A tiny primate may join the ranks of the world’s model organisms
Dec 8th 2021TREE 2B, RANOMAFANA, is not an address recognised by Madagascar’s postal service. It is, though, someone’s home. The someone is question is a mouse lemur called Judah, the 349th participant to be enrolled into a project run by Mark Krasnow, a biochemist at Stanford University, in California.Judah’s involuntary membership of the project began when he found himself trapped inside a metal box. He had been lured there by a bait of banana put there by Dr Krasnow’s collaborators, Haja Ravelonjanahary and Mahery Razafindrakoto of the ValBio research centre on the edge of Ranomafana National Park, 260km south of Antananarivo. Judah’s captivity was temporary, for he was released back into his home at 2B about six hours later. But in the interim he was subjected to various indignities. He had his testes measured, a blood sample taken and he was made to do exercises to see how strong he was. He also had a tiny transponder inserted under his skin so that he could be identified next time he was caught. Judah, and his 348 predecessors similarly trapped and released by biologists at ValBio, are among the first recruits to what is, on the face of it, an extraordinarily ambitious undertaking. For Dr Krasnow’s plan is to add mouse lemurs to the short and rather random list of so-called model organisms. These are species which, for various reasons, biologists know a lot about. And, since knowledge breeds knowledge, they tend to be the ones about which further knowledge accumulates.The recruiting sergeant callsModel organisms assist all sorts of biological research, but a lot of it is medical. And here there is a problem. Ideally, medical research would be done on species that resemble Homo sapiens. But working on human beings’ closest relatives—apes and monkeys—is increasingly hard to do. First, such large animals are expensive to keep. Second, that expense means they are often unavailable in the numbers needed for statistically significant work. Third, public opinion, at least in the West, is swinging against their use.Mice, one common alternative to primates, are cheap, abundant and less prone to stir consciences. But they can only take you so far. Though mammals, they are not close relatives of people. Sometimes that lack of relatedness can be finessed by inserting human genes that are relevant to the matter under investigation. But even then, the underlying platform is still a rodent, not a primate. By contrast, a mouse lemur, though it looks and behaves a bit like a mouse, and is not much bigger, is indeed a primate, and so is much more similar to a human being than a rodent is. Mice, moreover, have short lives, and thus high turnover. But mouse lemurs can live for 14 years in captivity and maybe ten in the wild. That is a nice compromise between a period brief enough to arrive at conclusions that are useful (and will result in career-enhancing research papers), and long enough to be more similar to a human being’s life-history. Yet, like mice, mouse lemurs breed prolifically and quickly, with a gestation period of just two months and maturity achieved within six to eight months. And not just in a laboratory. In Madagascar there are millions of them—for, contrary to common perception, not all lemur species are endangered. What is particularly intriguing for Dr Krasnow and his colleagues, though, is that, in captivity at least, mouse lemurs suffer several illnesses which affect humans too. These include Alzheimer’s and other neurodegenerative disorders, cardiac arrhythmias, metastatic uterine cancer, strokes and atherosclerosis, the furring of the arteries that can lead to a heart attack. Model organisms tend to happen by accident. Yeast is used by brewers and bakers, so is an obvious topic for study. Fruit flies were picked by Thomas Morgan, an early geneticist, because they are easy to breed in large numbers—and it helped that some of their cells have giant chromosomes which showed up well under the microscopes of the day. And mice were kept as pets by fanciers long before one saw the inside of a laboratory cage. Dr Krasnow’s plan to add mouse lemurs to the list was slightly less accidental than these. It began in 2009, when he charged his daughter Maya, then still at school, and two of her friends to come up with a new model organism for studying primates as a summer project in his laboratory. After reviewing the gamut of the primate order, which contains about 500 species, and also looking at a few outliers such as tree shrews, Krasnow junior and her two compadres settled on mouse lemurs. Not only are these abundant and fast-breeding, they also do well in captivity, as a 60-year-old colony of them in France testifies.Not one to ignore his daughter’s advice, Dr Krasnow investigated in more detail. In 2011, he organised a workshop of lemur biologists at the Howard Hughes Medical Institute, in Virginia, to kick the idea around. It found favour, and in particular it accelerated the completion of a genome-sequencing project for the animals—a sine qua non for any self-respecting model organism. It also introduced Dr Krasnow to the idea that fieldwork might be an important part of his proposal.That, in some ways, is the most