New clues to a 500-year old mystery about the human heart

 Scientists show that muscular structures first described by Leonardo da Vinci are essential for heart function

Researchers have investigated the function of a complex mesh of muscle fibres that line the inner surface of the heart. The study, published in the journal Nature, sheds light on questions asked by Leonardo da Vinci 500 years ago, and shows how the shape of these muscles impacts heart performance and heart failure.

This project included collaborators at EMBL’s European Bioinformatics Institute (EMBL-EBI), Cold Spring Harbor Laboratory, the MRC London Institute of Medical Sciences, Heidelberg University, and the Politecnico di Milano.

In humans, the heart is the first functional organ to develop and starts beating spontaneously only four weeks after conception. Early in development, the heart grows an intricate network of muscle fibres – called trabeculae – that form geometric patterns on the heart’s inner surface. These are thought to help oxygenate the developing heart, but their function in adults has remained an unsolved puzzle since the 16th century.

To understand the roles and development of trabeculae, an international team of researchers used artificial intelligence to analyse 25 000 magnetic resonance imaging (MRI) scans of the heart, along with associated heart morphology and genetic data. The study reveals how trabeculae work and develop, and how their shape can influence heart disease. UK Biobank has made the study data openly available.

Solutions to da Vinci’s biological enigma

Leonardo da Vinci was the first to sketch trabeculae and their snowflake-like fractal patterns in the 16th century. He speculated that they warm the blood as it flows through the heart, but their true importance has not been recognised until now.

“Our findings answer very old questions in basic human biology. As large-scale genetic analyses and artificial intelligence progress, we’re rebooting our understanding of physiology to an unprecedented scale,” says Ewan Birney, Deputy Director General of EMBL. 

The research suggests that the rough surface of the heart ventricles allows blood to flow more efficiently during each heartbeat, just like the dimples on a golf ball reduce air resistance and help the ball travel further.

The study also highlights six regions in human DNA that affect how the fractal patterns in these muscle fibres develop. Intriguingly, the researchers found that two of these regions also regulate branching of nerve cells, suggesting a similar mechanism may be at work in the developing brain.

“Our work significantly advanced our understanding of the importance of myocardial trabeculae,” explains Hannah Meyer, Principal Investigator at Cold Spring Harbor Laboratory. “Perhaps even more importantly, we also showed the value of a truly multidisciplinary team of researchers. Only the combination of genetics, clinical research, and bioengineering led us to discover the unexpected role of myocardial trabeculae in the function of the adult heart.”

Trabeculae and the risk of heart failure

The researchers discovered that the shape of trabeculae affects the performance of the heart, suggesting a potential link to heart disease. To confirm this, they analysed genetic data from 50 000 patients and found that different fractal patterns in these muscle fibres affected the risk of developing heart failure.

Further research on trabeculae may help scientists better understand how common heart diseases develop and explore new approaches to treatment.

“Leonardo da Vinci sketched these intricate muscles inside the heart 500 years ago, and it’s only now that we’re beginning to understand how important they are to human health. This work offers an exciting new direction for research into heart failure, which affects the lives of nearly 1 million people in the UK,” says Declan O’Regan, Clinical Scientist and Consultant Radiologist at the MRC London Institute of Medical Sciences.

Learning from Deep Learning: the inspirational story behind AlphaFold

 AlphaFold is an Artificial Intelligence (AI) tool that predicts protein structure from sequence. In July 2021, DeepMind  made the AlphaFold database public and freely accessible to users worldwide. By the beginning of 2022, the curated database had grown to contain one million protein structure predictions, and the ability to predict protein structures from amino acid sequences was coined scientific breakthrough of the year 2021.

Scientists have used structural biology approaches to reveal, probe and manipulate protein structures for many decades. With the launch of the AlphaFold Protein Structure Database, Researchers have also begun to explore how the AI tool can drive new approaches and understanding of protein structure and function. 

Following the successful collaboration on the AlphaFold database, a delegation from DeepMind visited EMBL Heidelberg to learn more about EMBL research and services, and to discuss with scientists potential future directions in the application of AI in the life sciences.

During the visit, DeepMind founder and CEO Demis Hassabis, and AlphaFold team lead John Jumper, explained their work to develop AlphaFold as a new deep learning-based system. From the first steps towards developing the methodology and underlying machine learning ideas to the immense implications for molecular biological research now and in the future, Hassabis and Jumper shared their story and the inspiration behind AlphaFold.

“This is an incredibly exciting new era in digital biology, and AI is a powerful tool for accelerating scientific discovery. Our partnership with EMBL on the AlphaFold Protein Structure Database has been a wonderful and extraordinarily fruitful collaboration, and we have enjoyed this opportunity to brainstorm future ideas together,” Hassabis said.

Ewan Birney, EMBL Deputy Director General and EMBL-EBI Director, added: “The cooperation with DeepMind on AlphaFold has really been successful, and we want to extend that collaborative spirit between EMBL and DeepMind to more parts of EMBL. Artificial intelligence is a game changer and will fast-track biological discoveries in various ways in the years to come.”

 “It was a great pleasure to host the DeepMind team,” said EMBL Director General Edith Heard. “EMBL is proud to have helped ensure the AlphaFold tool was made freely available, and are looking forward to the next developments in AI-assisted research.”

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Related links

• AlphaFold Protein Structure Database