How 'bat power' cures

Thomas Zwaka had always found bats to be strange: living in caves, hanging upside down, and flying through the night. During his stint as an Associate Professor at Baylor College of Medicine in Houston, Texas, about 10 years ago, he would take his young son to see bats, driving three hours to Austin. In caves just outside that city resided millions of bats, which emerged every evening to forage. Those excursions and the sightings further piqued Zwaka's interest in bats.

But it wasn't until 2020, while working at Icahn School of Medicine at Mount Sinai, New York, that his interest transformed into a full-fledged scientific quest. It was the early days of the COVID-19 pandemic when his colleague Adolfo García-Sastre, a virologist at Mount Sinai, asked if he could develop human lung cell lines to study a new virus. Zwaka's expertise lay in developing pluripotent cells: cells that can develop into any kind of cell, be it lung, muscle or skin. The two agreed to collaborate and soon prepared a lung cell culture to probe the effect of the virus on lung cells.

As the pandemic unfolded and its connection to bats became clear, Zwaka's interest in bats was rekindled. In particular, he started looking for answers to a question that bat biologists across the globe want to answer: how do bats withstand many different types of viruses without themselves getting sick? This was not the first time a virus perfectly tolerated in bats was causing disease in humans. There are well-known cases of spillovers from bats: SARS-CoV-1, MERS, Marburg, Ebola, and Nipah, which reappeared in India in 2023.

As Zwaka dived into the existing literature on bats, he was surprised to find that "despite their interesting biology, and despite the fact that they are a carrier of some of the deadliest viruses, no one had made bat pluripotent cells". No stranger to pluripotent cells, and confident that they could be a great tool to understand how bat cells react to viruses and tolerate them, he started working on developing bat pluripotent cells. For starters, he wanted to see how bat lung cells responded to the SARS-CoV-2 virus. "I was thinking: wouldn't it be really fascinating to do the same experiment as with human lung cell lines, but use pluripotent stem cells from bats to make lung tissue and infect them with SARS-CoV-2 to see how they responded to the virus," he recalls.

In March 2023, Zwaka and his colleagues published a paper (bit.ly/bat-stem-cell) in Cell describing the first ever pluripotent stem cell lines of bats that could be turned into any kind of bat tissue. While studying these cells, they noticed something peculiar: each cell had several small round structures that were filled with viruses. Further investigation showed that the structures were actually coming from the bat's own DNA, which had incorporated the viral sequences into its genome. The researchers speculate that by coexisting together for a long time, bats have evolved to integrate viral sequences into their genome and use them to 'train' their immune system. It is almost like a self-vaccination scheme, says Zwaka.

In still-unpublished studies, when the researchers infected bat cells with the SARS-CoV-2 virus, the virus replicates, but there is no cytokine storm, no interferon response, says Zwaka. It looks like the cells allow the virus to replicate and mount only an "attenuated" response to the infection to stop the virus from taking over the cell. This was in stark contrast with what they saw in human cells, where the virus replicates at a fast rate, the cells mount a strong and swift response, and within a day or two of the infection, lung cells start dying.

Some researchers think this tolerance to viruses is actually a fallout of another ability of bats that sets them apart from other mammals: powered flight. Bats can fly at great speeds but that ability places big metabolic demands on their body: their core body temperature can go up to 40-43^°C and heart rate can go up to 1,000 beats per minute. And they have to do this every night for hours when they go foraging.

The stress of flying should be enough to put bats in a state of inflammation, when the body mounts a response to external threats like viruses and bacteria or internally produced stress. But no such inflammation is seen. "Bats have evolved to have a dampened inflammatory response so they can fly longer without getting sick," says Akshamal Gamage, Research Fellow in the Emerging Infectious Diseases Programme at Duke-NUS Medical School in Singapore.

A 2023 study (bit.ly/bat-ASC2) published by researchers from the Programme showed that a bat protein called ASC2 inhibits the assembly of large multi-protein complexes called inflammasomes that are produced during inflammation. Interestingly, an analogue of ASC2 protein is also present in humans but it does not inhibit inflammasomes as strongly as its bat counterpart. By understanding which parts of the bat ASC2 protein make it effective, researchers can tweak human ASCs to minimise inflammation. "This is a direct example of how insights into the bat's immune system dampening can give us novel ways to target various diseases," says Gamage.

Increasingly, research has shown that not only is inflammation associated with infections, it is also an underlying factor for a host of metabolic disorders, including obesity, type 2 diabetes and coronary heart disease. Many researchers believe that understanding how to dampen inflammation will lead to potential ways to target each of these diseases.

Zwaka sees enough potential in the idea to have co-founded a start-up, Paratus Sciences, which aims to study bat biology to come up with therapeutics for viral diseases and other conditions.

In addition to powered flight and a unique immune system, bats have several other special abilities that researchers are discovering. For example, Gamage is now working on dietary adaptations of Eonycteris spelaea, which lives on a nectar-exclusive diet. Every day, for their entire lives, these bats feed on pure liquid sugar without getting any metabolic diseases like type 2 diabetes or fatty liver disease. Gamage wants to understand the adaptation and genetics that enable them to thrive on such a diet.

Bats are a highly diverse group of mammals with nearly 1,500 different species living in widely different habitats. They can feed on insects, fruit, leaves, nectar, blood and even fish. They are capable of finding their way in the dark through echolocation, can hibernate, and are one of the longest-living mammals for their body size. (See box: Living on biology's extreme).

The code for all their unique attributes is written in their genome, which is why researchers across the globe are trying to sequence their genomes. A global consortium of researchers has launched Bat1K Project that aims to sequence the genomes of all 1,500 bat species. The project will create a treasure trove of genetic data that underpins their evolutionary trajectory and unique adaptations.