U.S., the hunt is on to better understand the molecular mechanisms of the heart so we can develop better treatments. (Learn more about heart disease at our upcoming SBP Insights event.) 

Research is revealing that altered communications between skeletal and heart muscle increases the risk of heart disease. But the molecular mechanisms behind this link are currently unknown. 

Now, the American Heart Association has awarded a two-year postdoctoral fellowship to SBP’s Chiara Nicoletti, PhD, to study the genetic basis of metabolic changes in skeletal muscle that ultimately lead to heart disease. Nicoletti works in the lab of Pier Lorenzo Puri, MD, professor in the Development, Aging and Regeneration Program at SBP. 

Findings from Nicoletti’s work could uncover therapeutic targets for heart disease and/or lead to a prognostic tool that could predict heart disease risk. Both developments would be much-needed advances in the battle against heart disease. 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

“Flying” high to understand what happens when hearts don’t get enough oxygen

AuthorSusan Gammon
Date

October 23, 2017

A good supply of oxygen is important for the survival of tissue, but it’s especially critical for organs with high-energy demands, such as the heart. Lack of oxygen (hypoxia) can occur under a variety of conditions, including high altitude, inflammation and cardiopulmonary disorders such as heart attacks and blood clots. Understanding how the heart compensates—or doesn’t compensate—under hypoxic conditions can open avenues to find treatments for hypoxia-related cardiac diseases.

Rolf Bodmer, PhD, director and professor of the Development, Aging and Regeneration Program, and Karen Ocorr, PhD, assistant professor at SBP, study hypoxia in the Drosophila model. Drosophila, a common fruit fly about 3mm long has a heart that doesn’t look much like a human’s—it’s a long tube—but it has many of the same components and genes as a human heart, making it a very useful model to study how genes and environmental conditions affect heart function.

Bodmer and Ocorr’s new study, published in the journal Circulation Cardiovascular Genetics, looked into how hypoxia can lead to long-term heart defects in Drosophila. Their research team studied two sets of flies that underwent different hypoxia treatments: Set (1) flies were subjected to chronic hypoxia for three weeks (hypoxia-treated flies), which is about half of a fly’s life, and Set (2) flies were selected for survival in hypoxic conditions over 250 generations (hypoxia-selected) flies.

While there were some significant differences discovered in the hearts of the two sets of flies, one thing was the same—the expression profile of calcineurin genes were much lower under both conditions.

“Calcineurin is actually an enzyme that promotes the enlargement of the heart (hypertrophy) under some prolonged stress conditions,” says Bodmer. “In mammals, we knew that inhibiting calcineurin reduces the pathological condition of an enlarged heart, but we didn’t know how calcineruin worked in long-term hypoxia, where hypertrophy is a defining feature of diseases linked to chronic hypoxia, most notably known as chronic mountain sickness, which is notorious for affecting high altitude dwellers in the Andes, but surprisingly not as much in Tibet.

Using calcineurin knockdown flies, the team found that without the enzyme, hearts were impaired in normal oxygen conditions. In hypoxic conditions, the damage was even worse, suggesting a careful balance of pro- and antigrowth signaling is necessary for a well-functioning and responsive heart.

“Our study in Drosophila shows that reduced cardiac calcineurin levels cause heart defects that mimic some characteristics we see during long-term hypoxia,” explains Bodmer. “Since calcineurin genes are very similar between Drosophila and human—approximately 75% identical—we believe that reduced levels of calcineurin in mammals—including humans—may play a crucial role in the progression of heart disease during long-term hypoxia exposure, and help understand cardiac complications associated with hypoxia, including population living at high altitude.”

Institute News

Will flies help fix heart rhythm problems?

AuthorSusan Gammon
Date

July 12, 2017

Your heart beats about 35 million times in a single a year. That’s a whopping number of beats—each generated by electrical signals that make the heart contract. Occasionally problems with heart’s electrical system can cause irregular rhythms, or arrhythmias. Some types of arrhythmias are merely annoying; others can last long enough to affect how the heart works, or even cause sudden cardiac arrest.

Although certain arrhythmias can be successfully treated with medication, surgery and/or devices such as pacemakers, cardiac disorders and heart disease still account for more deaths than any other disease.

Finding new treatments for arrhythmias requires a deep understanding of how the heart beats, and specifically the intricate electrical system that prompts the heart to contract. It also requires a model to study. Is Drosophila melanogaster—a type of fruit fly—the answer?

Using flies to study the heart

Both the human heart and fly hearts have four chambers and both start out as linear tubes in embryos—but ours loops during development to form a more compact structure where as a the fly heart does not. Despite this structural difference there are many functional similarities between the fly and human heart.

“One of the similarities that we focus on in my lab is the way ion channels work—and don’t work—to fully understand how faulty ion channels contribute to heart arrhythmias,” says Karen Ocorr, PhD, assistant professor at SBP.

Ion channels are proteins found in cell membranes that allow specific ions such as potassium, sodium and calcium, to pass through cells. When ion currents travel into heart muscle cells, the muscle becomes depolarized, creating an electrical current that causes the heart to contract. A second set of channels are important in repolarization of the heart, which allows it to relax and refill with blood.

In her new paper published in PLOS Genetics, Ocorr describes how two repolarizing potassium ion channels called hERG and KCNQ control the rate and efficiency of fly heart contractions—similar to their role in human heart muscle. The research also shows that mutations in hERG and KCNQ lead to arrhythmias that worsen with age—as they do in humans.

