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BiologyAdvancedUnit 5: Energy, Exercise and Coordination

June 2013

Scientific Article for use with Question 7 6BI05/01R

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Scientific article for use with Question 7

Naked and ugly: The new face of lab rats

1. In a small room in the lab-animal wing o the University o Illinois at Chicago, biologist ThomasPark peers into a plastic box ull o naked mole rats. You guys are so cute, he says sotly, in a voice

usually reserved or babies or puppies.

2. Park is mistaken. Naked mole rats are not cute. They are bald, wrinkled and purply pink, with tinynear-blind eyes and huge yellow teeth. Ranging rom the size o a large mouse to that o a smallrat, these odd rodents are among the strangest looking mammals on the planet. But dont judge anaked mole rat by its unortunate appearance. These bizarre creatures could help us tackle all sortso human maladies, rom cancer and stroke to pain relie and ageing.

3. A dozen species o mole rat exist, all native to sub-Saharan Arica. Naked mole rats stand out,though, not least because they appear completely bald. They are also extremely social, livingunderground in elaborate networks o tunnels and chambers in groups o up to 300. Here in thelab, Park mimics their burrow system by connecting several dozen plastic boxes with long tubes.

The animals spend their days pushing bedding around the tubes and nibbling on bits o sweetpotato.

4. Naked mole rats are a really odd mammal species, Park tells me. Their social structure is like thato insects. Akin to bees and ants, they live in a eusocial society in which a single breeding queen

churns out all the ospring, with help rom between one and three kings. The rest o the animalswork or a living: soldiers deend the colony against predators and rivals, while housekeepers orageor root vegetables and tidy up the tunnels.

5. Many eatures o the skin o the naked mole-rat, such as the lack o an insulating layer and theloosely olded morphological arrangement contribute to poikilothermic responses to changingtemperatures o this mammal. Further evidence or poikilothermy in the naked mole-rat isindicated by the presence o pigment containing cells in the dermis, rather than the epidermis, ascommonly occurs in homeotherms. Lack o ur is compensated by a thicker epidermal layer and amarked reduction in sweat glands.

Naked Mole Rat

Magnifcation0.3


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6. This unusual social arrangement is what irst drew scientists to study the wrinkled rodents. Formany years, most o the studies were on their behaviour, says Rochelle Buenstein, a physiologistat the University o Texas Health Science Center in San Antonio. In time, though, researcherscouldnt help but notice another intriguing aspects o naked mole rat biology. They are incrediblylong-lived creatures, she says.

7. In general, liespan tends to correlate with body size. Large animals, on average, live longer thansmall ones. However, while mice and rats are lucky to survive three years in captivity, similar-sizednaked mole rats live three decades, making them the longest-lived rodents on Earth. Thats not all.

They also maintain excellent health well into their sunset years. Their bones remain strong, theirbodies stay it and they dont show signs o heart disease or mental decline. Breeding emalescontinue to produce pups right up to the end and, to top it o, naked mole rats dont even getcancer.

8. Naturally, scientists are eager to understand the secrets o this small, bald Methuselah. Buenstein,who has been studying naked mole rats or 30 years, is among those looking or molecularexplanations or their astounding longevity. She began by investigating their response to oxidativestress, one o the leading theories o how the ageing process works.

9. According to this theory, oxygen-containing ree radicals damage the molecules o the body, causingthem to deteriorate over time until they stop unctioning altogether. This oxidative damage, as itis known, is apparent as extra molecules that attach to DNA and proteins like chewing gum stuckto the bottom o a shoe, Buenstein says. I oxidative stress is truly an important mechanism oageing, she predicted, naked mole rats should have lower rates o oxidative damage than moreshort-lived species.

10. To her surprise, Buenstein ound the opposite: more telltale oxidative damage in 6-month-oldsthan in mice o the same age. Remarkably, however, the damage had no obvious impact on theirwell-being.

Keeping in shape

11. Why is this? To ind out, Buenstein took a closer look at the 3D structure o proteins, which iscritical to their unctioning. Mouse proteins begin misolding very quickly ater suering oxidativedamage a kind o anti-origami that causes them to stop working properly. But naked mole ratproteins can withstand signiicantly more damage beore they lose their shape (Proceedings of theNational Academy of Sciences, vol 106, p 3059). We think [protein stability] is a very importantcomponent o their extraordinary longevity, she says. I your proteins maintain their integrity, ithey have the mechanisms to protect themselves, it doesnt matter what stress comes along.

