by Kate Wheeling
BU News Service

Sloths are known for their slow-paced lifestyles. Their sedentary habits allow sloths to pick up a wide variety of microscopic passengers that settle down in the cracks that crisscross their coarse, spongy hair.

A vast fungal community thrives in this shaggy, green-algae glazed coat, churning out bioactive compounds that could one day serve as the basis for new drugs, according to a new study published January 15^th in PLoS ONE. The study’s authors identified over 80 distinct fungal species from sloth hair samples, many of which proved to have anti-parasitic, anti-bacterial and even anti-cancer activity.

“The structure of sloth hair itself is ideal,” says Higginbotham. The crazed hairs absorb water like a sponge, creating a warm damp environment where myriad microorganisms cohabitate in a fast-paced community that drives up competition for space and thus the production of bioactive compounds.

“It’s a pretty clever study,” says Nicholas Oberlies, professor of chemistry and biochemistry at the University of North Carolina at Greensboro. It’s a new niche for scientists to explore in their search for new bioactive compounds.

The researchers took hair samples from nine living three-toed sloths living in Soberanía National Park, Panama in February 2011. Higginbotham and her colleagues at the Smithsonian Tropical Research Institute, UC Santa Cruz, and the University of Arizona, chopped up the hair samples, placed them on agar plates and collected anything that would grow—an important step in drug development research; if it doesn’t grow in the lab, it can’t be used to make drugs. They identified 84 fungal species, three of which were previously unidentified.

The authors used concentrated samples of the fungi, to test for bioactivity against parasitic diseases, cancer cells, and pathogenic bacteria. The crude fungal extracts were considered highly bioactive if they inhibited 50% of the growth of the pathogens and cancer cells they were tested against. They found two fungi that were highly bioactive against the malaria parasite, eight active against the parasite that causes Chagas disease, and a full 15 fungal species that produced compounds active against the breast cancer cell line MCF-7. Another 20 fungi had antibacterial properties. At least one killed off Gram-negative bacteria in a way that didn’t match up with any known antibiotics, suggesting a completely new mode of action—a valuable attribute for potential drugs.

This is just the first step towards the identification of bioactive compounds suitable for drug development. Future studies will need to look at purer, more concentrated samples of the bioactive fungi identified, rule out anything with less than 90% inhibition rates, and tweak growing conditions in the lab so that they’re closer to nature. In the lab, under ideal conditions, fungi might quit producing the same bioactive compounds they need to compete out in the wild.

“It’s quite likely that what they produce in the lab is only a snapshot of what they produce in the wild,” says Higginbotham.

Higginbotham and her co-authors demonstrate that there are still plenty of places to look for new antimicrobials, but in order to tap into those resources we have to preserve them. Some species of sloth, like the pygmy three-toed sloth, are critically endangered. Studies like this demonstrate why “it’s more valuable to have that rainforest as a rainforest than it is to turn it into some sort of turpentine plantation,” says Oberlies. “The conservation aspect transcends the science.”

By Sara Knight
BU News Service

You eat right, you exercise, you meditate daily. You had an ideal childhood with loving parents and a healthy social life. Cigarettes and alcohol? Never! And yet despite your textbook health precautions and lack of turmoil, you find yourself diagnosed with a serious mood disorder. Why? The answer may lie with the type of childhood one of your grandparents experienced – maybe your maternal grandfather was neglected as a boy and experienced social isolation from his peers. This obviously extreme illustration may be overly simplistic, but current research hints that this story may not be all that ridiculous or fictional. In mice, researchers have found evidence of grandparents’ distress manifest in the genetic code of their grandpups.

Developing a psychiatric illness may not rely so much on the genes you inherit, but rather the accessories that accompany them. Evidence is mounting that chemical changes on genes actually contribute to certain mental illnesses, not the presence or absence of a gene itself. These alterations, called epigenetic markers, influence how lively or inertly a gene acts and result directly from environmental factors. Intriguingly the evidence that these changes are heritable is also mounting, meaning for example your grandfather’s lifestyle could affect your likelihood of suffering schizophrenia. Because the changes are simple chemical reactions they may be also reversible – a fact that excites many doctors frustrated by the trial-and-error style of most psychiatric medications.

