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Leslie Tung

Leslie Tung

Leslie Tung of Biomedical Engineering on studying the beating of heart cells in a dish:

What kind of research do you do?

We study how electrical waves propagate in heart cells grown in a dish as a model system to study mechanisms for cardiac arrhythmias—otherwise known as irregular heartbeats. The reason for growing the cells in a dish is that it’s a very simplified system and in many ways is divorced from the heart, which has its own pros and cons. The pros are that it simplifies the mechanisms and makes them more transparent. The cons are that it eliminates complexities of what really happens in the heart, but at the same time I think we’ve elevated the state of the art technology of what one can do to grow the heart cells in a tissue-like environment.

When you grow heart cells in a dish, do they pump like they do in a whole heart?

Sometimes the ventricular cells in a dish will beat on their own, particularly if pacemaker cells—the cells that set the pace for the beat of the heart—accidently get mixed in with the ventricular cells. The cells we experiment with though, we take from the ventricle of newborn rats, and these don’t normally beat after a while, so we have to electrically stimulate them with little shocks at prescribed rates to make them beat.

How do you measure the electric waves in the heart cells?

TUNG: We use a technique called optical mapping. This involves staining of the cells with a fluorescent dye that changes its intensity at certain colors with the voltage of the cells. It’s rather amazing because now you can visualize electrical waves by looking at optical waves.

How do you replicate heart disease in a dish?

TUNG: One of the diseases that we have set our sights on is called fibrosis, which is associated with almost all heart diseases. Fibrosis arises from excessive connective tissue and collagen, which makes the tissue stiff and affects the heart’s ability to pump properly. To recapitulate fibrosis in a dish, we grow heart cells with lots of fibroblasts that turn into myofibroblasts. The myofibroblasts act as little factories that churn out connective tissue, and the myofibroblasts themselves seem to have the ability to alter the electrical function of the heart cells. We are looking at how arrhythmias occur in our fibrosis model.

How does one mimic a whole tissue in a dish?

TUNG: Normally cells in a heart are elongated and rod-shaped, but when you break up the tissue and put the cells on a dish, the cell’s shape becomes many-sided and the distribution is random.  We have developed a way to grow the cells in long, parallel lines, which makes the cell geometry mimic that in a tissue slice and thus makes their responses more akin to the behavior they display in tissue.

Our technique to create organized cells is just like pressing a rubber stamp on an ink pad and then pressing it to paper to make an image, except we use different materials. To do this, we design patterns on a computer and print them out.  Then, we use the printout to create tiny stamps made out of an elastic polymer which can be used to press a certain protein, to which cells stick, onto a glass slide in the shape of the pattern. Heart cells placed on top of the slide will bind to the sticky proteins, and after a few days, the cells adopt the pattern that we specify.

We have also been able to imitate fibrosis in a dish without having to use myofibroblasts by patterning the cells in zigzag patterns that disrupt the flow of the electrical waves.

What else do you have in the works?

We are collaborating with a team of other scientists at Hopkins to study a new form of defibrillation—the process of interrupting stray electrical waves in the heart to reinitiate a regular heart beat—using a new kind of a wave form. During fibrillation, there are spiral waves that are self renewing much like you see in a tropical storm or hurricane that aren’t synchronized with the heart’s normal electrical waves. The trick of defibrillation is to interrupt and terminate all of the multiple spiral waves at once by applying an electrical pulse.

We are working very closely in analyzing wave forms using alternating current as opposed to direct current. This has not been heavily investigated before, but it may work differently and may have certain advantages over conventional methods. We are testing these wave forms out in our “heart in a dish” model and also in fibrillating animal hearts.

--Interviewed by Vanessa McMains

Les Tung on engineering heart cells in a dish:

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