12. Another actor that helps naked mole rats reach an advanced age is their remarkable ability to avoidcancer. Nearly all mice have cancerous cells lurking in their bodies by the time they die but cancerhas never been seen in a naked mole rat. Every time one o our animals die, we try to igure outwhat they die o, Buenstein says. We havent seen a tumour, we havent seen lesions, we haventseen signs o lymphoma. We know they dont get age-related cancer.

13. To understand why, Buenstein and her colleague Peter Hornsby introduced cancer-causing genesinto cells rom rats, mice, humans and naked mole rats. They then inserted the altered cells intoimmune-compromised mice. In two to our weeks, the mice injected with modiied cells rom rats,mice and humans developed highly invasive tumours. In the case o naked mole rats, six monthslapsed and there were still no tumours, Buenstein says.


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14. The abnormal cells were still alive but had stopped replicating. We think mole rats have bettersurveillance mechanisms to assess whats going on in their DNA, she says. When things go awry,the deviant cells are essentially locked away, unable to replicate and cause tumours (Aging Cell,vol 9, p 626).

15. This is probably just one o several tricks that allow these animals to avoid cancer. Another possible

mechanism being investigated centres on how cells multiply. When cultured in a Petri dish, cellsrom both mice and humans multiply until they orm a single dense layer. At that point, they stopdividing, halted by a process called contact inhibition. In cancerous tissues, however, the abnormalcells continue to multiply, piling up and growing out o control.

16. We think weve ound the reason these mole rats dont get cancer, and its a bit o a surprise, saysVera Gorbunova, associate proessor o biology at the University o Rochester and lead investigatoron the discovery.

17. Naked mole rats can live up to 30 years, which is exceptionally long or a small rodent. Despitelarge numbers o naked mole-rats under observation, there has never been a single recorded caseo a mole rat contracting cancer, says Gorbunova. Adding to their mystery is the act that mole rats

appear to age very little until the very end o their lives.

18. Over the last three years, Gorbunova and Andrei Seluanov, research proessor o biology atthe University o Rochester, have worked an unusual angle on the quest to understand cancer:Investigating rodents rom across the globe to get an idea o the similarities and dierences o howvaried but closely related species deal with cancer.

19. In 2006, Gorbunova discovered that telomerase an enzyme that can lengthen the lives o cells, butcan also increase the rate o cancer is highly active in small rodents, but not in large ones.

20. Until Gorbunova and Seluanovs research, the prevailing wisdom had assumed that an animal thatlived as long as we humans do needed to suppress telomerase activity to guard against cancer.

Telomerase helps cells reproduce, and cancer is essentially runaway cellular reproduction, so ananimal living or 70 years has a lot o chances or its cells to mutate into cancer, says Gorbunova. Amouses lie expectancy is shortened by other actors in nature, such as predation, so it was thoughtthe mouse could aord the slim cancer risk to beneit rom telomerases ability to speed healing.

21. While the indings were a surprise, they revealed another question: What about small animals likethe common grey squirrel that live or 24 years or more? With telomerase ully active over such along period, why isnt cancer rampant in these creatures?

22. Gorbunova sought to answer that question, and in 2008 conirmed that small-bodied rodentswith long liespans had evolved a previously unknown anti-cancer mechanism that appears to bedierent rom any anticancer mechanisms employed by humans or other large mammals.

23. At the time she was not able to identiy just what the mechanism might be, saying: We haventcome across this anticancer mechanism beore because it doesnt exist in the two species mostoten used or cancer research: mice and humans. Mice are short-lived and humans are large-bodied. But this mechanism appears to exist only in small, long-lived animals.

24. Now, Gorbunova believes she has ound the primary reason these small animals are staying cancer-ree, and it appears to be a kind o overcrowding early-warning gene that the naked mole ratexpresses in its cells.


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25. When Gorbunova and her team began speciically investigating mole rat cells, they were surprisedat how diicult it was to grow the cells in the lab or study. The cells simply reused to replicate oncea certain number o them occupied a space. Other cells, such as human cells, also cease replicationwhen their populations become too dense, but the mole rat cells were reaching their limit muchearlier than other animals cells.

