When the heart loses its ability to pump blood, either as a result of a major trauma, or a comorbidity like obesity or diabetes, the condition is commonly known as heart failure. In the United States, heart failure is at least partly to blame for 13% of all deaths. According to the NIH, one in four Americans will develop heart failure at some point in their lives and the incidence has increased over the last 25 years, especially among younger adults. At the same time, there have been few significant improvements in the treatment of heart failure.
One solution to this very large and growing problem may exist within the machinery of the heart itself. The muscle contractions that allow the heart to beat are generated by interactions between actin and myosin, proteins that enable movement at the molecular level by converting energy-rich molecules of ATP into muscle power.
Mike Regnier, PhD is a Professor of Bioengineering, a faculty member in the Institute for Stem Cell and Regenerative Medicine, and the Director of the UW Center for Translational Muscle Research (CTMR). His lab studies how deoxy-ATP (a natural variant of ATP) can be used to promote stronger heart function. In recent years, Regnier and his team have shown how replacing even 1% of the ATP in cells with dATP can supercharge the contractile force of myosin.
The work of healing hearts is done by what Regnier calls small molecule factory and delivery cells. “We engineer stem cells to manufacture the enzyme that makes the dATP. These cells are differentiated into cardiac muscle cells, then transplanted into the heart, where they deliver the nucleotides into the heart muscle.”
Still, the mechanisms by which such small increases in cellular dATP seem to improve heart function remains a partial mystery. Shedding light on that question could help researchers like Regnier turn their discoveries about therapeutic potential of the molecule into desperately needed new treatments for heart failure.
Emerging data from the University of Washington and the University of California San Diego may bring this hope closer to reality.
Regnier is an author of a study, published this month in the Proceedings of the National Academy of Sciences (PNAS), that uses a sophisticated modeling tool to show in unprecedented detail how small doses of dATP, administered as medicine, stimulate the heart at the atomic, cellular, tissue, and whole organ levels. Matthew Childers, a postdoctoral fellow in the Regnier Lab, is also an author of the paper.
The research was led by Andrew McCulloch, PhD, a distinguished professor in the Shu Chien – Gene Lay Department of Bioengineering at UC San Diego and director of the Institute of Engineering in Medicine. The effort is the latest in a series of collaborations between Dr. Regnier and Dr. McCulloch over the past decade, and the most ambitious undertaking to date.
The investigation was led by first author Abby Teitgen and second author Marcus Hock, who both recently earned PhDs in bioengineering in McCulloch’s lab, and conducted in collaboration with Kimberly McCabe, a former PhD graduate of the McCulloch lab now at Simula Research Institute in Oslo, Norway. J. Andrew McCammon, distinguished research professor of Chemistry and Biochemistry at UC San Diego and an elected member of the US National Academy of Sciences also contributed to the work, along with Gary Huber, a project scientist in Chemistry and Biochemistry at UCSD.
“We have previously been able to model the effects of dATP at individual scales,” says Regnier. “Sometimes models can bridge a single scale, but this project with UCSD shows for the first time how infusing this molecule in small amounts can ripple upward through all of the spatial scales and have a big effect on whole heart function, and rescue heart failure.”
The question that the team set out to answer with the development of this multi-scale set of models has real-world implications for the clinic. How does a drug, engineered from miniscule human parts, that goes to work at an atomic point of attack, ultimately change the whole cardiovascular system in a way that doctors and patients would see and feel in the clinic?
The investigation capitalized on the complementary skills of several early-career scientists who were co-mentored in this study by UW and UCSD faculty. Teitgen, Hock, Childers and McCabe all specialized in a variety of computational modeling approaches to partner with experimentalists in the Regnier lab who have expertise in molecular, cellular, and cardiac mechanics.
“This project is really groundbreaking because of the novel insights gained by bridging each scale of model that you wouldn’t get in an isolated system,” says Dr. Hock.
Dr. Childers echoes that assessment, adding, “New multiscale modeling paradigms provide exciting opportunities to explore how changes in molecule structure impact the function of entire organs.”
By focusing Teitgen’ s modeling system first on myosin, then zooming out, the researchers tracked the increase in contraction force through escalating levels: sub-cellular sarcomeres, heart muscle cells, heart wall, and then whole heart. The study helps to explain why dATP is capable of helping heart muscle cells contract. Importantly, the computational experiments revealed how dATP recruits myosin from cell structures known as thick filaments, further enhancing contractile force, a finding that will inform the design of future cell therapies. Additionally, the presence of dATP seems to speed up the flow of calcium into storage sites within cells, which enhances relaxation after heart contraction.
The team also compared the effects on healthy and unhealthy hearts. The modeling showed that turning even 2% of ATP into dATP was enough to restore a failing heart’s capacity to pump blood without unintended consequences.
“Our efforts going forward will be aimed at the development of therapeutics,” says Regnier. “We’re using a mixture of experimental and modeling tools to develop a better gene therapy for heart failure. We’re working on new viral vectors that have improved targeting to the heart and enhanced promoters that are specific to the heart and skeletal muscle. And we are using the modeling to re-design the enzyme that produces dATP to optimize the therapeutic dose.”
Stem cells will continue to play an important role, says Regnier. “Once we calibrate the dose, our team will encode the genetic changes into stem cells, which will be programmed to become cardiomyocytes that are engineered to generate a measured amount of dATP – the small molecule factory. It’s sort of cell therapy 2.0. We’re putting in improved heart muscle cells that replace lost tissue and energize the whole heart.”
Within the next five years, Regnier hopes the treatment will be on a path to human clinical trials. “Eventually, the treatment we develop, based on what we learn in the experiments we’ve done, could become part of the heart failure management regimen,” says Regnier. “It’s the first therapeutic that isn’t designed to just slow the slide into end stage heart failure. It’s actually designed to reverse reduced heart function.”
Dr. Teitgen, the first author of the paper, summarizes the significance of the research.
“In this study, we successfully demonstrated how our novel multiscale computational modeling framework can be leveraged to enhance the understanding of existing experimental data while making predictions across various levels of function, from molecular interactions to cellular dynamics and whole-heart physiology. This approach holds exciting potential for future in silico studies of candidate therapeutics.”