Protecting human hearts and brains

Why do researchers want to know how naked mole-rats react to oxygen deprivation?

Cells begin to die within two to three minutes after a clot closes off a blood vessel of the brain or the heart. This is because the cells are not receiving enough oxygen. The longer a heart attack or a stroke goes untreated, the more devastating the consequences. Naked mole-rats do not have this problem. Their hearts continue to function normally even if they must do without oxygen for quite a while. These animals fall into a kind of suspended animation, a state from which they emerge – after as much as 18 minutes – without injury. Researchers from the MDC, the University of Illinois at Chicago, and the University of Pretoria in South Africa as well as from other cooperation partners wanted to find out how naked mole-rats are able to survive such conditions, and for good reason: it would save a lot of lives if physicians were able to replicate this process in humans. The scientists also hope this research might lead to a better way to preserve organs for transplants.

Do naked mole-rats ever experience oxygen deprivation in the wild?

They experience it on a daily basis. Naked mole-rats are very social animals that live in kilometer-long subterranean tunnel systems under the desert in eastern Africa. Their colonies number up to 300 individuals. If one goes to sleep, they all go to sleep – in a tightly-packed heap. Since the air is very stuffy in the underground burrows, it is usual for naked moles-rats that get stuck in the middle to receive little or no oxygen. These animals need somewhat longer to wake up, but after doing so they return to normal activity. Over the last 30 million years, naked mole rats have adapted themselves perfectly to the extreme living conditions of the underground burrows – with a DNA that is 94 percent identical to that of mice. They haven’t invented anything new but have instead expanded on and perfected existing mechanisms. The results are astounding – from exceptionally long life spans to an extremely high pain tolerance to the ability to ward off cancer and tolerate oxygen deprivation.

What experiments were conducted in Berlin?

The study, which was published in the journal Science in spring 2017, is a collaboration between laboratories in Chicago, Berlin, Pretoria, and Cambridge. The experiments to determine how long naked mole-rats – in comparison to mice – can survive with little or no oxygen took place at the University of Illinois at Chicago. The researchers there used as few animals as possible in each experiment. In addition, the atmospheric chambers contained nitrogen and not a gas like carbon dioxide. Nitrogen is not detectable by animals and doesn’t cause them to panic. They instead fall into a coma-like state within seconds – a state from which naked mole-rats usually emerge without any damage.

None of the experiments for this study were performed in Berlin on living animals. The research team at the MDC identified the molecular mechanisms underlying the naked mole-rats’ survival skills. To do this, from 2010 to 2017 they put 14 naked mole-rats and 16 mice to death and removed the animals’ organs in order to analyze the metabolism in the tissue. Here too, each experiment was meticulously planned in accordance with the 3Rs principle – so as to use as few animals as possible and to cause them as little suffering as possible. The experiments were approved by the Berlin State Office for Health and Social Affairs (LaGeSo) after an extensive application procedure. LaGeSo also rigorously monitored the experiments.

What discoveries did the researchers make?

They found that the naked mole-rats have a back-up system to carry out metabolism without oxygen – a system previously unknown among mammals. When the oxygen levels are too low to process glucose, a normal source of energy, the animals switch to metabolizing fructose. This supplies energy to cells in vital organs such as the heart and the brain that are highly sensitive to reduced oxygen levels.

In the MDC’s Metabolomics Unit, the research team first analyzed 86 different metabolism products (metabolites) in the blood and tissue samples and found high levels of fructose and especially sucrose in the blood of oxygen-deprived naked mole-rats. A special transporter molecule draws the fructose from the blood into cells. The researchers hypothesized that the survival of the naked mole-rat was due to a metabolic switch from glucose to fructose, which maintained the animal’s energy supply and prevented damage when oxygen went missing. They tested the assumption by supplying the brains and hearts of naked mole-rats and mice with a solution containing fructose as its sole sugar. The organs of the naked mole-rats performed much better than those of mice. Even after one hour, synapses continued to transmit signals. The naked mole-rat’s heart continued to beat normally, performing just as well with fructose as with glucose.

How do the researchers plan to use this discovery to develop new therapies?

Using another source of energy to survive oxygen deprivation is not the only trick up the naked mole-rat’s sleeve. The animal can also shut down its cellular energy factories, called mitochondria, within seconds. Humans and mice do not have this ability; their mitochondria keep running without oxygen. This damages the machinery of the organelle. Naked mole-rat researchers are still looking for a way to prevent this from happening. If they are successful, there is a good chance of discovering a new drug that diminishes the consequences of heart attacks and strokes.

Initial plans include a collaboration between aerospace medicine specialists at the German Aerospace Center (DLR) and the MDC research team on a study investigating whether pilots and extreme divers also experience a metabolic switch from glucose to fructose in some tissues when deprived of oxygen temporarily.

How was the research on naked mole-rats funded?

In addition to funding from the MDC, the European Research Council awarded Gary Lewin an ERC Advanced Grant worth 2.5 million euros. The money was earmarked for research into naked mole-rat physiology.

Lewin received a second ERC Advanced Grant in 2018. The new ERC grant supports a second focus of his laboratory: Lewin and his research team are attempting to understand how the sense of touch works and how neurons perceive mechanical stimuli. It is already known that when skin is touched, an electric signal is generated in the ionic channels of the neuronal membrane. Similar to ships moored in a harbor, ion channel proteins are attached to the surrounding connective tissues and can thus feel the “swell of the waves” in their periphery. But it is still unknown what the molecular tethers are made of.

The research project aims to identify ion channel anchors and characterize them at the molecular level. The scientists also want to find out how these anchors can be untethered in a targeted and reversible way. Neuropathies are associated with ion channel defects; people affected by these disorders experience even the slightest touch as very painful. Through mouse and human studies, the researchers hope to lay the groundwork for therapies that address tactile disorders.

How realistic is the prospect of patients benefiting from basic research?

One must be patient. Gary Lewin, for example, worked with rats in the 1990s during his postdoc. The animals developed chronic pain after receiving nerve growth factor (NGF), but it was possible to stop the pain with an antibody. In 2018, Pfizer and Eli Lilly tested the antibody, called tanezumab, in large-scale phase III clinical trials involving some 7,000 patients with osteoarthritis , back pain, and cancer pain. The chances of tanezumab winning approval are good, because it showed strong signs of effectiveness in patients. It would be the first pain drug in 50 years based on a new mechanism, and one that also causes hardly any side effects. Gary Lewin will not earn any proceeds from the drug – he never filed a patent application.