26. Since cancer is basically runaway cell replication, we realized that whatever was doing this wasprobably the same thing that prevented cancer rom ever getting started in the mole rats, saysGorbunova.

27. Like many animals, including humans, the mole rats have a gene called p27that prevents cellularovercrowding, but the mole rats use another, earlier deense in gene p16. Cancer cells tend to indways aroundp27, but mole rats have a double barrier that a cell must overcome beore it can growuncontrollably.

28. We believe the additional layer o protection conerred by this two-tiered contact inhibitioncontributes to the remarkable tumor resistance o the naked mole rat, says Gorbunova in the PNASpaper.

29. Gorbunova and Seluanov are now planning to delve deeper into the mole rats genetics to see itheir cancer resistance might be applicable to humans.

30. This inding could be an important step towards new cancer therapies. Gorbunova and hercolleagues are now trying to decipher the extracellular signals that prompt early contact inhibition.In theory, such a signal might be co-opted to stimulate the process in human cells, and preventtumours rom orming. I this is some kind o extracellular molecule, then we could actually applyit to people as an injection or a drug, she says.

31. Exciting as that research may be, cancer and ageing are only the tip o the iceberg as ar as thenaked mole rats peculiar biology is concerned. The rodents neurobiology is also o interest, as Parkis discovering. Setting out to better understand their sense o touch, he stumbled across somethingsurprising: they lack a receptor that transmits messages about chemical pain. Inject lemon juiceor the essence o chilli pepper, capsaicin, beneath the skin o a mouses paw, and it will shake andlick it like crazy. I you do that with naked mole rats, they dont do anything, Park says. Theycouldnt care less. Naked mole rats do eel acute pain such as cuts and burns, he says, but they areimpervious to chemical pain (PLoS Biology, vol 6, p e13).

32. This inding is particularly signiicant because the nerve ibres associated with chemical pain arealso involved in post-traumatic pain in people precisely the type o discomort researchers wouldlike to eliminate. Its OK to have pain sensation to tell you to get your hand o the stove, or tostop exercising because your knee is in trouble, says Park. But post-surgical pain, or joint painater a knee injury, those types o pain we could do without. The naked mole rats are laying thegroundwork or potentially inding new ways to treat the kinds o pain we dont want.

33. Though the applications are intriguing, Parks own interests are more basic: why would nakedmole rats lack this type o pain? The answer, he suspected, stemmed rom their unusual habitat.Although many animals live underground, ew live in such close quarters and in such large numbersas naked mole rats. The air in their burrows is rank, with low oxygen levels and extremely high levelso carbon dioxide. While normal air is about 0.03 per cent CO

2, levels in naked mole rat burrows

can easily reach 5 per cent or more an intensity that would sting our eyes and noses and leave usgasping or air. The rodents, however, are unaected. They will stay away rom 10 per cent CO

2,

but theyre perectly happy to wallow around in 5 per cent, Park says. It turns out that high levelso CO

2aect the types o nerves that the naked mole rats have disconnected, he says. I think thats

the evolutionary driving orce to disconnect these pain nerves.


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34. This isnt the only eect the naked mole rats burrows have on their physiology. The low oxygenlevels are just as important. Fresh air contains about 21 per cent oxygen, whereas levels in theburrows can be as low as 12 per cent in captive colonies, and are probably much lower in the wild.Park has ound that naked mole rat brains are incredibly resistant to oxygen deprivation, with theirbrain tissue able to bounce back ater 30 minutes without the gas (NeuroReport, vol 20, p 1634).

35. Two University o Illinois at Chicago researchers report that adult naked mole rat brain tissue canwithstand extreme hypoxia, or oxygen deprivation, or periods exceeding a hal-hour muchlonger than brain tissue rom other mammals.

36. The indings may yield clues or better treatment o brain injuries associated with heart attack,stroke and accidents where the brain is starved o vital oxygen.

37. John Larson, associate proessor o physiology in psychiatry, and Thomas Park, proessor o biologicalsciences, studied Arican naked mole rats small rodents that live about six eet underground in bigcolonies o up to 300 members. The living is tight and the breathing even worse, with the limitedair supply low in oxygen.

