Mystified by the need for defibrillation to save a 10-year-old from drowning, Michael Ackerman, M.D., Ph.D., vowed to dig for answers. That pivotal case during a Mayo Clinic pediatric cardiology residency was the catalyst for Dr. Ackerman’s career in genetic sleuthing of inherited sudden cardiac death syndromes. With help from the Center for Regenerative Medicine Biotrust, Dr. Ackerman’s team reprograms cell lines to zero in on precise causes and possible treatments for genetic heart disorders that increase the risk of sudden cardiac death. His research and practice focus on inherited conditions like long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome (BrS) along with heart muscle diseases such as hypertrophic cardiomyopathy (HCM).

“Working with the Center for Regenerative Medicine has opened up a whole new investigative arm to our lab. It is bench to bedside research. We take cells from a blood sample from my patients and then reprogram those cells to become cardiac cells. This research effort has been a powerful tool in gene discovery to prove beyond a shadow of a doubt when a monogenetic variant is indeed the cause of a sudden cardiac death syndrome,” says Dr. Ackerman.

Reprogramming cells to identify disease-causing mutations

Reprogramming a patient’s cells is like a step back in time to when the cells were initially forming in the mother’s womb. At that time, cells were dividing and could become any type of cell or tissue in the body. Reprogrammed cells, known as induced pluripotent stem cells, can be redirected to become new heart cells. Dr. Ackerman’s team uses these patient-specific cell lines to create a ‘disease in a dish’ model and investigate whether genetic mutations are causing the patient’s genetic heart disease such as long QT syndrome. 

“Once we think we’ve found the root cause of disease, we then go to the patient’s cell line. We ask, ‘does it show in the dish, in that patient’s re-engineered heart cells, a prolonged QT cellular phenotype?’  If it does, then we edit out and correct that variant of interest and at the cellular level test whether the abnormality disappears,” says Dr. Ackerman.

Dr. Ackerman’s team then introduces that genetic variant into normal, healthy cells. If those cells produce a long QT phenotype, they have proof that exact genetic variant is the cause.

Using this disease in a dish model and other genetic sleuthing strategies, Dr. Ackerman’s team has discovered six of the 17 known genes that cause long QT syndrome. And, they have recently described two entirely new syndromes. One is triadin knockout syndrome, a heart arrhythmia that could lead to cardiac arrest in children during exercise. The second is an autosomal recessive genetic mechanism for calcium release channel deficiency syndrome, prevalent within Amish communities. That key discovery solved the mystery of why so many Amish children were dying suddenly during ordinary childhood play. The disease in a dish model is also useful for discovering new therapies. After creating the patient’s disease in a dish, Dr. Ackerman’s team tests potential new drug compounds to see if they could be effective.   

“We are developing a new gene therapy for the most common genetic subtype of long QT syndrome. With this model, the gene therapy vector is essentially curing the diseased long QT phenotype in the dish,” says Dr. Ackerman.

Almost quit research

Dr. Ackerman began medical and graduate school at Mayo Clinic in 1988, where he worked in a research lab next to then fellow trainee, Andre Terzic, M.D., Ph.D., who now is director of Mayo Clinic Center for Regenerative Medicine. Initially not seeing the relevance to patient care, Dr. Ackerman finished his Ph.D. and left research vowing to “never, ever return.” True to his mentor’s predictions that “you’ll be back, Mike,” Dr. Ackerman felt the pull back to research to address unmet medical needs of his patients. He joined Mayo Clinic’s faculty in 2000 as one of the first genetic cardiologists with a goal of establishing a practice for patients at risk of sudden cardiac death from genetic heart diseases. Dr. Ackerman now directs the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory. 

Dr. Ackerman’s return to research has provided many answers for patients, with over 600 peer-reviewed publications that have occurred since that time 23 years ago when Dr. Ackerman and his team first solved that 10-year-old boy’s near fatal drowning. It was a mutation in the gene causing type 1 long QT syndrome.

Dr. Ackerman is one of the innovators the Center for Regenerative Medicine collaborates with as it seeks to be a global leader and trusted destination for regenerative care driven by research and education.

###

Related Articles