The backbone of this research is a fusion of developmental biology and genetics called epigenetics, epi- meaning “above” in Latin. Developmental biologist Conrad Hal Waddington coined the term in the early twentieth century to describe, for example, how a blood cell is able to “know” how to function as an oxygen carrier rather than a liver cell, despite containing the same instruction manual (DNA) as the cells within the liver. ‘Epigenetics’ refers to molecular “light switches” that act on DNA, telling which genes to turn on and which to turn off.

These switches consist of different molecular markers attached to your DNA. Methylation, or the addition of a methyl group to a segment of DNA, effectively tells a gene to stop interacting or to increase its output within a cell. The changes can also tighten or loosen the coil around your DNA – the looser the coil the more likely the DNA will interact with other chemicals, causing increased expression.

Environmental stressors, diet, and exposure to chemicals all affect the changes to your DNA that can lead to altered expression. This means that your environment leaves a physical imprint on your genes and subsequently affects how your DNA is expressed. Epigenetics silences the old nature versus nurture “debate” – our genetic material (nature) is honed by our environment (nurture); there is no actual discrepancy between the two.

Doctors have used epigenetics to examine differences between cancerous cells and their healthy counterparts, but now some epigenetics researchers are setting out to tackle the notoriously complex problems presented by mental illness. Diseases like schizophrenia, depression, and bipolar disorder possess a genetic component – they run in families but there has been no conclusive “smoking gene” to predict who will develop the conditions. Mental illness and childhood trauma correlate; leading researchers to hypothesize early stress may trigger alterations on genes important in mental illness.

Researchers found mice that were traumatized in early life had grandpups with DNA that was more heavily methylated – indicating the trauma’s physical alterations on their genes could be passed down their familial line. In 2010 Isabelle Mansuy, a neurobiologist at the University of Zurich, randomly separated mice pups from their moms for a period of 14 days immediately after their birth. After that stressful period, she raised the pups normally. Mansuy found the pups that suffered early trauma had epigenetic modifications on genes related to emotional regulation and stress response. The genes were more heavily methylated. This reflected in the behavior of the mice – they had a higher incidence of the mousey version of depression and anxiety, namely increased stress and lowered grooming and social behavior.

Most intriguingly Mansuy’s male mice seemingly passed on their early ordeal’s genetic legacy through their sperm – their pups also showed the same methylated DNA despite a lack of early trauma. Dr. Tracy L. Bale of the University of Pennsylvania has found that the genetic effects of early stress can be seen in up to three generations of mice, even if the subsequent two generations are raised without stress or separation. Bale also has isolated key developmental windows in which mice are particularly vulnerable to modification.

Were the mice born with genes “marked” for depression and anxiety, or were they simply born more sensitive to environmental stressors? The research community has not reached a consensus, but Bale found the telltale methylation in the mouse sperm, indicating it is a physical transmission. Not all researchers are convinced though, especially when humans are involved.

These molecular light switches are fused onto our DNA through simple chemical reactions, leading many researchers hopeful about potential treatment options. Medications could potentially reverse these modifications and change how a gene functions, as happens in several cancer medications currently on the market. Understanding the underlying causes of mental illness could lead to an increased ability for doctors to intervene before symptoms hit. “The implications are huge from a social public health standpoint,” says neuroscientist David Dietz of the University of Buffalo. He believes that being able to identify and treat vulnerable populations means the next generation “may not be in such a doomed state.”

Though most of the hard evidence for generational transmission has been found in mice, researchers have collected retrospective data on humans that hints the same may be true for us. Researchers Alan S. Brown and Ezra Susser, both of Columbia University, linked prenatal malnourishment to an increased incidence of schizophrenia in children conceived during the Dutch famine of 1944. Humans, however, have lengthier lifespans and less motivation to faithfully participate in multi-generational studies compared to mice, so researchers have a much harder time gathering convincing data. Most human epigenetic studies concerning mental illness are ongoing and the evidence is anecdotal.

Neuroscientists studying epigenetics are still in the first phase of discovery – techniques need refining before any grand statements can be made. Researchers like Johns Hopkins researcher Zachary Kaminsky is working towards developing cleaner research techniques by cataloguing different kinds of genetic markers that may indicate the sort of genetic changes found in mental illness.