38. But naked mole rats studied were ound to show systemic hypoxia adaptations, such as in the lungsand blood, as well as neuron adaptations that allow brain cells to unction at oxygen and carbondioxide levels that other mammals cannot tolerate.

39. In the most extreme cases, naked mole rat neurons maintain unction more than six times longerthan mouse neurons ater the onset o oxygen deprivation, said Larson.

40. We also ind it very intriguing that naked mole rat neurons exhibit some electrophysiologicalproperties that suggest that neurons in these animals retain immature characteristics.

41. All mammal etuses live in a low-oxygen environment in the womb, and human inants continue toshow brain resistance to oxygen deprivation or a brie time into early childhood. But naked molerats, unlike other mammals, retain this ability into adulthood.

42. We believe that the extreme resistance to oxygen deprivation is a result o evolutionary adaptationsor surviving in a chronically low-oxygen environment, said Park.

43. The trick now will be to learn how naked mole rats have been able to retain inant-like brainprotection rom low oxygen, so we can use this inormation to help people who experiencetemporary loss o oxygen to the brain in situations like heart attacks, stroke or drowning, he said.

44. Larson said study o the naked mole rats brain may yield clues or learning the mechanisms thatallow longer neuronal survival ater such accidents or medical emergencies, which may suggestways to avoid permanent human brain damage.


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Sociable by nature

45. Medical beneits may even arise rom continuing research into naked mole rat behaviour. Previousstudies in voles and other mammals have shown that behaviours such as monogamy and maternalperormance can be explained, in part, by genetic dierences that inluence the patterns o certainhormone receptors in the brain. To ind out whether naked mole rats sociability has a genetic

actor, Chris Faulkes at Queen Mary, University o London and colleagues compared their brainswith those o the solitary cape mole rat. They were looking or receptors that bind to the cuddlechemical oxytocin. The team ound that the naked mole rat has ar more o these receptors inseveral brain regions including the nucleus accumbens, an area known as the brains pleasurecentre, and assume this is under genetic control (Journal of Comparative Neurology, vol 518, p 1792).Its a good example o a change in a gene giving a change in complex behaviour, says Faulkes.Changes in the oxytocin receptor in humans are associated with certain kinds o autism, he adds,so the inding could have direct implications or humans.

46. The possibilities dont end there. Naked mole rats do not experience menopause or osteoporosis,so perhaps they could help researchers develop osteoporosis treatments without the side eectso hormone replacement therapy. And, as they spend 24 hours a day in the dark, naked mole rats

dont ollow normal circadian rhythms. Studies o their sleep patterns could easibly help treatdisordered sleep in humans.

47. Even their incisors are ascinating. Instead o staying put in their mouths, they grow right throughthe skin o the lips, something o great interest to prosthetics designers. Traditional prosthetics putpressure on delicate sot tissue causing sores and cell death, so a team led by Gordon Blunn andCatherine Pendegrass at University College London are testing new prosthetics that are attacheddirectly to the bone o an amputated limb. To avoid inection, however, there needs to be apermanent seal where the skin meets the metal implant. This is where naked mole rats come in.Understanding the interace between their teeth and skin may help in the development o newcoatings or structures that can be applied to the prosthetics.

48. Our current hypothesis is that behavioural interactions between the queen and non-breedersare translated into a suppression o gonadotrophin-releasing hormone in the hypothalamus,which in turn suppresses the release o gonadotrophins rom the anterior pituitary. This resultsin a suppression o ovulation in non-breeding emales, while in non-breeding males testosteroneconcentrations and sperm numbers are lower, and in most males sperm are non-motile. Not onlydoes the queen suppress reproductive unction in the non-breeders, but she also apparentlyexerts some control over the breeding male(s), such that concentrations o testosterone in thelatter are suppressed except around the time o ovulation in the queen. Despite these endocrinedeiciencies in non-breeders that may persist or many years, the block to reproduction is reversible.Non-breeding males and emales will rapidly become reproductively active i they are removedrom the suppressing inluences o their colony and housed singly or in male-emale pairs, or i thequeen in a colony dies.

49. Patterns o genetic structure in naked mole-rat populations were quantiied within and amonggeographically distant populations using DNA ingerprinting. Individuals within colonies weregenetically almost monomorphic, having coeicients o band sharing estimated rom DNAingerprints ranging rom 0.93 to 0.99.


