Lessons from the Tarantula

Picture an organism the size of your hand, with a bristly body and eight bushy legs. Chances are, you’re thinking of a tarantula. As familiar as these shaggy arachnids are, it may surprise you to learn that they harbor a secret about human health: the muscles that control each spindly limb bear a remarkable molecular resemblance to the muscle beating in our chests.

For Christine Seidman, a human molecular geneticist and HHMI investigator at Brigham and Women’s Hospital and Harvard Medical School, that likeness gave her a new perspective on heart disease. Seidman studies a heart disease called hypertrophic cardiomyopathy (HCM). For those with HCM, the heart contracts too well, and does not relax properly, which increases energy consumption and leads to adverse events such as arrhythmias and heart failure.

Seidman’s past work has identified eight genes encoding for muscle proteins that, if mutated, cause HCM. Most commonly these mutations occur in two of the genes, one of which codes for myosin, a protein crucial to muscle contraction. The myosin-related mutations simply switch one amino acid for another during the protein-building process. These findings prompted a new question: “How could such a subtle change have such profound effects?” In search of an answer, Seidman looked beyond genetics.

During an HHMI science meeting in 2011, Seidman sought help from Raúl Padrón, a structural biologist at the Venezuelan Institute for Scientific Research (I.V.I.C.), whose journal articles she’d been following. At the time, Padrón was an HHMI international research scholar studying how muscle proteins interact in tarantulas (which he describes as “very friendly”).

“One of the critical proteins that Raúl was studying was – big surprise – myosin,” said Seidman.

Armed with the title of Padrón’s poster at the HHMI meeting, she set out to find him. Padrón recalls their first interaction in vivid detail: “I was in complete shock when Christine came to my poster; I had never met her before, and she was very well-known in my field, as she discovered many of the mutations we were mapping in the myosin model in our poster. She walked up to me and said ‘We need to work together to understand how different mutations affect the myosin motif.’”

And so, they did. Padron paired his expertise in structural biology with Seidman’s keen knowledge of genetics. Together with collaborators Lorenzo Alamo and Antonio Pinto, they investigated how HCM-associated mutations change the structural interactions of myosin that occur during cardiac relaxation.

As a geneticist, Seidman says it was beautiful to see the actual myosin structure, even at low resolution. “And there was another piece that was very important to me – Raúl could tell me the amino acids that participate in myosin interactions during relaxation.” It turned out that many of the amino acids involved in the molecular interactions that occur with relaxation are the very ones that are altered by HCM mutations. That, she said, was “an a-ha moment.”

Baby Venezuelan tarantula. Image credit: Raúl Padrón

Now, the two are planning next steps, asking the natural follow-up questions in their respective fields.

“We hope to take advantage of the ongoing ‘cryo-EM resolution revolution’ to achieve near-atomic resolution of myosin interactions by using this technique, which was actually invented by Humberto Fernández-Morán, a Venezuelan scientist working at Chicago University in 1966,” Padrón says. Seidman, too, hopes to continue structural analyses. “We’d very much like to work with Raúl to solve these structures using human specimens, with and without HCM mutations,” she says. “That would be a big step."

But the clinician side of Seidman hopes the information will help them answer a different question.

“We also want to know if there is a way to reduce the symptoms and adverse outcome that occur in HCM, by improving relaxation, with small molecules in the heart. In addition, we know that abnormal relaxation of the heart occurs in a lot of different diseases, not just HCM, so understanding if these structures might contribute to broader cardiovascular disease will also be very, very important.”