Mending A Broken Heart

The cardiovascular research of award-winning Li Qian, PhD, of the UNC McAllister Heart Institute, included at #2 on the American Heart Association “Top Ten Advances in Heart Disease and Stroke Research” during 2012

Mending A Broken Heart click to enlarge Li Qian, PhD, McAllister Heart Institute
Mending A Broken Heart click to enlarge Dr. Li Qian at work in her laboratory in the McAllister Heart Institute on the campus of the University of North Carolina—Chapel Hill

This is, first and foremost, a love story.

Any great love story begins with realizing a passion that moves you and inspires you.  Li Qian, PhD, discovered that passion as a young biology undergraduate at Fudan University in Shanghai, China.  As she studied the human heart, many questions fascinated her and her infectious enthusiasm grew.  But there was one question to which she kept coming back.

How can you mend a broken heart?

The human heart can be “broken” or damaged in many ways. Dr. Qian began to think about the damage that occurs during myocardial infarction (MI), or a heart attack.  “Heart muscle cells die and scar, which eventually leads to heart failure,” says Dr. Qian.  “It is important to avoid the loss of heart muscle cells because they cannot grow back by themselves.  Scar tissue replaces the heart muscle cells.”

Dr. Qian made a major breakthrough in 2011 when her research on mice showed that damaged cardiac fibroblasts (the cells that form the heart’s support system) could be reprogrammed into functioning cardiomyocytes (beating heart muscle cells).  She was able to take scar tissue in the heart and reprogram it at a cellular level to rescue heart function and reduce scar size after a heart attack. (see Figure 1 below)

Figure One Li Qian

Figure 1 — The first image (dsRed) shows the ventricles of the mouse heart with functioning cardiomyocytes (in red) and scar tissue (in blue) from damaged cardiac fibroblasts following myocardial infarction.  The second image (GMT) shows the ventricles of the mouse heart after the damaged cardiac fibroblasts were reprogrammed at the cellular level into functioning cardiomyocytes.

This research earned Dr. Qian the #2 ranking on the American Heart Association “Top Ten Advances in Heart Disease and Stroke Research” during 2012 in addition to a host of other awards and honors.

So, if this is a love story, every story has a beginning.

After completing her undergraduate degree, Dr. Qian decided to follow her passion and pursue her doctoral work in the United States, focusing on developmental, cell and molecular biology.

“I kept asking myself,” says Dr. Qian, “‘How is the heart initially developed?’ It is one of the very first organs formed in the body as a fetus develops.  At 8 weeks, what do we look for in a fetus?  A beating heart!  But how is it formed?”

“I wanted to understand the biology of the heart, so I could figure out how to fix it.”

In 2001, she joined the University of Michigan lab of acclaimed cardiovascular researcher Rolf Bodmer, PhD, a pioneer in the study of heart development through research of embryonic fruit flies.

Dr. Qian wanted to take the research further and work on larger adult animals, so in 2003, she continued her graduate work at the Sanford-Burnham Institute in California.  She was excited that several of the genes and genetic interactions she discovered in flies also have counterparts in vertebrate animals and human, surprisingly working in a remarkable similar fashion.

At this time, her personal life was developing into a different kind of love story. Working in the Bodmer lab at the University of Michigan was another young cardiovascular researcher named Jiandong Liu.  Also a PhD candidate, he was pursuing research on cardiac differentiation and how the fates of different types of heart cells are determined.  After a whirlwind “lab romance”, they married and continued their journeys together to discover how to mend a broken heart.

They completed their PhDs and moved to the University of California-San Francisco to continue their post-doctoral training.  Dr. Liu continued his research on cardiovascular disease with Didier Stainier, PhD, the leading expert on using zebrafish as a model organism for human diseases.  Dr. Qian joined the lab of Deepak Srivastava, PhD, the internationally renowned cardiac biologist at the Gladstone Institute for Cardiovascular Research.

Dr. Qian continued to seek new ways to fix a broken heart, now with a much stronger background on the biology of the heart.  “We were working toward answering the question, ‘How can we rescue heart function?’ explains Dr. Qian.  “Working on adult mice, we took skin cells and transformed them into stem cells then put them into the heart cells to study the survival rate,” explains Dr. Qian.  They wanted to see if the stem cells could survive and become heart muscle cells.

One of the major problems of this approach is the probability of rejection of the cells by the heart. “Anytime you put foreign cells into an organ, there is the risk of rejection,” stated Dr. Qian.  She wanted to look for a better approach to cell survival, which led back to her passion for the basic science and biology of the heart.

Dr. Qian knew that in the heart, 50 percent of cells are cardiac fibroblasts, which form the support structure of the heart, making sure the heart functions properly.  “However, upon injury, these become bad cells,” exclaims Dr. Qian.   “They divide quickly and become scar tissue in the end.”