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50. Prolonged inbreeding is usually associated with lowered itness, and it has been shown that mosthighly inbred small mammals have inbreeding-avoidance mechanisms that promote some degreeo outbreeding. Although rare, a dispersive morph exists within naked mole-rat colonies that mayoccasionally promote outbreeding. These dispersers are morphologically, physiologically andbehaviourally distinct rom other colony members. They are laden with at, exhibit elevated levelso luteinizing hormone, have a strong urge to disperse, and only solicit matings with non-colonymembers.

51. Kin recognition and emale mate choice using a series o choice tests in which the odour, social andmate preerences o emales were determined. Discrimination by emales appears to be dependenton their reproductive status.

52. Reproductively active emales preer to associate with unamiliar males, whereas reproductivelyinactive emales do not discriminate. Females do not discriminate between kin and non-kinsuggesting that the criterion or recognition is amiliarity, not detection o genetic similarity per se.In the wild, naked mole-rats occupy discrete burrow systems and dispersal and mixing with non-kin is thought to be comparatively rare. Thus, recognition by amiliarity may unction as a highlyeicient kin recognition mechanism in the naked mole-rat. A preerence by reproductively active

emales or unamiliar males is interpreted as inbreeding avoidance. These indings suggest that,despite an evolutionary history o close inbreeding, naked mole-rats may not be exempt rom theeects o inbreeding depression and will attempt to outbreed should the opportunity arise.

53. With so much to oer science, it is no surprise that naked mole rats are becoming more commonin labs. Unlike mice, the naked mole rat hasnt yet had its genome sequenced yet. With nakedmole-rats, we have to start rom scratch with many things, Gorbunova says. Its not very convenient,but I think its deinitely worth it.

Acknowledgements

Adapted text taken rom: Naked and ugly: The new ace o lab rats, Kirsten Weir, New ScientistMagazine, 23 October 2010, Issue 2783 Copyright Reed Business Inormation Ltd

Adapted text taken rom: University o Rochester (October 26 2009), Scientists Discover Gene ThatCancer-proos Naked Mole Rats Cells, ScienceDaily, retrieved 11 November 2011, romhttp://www.sciencedaily.com/releases/2009/10/091026152812.htm

Adapted text taken rom: A dispersive morph in the naked mole-rat, ORiain, MJ, Jarvis, JUM andFaulkes, CG, Nature 380, 619621 (18 April 1996); doi: 10.1038/380619a0, retrieved 11 November 2011rom: http://webspace.qmul.ac.uk/cgaulkes/abstract7.html

Adapted text taken rom: University o Illinois at Chicago (November 30 2009), Naked mole rats mayhold clues to surviving stroke, ScienceDaily, retrieved 11 November 2011, romhttp://www.sciencedaily.com/releases/2009/11/091130141313.htm

Adapted text taken rom: A Reproductive Dictatorship: The Lie and Times o the Arican NakedMole-Rat, http://webspace.qmul.ac.uk/cgaulkes/CGFNMR.htm

Adapted text taken rom: Micro- and macrogeographical genetic structure o colonies o nakedmole-rats Heterocephalus glaber, Faulkes, CG, Abbott, DH, OBrien, HP et al. (1997), Mol Ecolvol. 6, (7)615628, retrieved 11 November 2011, rom http://www.ncbi.nlm.nih.gov/pubmed/9226945


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Adapted text taken rom: Kin discrimination and emale mate choice in the naked mole-ratHeterocephalus glaber, Clarke, FM and Faulkes, CG (1999), Proc BiolScivol. 266, (1432) 19952002,10.1098/rspb.1999.0877

Adapted text taken rom: Skin morphology and its role in thermoregulation in mole-rats,Heterocephalus glaberand Cryptomys hottentotus, Daly TJ and Buenstein R (1998) J Anat. 193(Pt

4): 495502; doi: 10.1046/j.1469-7580.1998.19340495, retrieved 11 November 2011 rom PMCID:PMC1467874

Copyright 1998 Anatomical Society o Great Britain and Ireland

Every eort has been made to contact copyright holders to obtain their permission or the use o copyright

material. Edexcel, a product o Pearson Education Ltd. will, i notiied, be happy to rectiy any errors or omissions

and include any such rectiications in uture editions.


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June 2013 Scientific Article (International Only)