“In humans, when hERG is compromised, either by drugs or inherited mutations, hearts can take longer than normal to recharge between beats, causing a potentially fatal condition called long QT syndrome. In fact, some anti-arrhythmia drugs actually cause long QT syndrome, hence the need for better, more specific therapies,” explains Ocorr.

The capacity for drugs to cause long QT syndrome has led the Food and Drug Administration (FDA) to recommend including the evaluation of new cardiac and non-cardiac drugs for this possible side effect. The FDA is the United States agency that provides licenses to market new drugs.

Interestingly, neither of the ion channels we identified in the fly heart play a major role in the adult mouse heart, ruling it out as useful model to screen for drug-related long QT effects,” says Ocorr.

“We are encouraged that Drosophila may become an easy, accurate tool to pre-clinically screen for adverse cardiac events associated new anti-arrhythmia therapies—potentially making the next drug discovery for patients happen sooner.”

Read the paper here

Institute News

An “Odd” gene affects aging of the heart

AuthorJessica Moore
Date

February 1, 2017

As we get older, our hearts change in ways that make it harder for them to pump blood. They become stiffer, less efficient at generating energy, and more likely to respond to damage with inflammatory chemicals. To help find new ways to slow that decline, researchers in the laboratory of Rolf Bodmer, PhD, professor and director of the Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), are looking at how the heart ages at a molecular level.

Bodmer’s team recently discovered a new potential contributor to cardiac aging, a protein called Odd, opening up a novel direction for research on therapies to prolong heart health. In their study, published in the journal Aging Cell, the gene for Odd, which controls the activity of other genes by turning them on or off, was found to be turned up in the hearts of old fruit flies. Bodmer’s lab studies flies because their hearts deteriorate with age in the same ways that human hearts do, but their genetics are much simpler.

“It’s intriguing that Odd is linked to aging because its known function is in early development—it’s crucial for the heart to form properly, and, as we found here, is also important for preventing the heart from deteriorating prematurely,” says Bodmer.

Odd’s involvement in cardiac aging was uncovered by a genome-wide comparison of the genes that are active in the hearts of young and old flies. Odd was one of over 200 genes whose activity was significantly elevated in older flies. Remarkably, further analysis showed that in aging hearts, increasing Odd activity temporarily protects the heart from decline by supporting proper electrical function and heart rate.

“Our findings suggest that increased levels of Odd in older hearts may be a way to compensate for aging-associated loss of function,” comments Bodmer. “In combination with a companion paper showing that another gene-regulating protein, FoxO, helps preserve the adult heart, they support a growing body of evidence that genes that are crucial in development are also important to keep the heart running well into old age.”

Bodmer contributed to the other paper, from the lab of Anthony Cammarato, PhD, assistant professor at Johns Hopkins University School of Medicine, and previously a staff scientist in Bodmer’s lab. The paper showed that FoxO helps protect the aging heart by turning on genes that help get rid of unneeded proteins.

“Following up on the findings of both studies could point to ways to keep our hearts working better for longer,” Bodmer adds.

The Bodmer lab paper is available online here and the Cammarato lab paper is here.

Institute News

Scientific breakthrough may limit damage caused by heart attacks

AuthorJessica Moore
Date

June 30, 2016

A research advance from the Sanford Burnham Prebys Medical Discovery Institute (SBP) and Stanford University could lead to new drugs that minimize the damage caused by heart attacks. The discovery, published in Nature Communications, reveals a key control point in the formation of new blood vessels in the heart, and offers a novel approach to treat heart disease patients.

“We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart,” said Mark Mercola, PhD, professor in SBP’s Development, Aging, and Regeneration Program and jointly appointed as professor of medicine at Stanford University, senior author of the study. “RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes.”

In the US, someone has a heart attack every 34 seconds. The ensuing loss of heart muscle, if it affects a large enough area, can severely reduce the heart’s pumping capacity, which causes labored breathing and makes day-to-day tasks difficult. This condition, called heart failure, arises within five years in at least one in four heart attack patients.

The reason heart muscle dies in a heart attack is that it becomes starved of oxygen—a heart attack is caused by blockage of an artery supplying the heart. If heart muscle had an alternative blood supply, more muscle would remain intact, and heart function would be preserved. Many researchers have therefore been searching for ways to promote the formation of additional blood vessels in the heart.

“Studies in animals have shown that having more blood vessels in the heart reduces the damage caused by ischemic injuries, but clinical trials of previous therapies haven’t succeeded,” said Ramon Díaz-Trelles, PhD, staff scientist at SBP and lead author of the study. “The likely reason they have failed is that these studies have evaluated single growth factors, but in fact building blood vessels requires the coordinated activity of numerous factors. Our data show that RBPJ controls the production of these factors in response to the demand for oxygen.

“We used mice that lack RBPJ to show that it plays a novel role in myocardial blood vessel formation (angiogenesis)—it acts as a master controller, repressing the genes needed to create new vessels,” added Diaz-Trelles. “What’s remarkable is that removing RBPJ in the heart muscle did not cause adverse effects—the heart remained structurally and functionally normal in mice without it, even into old age.”

“RBPJ is a promising therapeutic target. It’s druggable, and our findings suggest that blocking it could benefit patients with cardiovascular disease at risk of a heart attack. It may also be relevant to other diseases,” commented Pilar Ruiz-Lozano, PhD, associate professor of pediatrics at Stanford and adjunct professor at SBP, co-senior author. “Inhibitors of RBPJ might also be used to treat peripheral artery disease, and activators might be beneficial in cancer by inhibiting tumor angiogenesis.”

The paper is available online here.