With her never-ending enthusiasm, Dr. Qian wondered, could she use damaged cardiac fibroblasts as a resource for regeneration, so foreign cells were not introduced into the heart?  Could she make fibroblasts useful again and convert them from bad to good cells?

Expanding on previous research, Dr. Qian knew that in order to do this, she had to find the right “cocktail” of ingredients within the heart cells to make reprogramming possible.  She found a combination of three – Gata4, Mef2c and Tbx5 – that she began to test on adult mice, which had damaged fibroblasts from induced MI.

Dr. Qian excitedly explains, “We took the cocktail, applied it to the damaged fibroblasts and successfully reprogrammed them into functioning heart muscle cells!  They were no longer bad fibroblasts, but beating heart muscle cells, cardiomyocytes.”

After eight weeks, heart function had improved after 8 weeks.  After 3 months, the heart function continued to improve.

When they looked at the new tissue within the scar tissue area, the new tissue were all newly-born cardiomyocytes. (see Figure 2)

Figure Two Li Qian

Figure 2 — From left to right.  Image one: Damaged cardiac fibroblasts that have become scar tissue (in blue) are surrounding reprogrammed functioning cardiomyocytes (in red).  Image two: Functioning cardiomyocytes are clearly seen within an area that previously was scar tissue caused by myocardial infarction.  Image three: Not only have damaged fibroblasts been reprogrammed into cardiomyocytes, they are functional, beating heart muscle cells.

During all of this research, Dr. Qian was experiencing her own “rebirth”, as a new mother.  Her first daughter was born during her PhD work, and her second daughter was born during her research at the Gladstone Institute.  Both provided her with additional motivation.  “During each of my pregnancies, I would see my baby’s heart beating during the ultrasounds, and it was just so perfect.  It inspired me to keep working so I could help those whose hearts were broken.”

In addition to achieving the #2 ranking on the American Heart Association “Top Ten Advances in Heart Disease and Stroke Research” in 2012 for her ground-breaking research on in vivo reprogrammed cardiomyocytes, she received the Louis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators in 2011 from the American Heart Association.  This prestigious award recognizes research involving biochemical, cellular, molecular and genetic sciences, and now includes whole animal studies, especially those related to the creation of new genetic lines.

However, Dr. Qian reminds herself that “nothing is perfect in science”.  Since coming to UNC in August 2012 as an assistant professor in the department of pathology and laboratory medicine and researcher at the McAllister Heart Institute, Dr. Qian has started to address the research challenges ahead of her.

She needs to find the “cocktail” to take her research from mice into pigs and, eventually, into humans.  “We need the cocktail for human reprogramming,” explains Dr. Qian.  “UNC immediately impressed me with its interdisciplinary environment.  The collaboration at UNC is excellent, and I am working with the UNC Gene Therapy Center, Cardiology Department, as well as other researchers, to further our study on the necessary reprogramming elements, as well as a safe, efficient delivery method of the cocktail.”

In Dr. Qian’s mice studies, she uses a virus to introduce the reprogramming factors.  “It all comes back to understanding the biological mechanism of the human heart,” smiles Dr. Qian. “Understanding the basic science of the heart could lead to improved efficiency and safe delivery of the reprogramming factors.  You need to fully understand the whole environment of the heart to figure out how to make this work.”

In the future, Dr. Qian is interested in studying if the research could be applied to treat a broader spectrum of cardiovascular illnesses.  Currently, her research is only applicable for the MI model in the ventricles of the heart.  Could it be applied to chronic heart failure or be introduced into the heart’s atrium?

Dr. Qian says, “UNC offers a platform to get involved with the next generation of scientists.  I want to help young scientists and encourage them. I want to help researchers and other labs with the study of the biology of the heart because the more people who work on this, the faster the research will happen, and it will benefit the field as a whole.”

“If I can convince one person out of a thousand to be a scientist, then I have been successful,” exclaims Dr. Qian definitively.  “In a laboratory, 99 percent of all experiments will be failures.  But the one percent that works is very rewarding.”

And so the love story of Dr. Qian continues.

Dr. Liu also came to UNC in August 2012 as an assistant professor in the department of pathology and laboratory medicine and researcher at the McAllister Heart Institute, continuing his work on cardiac development and function using zebrafish as his model system.  Their two children are happily settled in their new schools and new home.

Dr. Qian says with her infectious enthusiasm, “My two great loves are enjoying life with my family and continuing my cardiac research to mend broken hearts.  The environment at UNC, and my great mentors here, make this possible. This is a great occupation for a woman and mother.”

Qian with 2 daughters

Dr. Li Qian, enjoying life in Chapel Hill with her two young daughters.