intriguing idea of the lot. Most biologists working with model organisms make a fetish of control. Mice, in particular, are often bred deliberately to be as genetically similar to one another as possible, within a given line. Dr Krasnow has the opposite plan. Genetic analysis is now so cheap that every animal involved in a project can be sequenced. Made visible in this way, diversity is as much an opportunity as a problem, for that information can be correlated not only with obvious, medically relevant stuff, such as disease manifestation, but also with behaviour—and behaviour expressed in the wild, not just in the restricted environment of a laboratory.That insight led to collaboration with Patricia Wright, a primatologist at the State University of New York, Stony Brook, who helped encourage the Malagasy government to found Ranomafana, and who has been working there for decades. And that led to the lemur-trapping project now joined by Judah. One early discovery from the genetic analyses made possible by this project (admittedly, one that is not of much obvious medical use) is that what appeared to be one species of brown mouse lemur, the species Dr Krasnow and Dr Wright thought they were investigating, is actually two. They live in the same range and are indistinguishable to the human eye. But they can clearly tell each other apart because their genetics show that they diverged several million years ago, and do not interbreed.Dr Krasnow does, however, have high hopes of the medical side. In particular, as they age, mouse lemurs in captivity sometimes develop the plaques and tangles of abnormal protein seen in human Alzheimer’s patients. At the same time, they develop behavioural abnormalities, such as forgetfulness. Nothing similar happens naturally in mice. Nor do mice develop the sorts of heart arrhythmias seen in people. But mouse lemurs do. In fact, he and his colleagues have now identified nine types of arrhythmia in their lemurs, each of which corresponds to one found in people.Though the animals will not be subjected to invasive sampling while alive, the ability to identify them individually in the wild means that their behaviour can be studied, to see if it changes as they age in ways similar to ageing in people. What else might be discovered from this behavioural work remains to be seen, for this is an old-fashioned experiment of the sort that is not testing a specific hypothesis but, rather, searching for leads to pursue. Meanwhile, back in the lab, and thanks to a technique called single-cell rna expression profiling, Dr Krasnow and his Stanford colleague Stephen Quake have built a near-complete atlas of lemur cell types—about 750 in all. This permits a whole new level of investigation. For example, they were able to identify a metastatic cell in the lung of an animal that had had to be put down because it had cancer, as deriving from that animal’s uterus.Taking the shillingIt could all fall flat on its face, of course. For one thing, the field data may shed no light on disease-relevant biology after all. Most of the illnesses that Dr Krasnow is interested in manifest themselves in later life. In humans, such diseases are associated with behaviours which evolution did not foresee, such as consuming processed food or sitting at a desk all day. Since being locked up in a cage and fed a reliable supply of food is equally unnatural, that may also be true for lemurs. It is therefore by no means clear that looking at wild lemurs will add anything. Moreover, illnesses like Alzheimer’s are not exactly life-elongating. In the wild, any individual manifesting them would probably get short shrift from natural selection. Indeed, there is a whole body of theory which suggests the very reason they manifest only in old age is because, in a state of nature, a human being would probably have died or been killed before they had had a chance to appear.There is also the political side of things. Though researchers on other species are unlikely to be hostile in principle to mouse lemurs joining the model-animal-research party, whether they will co-operate with the group of newcomers in the far corner who are talking animatedly about the critters remains to be seen. Model animals do, however, require a consensus that that is what they are—and this consensus is best built by lots of people studying lots of different aspects of them. So if not enough people join the mouse-lemur clique, the project will be doomed.Another potential threat is that, although mouse lemurs do not truly share the mini-me human lookalikeness of monkeys and apes, they are still pretty cute. Those opposed to animal experiments of any sort—even the carefully non-invasive work being done by Dr Krasnow and Dr Wright—could probably make something of that. And the very similarity of physiology to humans that makes the lemurs an attractive subject of study might also be used to argue that they should not be used in research.Still, it is a bold idea, and certainly worth pursuing. Perhaps the cross-fertilisation of laboratory and field studies in this way will, indeed, turn out to be the wave of the future. In army terms, mouse lemurs are now at boot camp, undergoing basic training. Whether they will pass muster remains to be seen.