Itongadol.-It is hiding in underground darkness and looks like a hairy sausage, and an agricultural pest. But biologists Aaron Avivi, Imad Shams and Irena Manov from the Institute of Evolution at Haifa University in Israel, believe that the Israeli blind mole-rat may save millions of human lives. Will this project get the support from the scientific community and philanthropists to fulfill its promise?
Most of us have never seen these strange creatures that spend their entire lives in underground trenches. In Israel, those who like hiking in nature or living in suburban houses surrounded by a small garden are reminded of the existence of the blind mole-rat (BMR) during the winter, when lines of fresh, loose mounds of earth appear overnight after a rainfall.
The lines of small earth mounds consist of 2-4 kg of dirt that the little Israeli blind mole rat, which weighs 100-200 grams and is 15 cm long, pushes when it builds its underground architectonic tunnel system that collapses during a typical Israeli rain season. These above ground “footprints” are the reflection of the blind mole rat’s (BMR) tremendous potential for biomedical studies and may point the way to a cure for some human diseases.
A matter of oxygen
Because the mole rat lives its entire life underground, it has adapted to this challenging habitat. In particular, it has the ability to survive abrupt and sharp changes in oxygen supply. Most of us live in 21 percent oxygen. Those who are fortunate enough to ski in the Rocky Mountains might be surprised when their hotel supplies them with a pack of Headache pills to go along with coffee and tea packets. However, they soon discover that even at an altitude of only 4500 meters, with the relatively small decline in available oxygen, they often need these pills to relieve a headache, which is the first sign of suffering from lack of oxygen, namely hypoxia. In contrast, BMRs can survive for at least 8-14 hours even with only 3 percent oxygen, which is one third of the available oxygen on the top of Mount Everest. Rats, which are an above ground distant evolutionary relative of BMR, and of similar weight, would die after an hour or two in 3 percent oxygen.
Hypoxia is a phenomenon that is directly connected to the most lethal ailments humans face in the developed world, namely heart and lung disease, brain strokes and cancer. As a hypoxia-tolerant mammal, BMR does not suffer from these clinical conditions. According to professor Avivi:
“Actually, this creature can live for over 20 years, which is five times longer than its above ground relative, the rat, and shows no signs of aging and rarely suffers from any diseases. A twenty year old BMR is as strong and vivacious as a two-year-old, its muscle mass is also similar and its skin is as flexible and elastic as young family members. We hypothesized that if we succeeded in figuring out the mechanisms that endow it with a tolerance to a lack of oxygen and resistance to various diseases, we might understand better diseases in humans and hopefully find help and cure for people suffering from them.”
A “clinical goldmine”
In studying the hypoxia-tolerance of BMRs, the researchers noticed differences in structure and function in a long and growing list of genes when compared to rats and mice. Among these genes, there were quite a number that are major players in cancer initiation and development, as well as genes that contribute to the metastatic activity and capability of the original tumor, which is the worst and most horrible phenomenon of this deadly disease. Further studies using the state-of-the-art genomics that can reveal the pattern of expression of the whole repertoire of genes in a given tissue demonstrated that there are differences in expression profiles between BMRs and rats, exposed or not to hypoxia in molecular and biochemical pathways connecting hypoxia with cancer.
The team added to these observations the fact that since the founder of BMR research, Professor Eviatar Nevo, had started his interdisciplinary studies 40 years ago, no individual BMT among many thousands showed any signs of any spontaneous tumors. The scientists concluded that they might have a “clinical goldmine” in their hands
In a manuscript, just published in BMC Biology, Avivi, Shams and Manov, together with other colleagues, have tried to use this accumulated knowledge and take it to the next level. In their first experiment they decided to test if cancer can be induced in live BMRs. They took mice and rats and mole-rats—young ones, about 2 years of age, and old ones, more than 10 years old—and treated them with carcinogenic substances.
“The old BMRs were added because the older all of us are, the more susceptible to diseases we are,” said Avivi.
One carcinogen induced soft-tissues sarcoma. After two to three months, all of the mice developed the expected cancer. After four to six months, all of the rats did too. But nothing was observed in the BMRs! Nevertheless, they decided to follow them and see if something happened. After a year and a half, lumps were found in two of the BMR individuals, but the pathological analysis proved that they were not cancerous; they were abscesses, which are unresolved inflammatory reactions. After 22 months, we found one more treated old mole-rat with a lump, but this time it was cancerous. The scientists were then able to compare the expected tumors from mice and rats and the extremely delayed tumor from the mole-rat.
“First of all, I do not believe that any mammal is completely immune from cancer,” explained Avivi. “Such a declaration would be hasty in my opinion. Further, difference in time length and incidence in the development of cancerous cells in BMRs compared to mice and rats, might indicate different mechanisms employed by the extremely high cancer resistance of BMR.”
Another carcinogen induced skin carcinoma, which involves different cell types than sarcoma. Both mice and BMRs developed a necrotic wound after about 10 days.
“The wound in the mole-rats,” Avivi said, “seemed to be so serious. “I was sure that they were going to die just from its deterioration.”
However, in a week or two the treated BMR animals developed a scar, and then their skin completely healed. It took 3-4 months and all the mice developed the expected skin cancer. This demonstration by the Israeli researchers is the first time that scientists ever have showed a species that is highly resistant not only to spontaneously occurring cancer but also to chemical carcinogens.
The Israeli team then propagated healthy cells—fibroblasts type, from blind mole-rats, rats and mice—and added another wild, above ground short-lived rodent, the spiny mouse, and another subterranean, long-lived and cancer-resistance rodent, the naked mole-rat.
“We added the spiny mice, which is cancer-sensitive, as we wanted to avoid devil advocates from saying, what I tend to accept our controls are inbred, almost “artificial”, laboratory animals,” Avivi explained. “And we added the naked-mole rat to test how these two evolutionary distinct, though subterranean rodents known to be cancer-resistant will behave.”