Sperm production in humans and other mammals is known as spermatogenesis.  In the past, scientists investigating potential male pills have disrupted spermatogenesis via hormone regulation, often by targeting testosterone levels.  The best of these treatments successfully lower sperm count, but also produce side effects because they alter hormone levels that are crucial for the health of many male tissues.  Recently, scientists have changed their approach to identify a marketable male pill: instead of looking for ways to alter hormone levels, they seek a drug that will bind and repress the activity of a protein located only in the testes and devoted solely to spermatogenesis.

Using this approach, Dr. Bradner’s team identified a protein called BRDT as a target because it is essential to spermatogenesis and is located only in the testes.  After studying an array of available drugs, they earmarked JQ1 as a likely inhibitor of BRDT and thus a strong candidate for the male pill.

JQ1 was originally identified as a treatment option for cancers including those of the breast, prostate and colon, among others^{3, 4}. Dr. Bradner’s team was the first research group that recognized JQ1’s potential to be a type of male birth control.  Experiments support their hypothesis: it does bind to BRDT in a manner that blocks sperm production. Dr. Bradner’s team found that mice treated daily with this drug over a period of six weeks have an 89% lower sperm count than untreated control mice.  The treated mice also have decreased sperm motility and testes mass. Significantly, their hormone levels, which are essential for normal health, are unaffected by JQ1-treatment.

Dr. Bradner’s team also performed an eight-month experiment with 14 male mice and 28 female mice to monitor fertility during a period of JQ1-treatment and after treatment ended. The male mice were divided into three treatment groups: the first group (three males) was given a low-dose, the second group (four males) was given a high-dose, and the third group (seven males) was not given the drug.  Each male mouse was caged with two females.  Encouragingly, Dr. Bradner’s team observed that the low-dose group sired a total of only two pups; male mice on the high-dose regimen sired no offspring; and each of the males not administered JQ1 produced litters of regular sizes (six to nine pups).  These data show that JQ1 is an effective contraceptive agent, especially at high-doses.

Importantly, male mice receiving a low-dose regain their fertility one month after treatment ends; male mice receiving a high-dose require two months in post-treatment to regain their fertility. Furthermore, female mice, impregnated by male mice that are far enough into post-treatment so as not to experience contraception, have normal litter sizes. The pups of these litters are healthy and grow to be fertile adults; they are indistinguishable from the offspring of control males.

Male mice treated with JQ1 do not incur permanent physical changes: sperm count, sperm motility, testes mass and fertility return to normal within weeks during post-treatment. However, the possibility of long-term effects has not been completely disproved, and the dose-level required to sustain infertility is unacceptably high.  These results spur Dr. Bradner’s team to continue studying the safety of JQ1.  Currently, they are modifying the drug for enhanced specificity towards BRDT and thereby a decreased dose-requirement to achieve infertility and an increased likelihood of efficacy in clinical trials with humans.

Scientists could jump the queue and gain early insights to JQ1’s contraceptive effect next year when it is scheduled to enter human clinical trials as an anti-cancer drug. In the meantime, stay tuned; a male pill could be unveiled in the near future.

1. Matzuk M.M., McKeown M.R., Filippakopoulos P., Li Q., Ma L., Agno J.E., Lemieux M.E., Picaud S., Yu R.N., Qi J., Knapp S., Bradner J.E. (2012). Small-molecule inhibition of BRDT for male contraception. Cell. 150, 673-684.

2. Kean S. (2012). Contraception research. Reinventing the pill: male birth control. Science. 338, 318-320.

3.Delmore J.E., Issa G.C., Lemieux M.E., Rahl P.B., Shi J., Jacobs H.M., Kastritis E., Gilpatrick T., Paranal R.M., Qi J., Chesi M., Schinzel A.C., Mckeown M.R., Heffernan T.P., Vakoc C.R., Bergsagel P.L., Ghobrial I.M., Richardson P.G., Young R.A., Hahn W.C., Anderson K.C., Kung A.L., Bradner J.E., Mitsiades C.S. (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146, 904-917.

4. Toyoshima M., Howie H.L., Imakura M., Walsh R.M., Annis J.E., Chang A.N., Frazier J., Chau B.N., Loboda A., Linsley P.S., Cleary M.A., Park J.R., Grandori C. (2012). Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci USA. 109, 9545-9550.

Dear Twyla Bella,

W. Eugene Smith’s 1946 black and white photograph, A Walk To Paradise Garden, entered the depths of my psyche when I was perhaps 13 years old. In that image, the photographer’s young children walk, hand in hand, from dark into the light at the edge of a forest canopy. Upon finding it, I was taken into a world of contrasts that emanated as much from the luminosity of that forest edge as from the horror of Smith’s earlier work.

In 1944 and 1945, on the Pacific islands of Iwo Jima, Saipan and Okinawa, Smith had been following American soldiers in battle against the Japanese. Snapping photos as they died. Snapping photos as they killed. Snapping photos as one soldier—framed by a jungle darkness and lightness that hinted of the image Smith would one day take of his own children—wearily stared from under the canopy of his helmet into a wounded, naked, baby who was dying in his hands while a second soldier—cigarette in mouth, legs spread forward into a stable stance, rifle at the ready held hip level—stared past the dying infant and straight at, I imagine, the photographer’s soul. Committed to bringing back the war to whoever was willing to see it for what it really was, on 23 May 1945 in Okinawa, Smith was absorbed in taking a picture. A Japanese shell fragment went through the hand that held the camera, blasting into his head and face. Survival. Surgeries. Pain. No photography. Until, more than a year later, the antithesis of Okinawa brought him A Walk To Paradise Garden¹.

Three decades later, I—who had been hiding from teenage angst among my father’s photography books—felt I could glimpse into the breadth of humanity through Smith’s images. Whatever that soldier staring towards Smith had seen, I, too, wanted to see. Whatever those children were walking into, I, too, wanted to find.

And I did fantasize about becoming a war photographer. Yet, whether it was legitimate contingencies or the reality that I was plain chicken, I became an ecologist. Like many of my colleagues, I entered the discipline because I loved nature and wanted to make my living by spending time in it. I wanted to study mountain sheep (which I did), marine predators (which I do) and ancient rainforests (which I helped others do). But as time goes by, the line between Smith’s work and that of some environmental scientists keeps blurring in ways that are not entirely metaphorical.

In February 2012, I found myself in a seminar room, attending a meeting of the American Association for the Advancement of Science. The session, organized by the Asia-Pacific Center for Security Studies, a US Department of Defense academic institute, focused on climate change impacts on Bangladesh. The statistics were staggering. Eighty percent of the country is 12 metres above sea level or lower. Consequently, a fifth of Bangladesh floods on an average year and nearly 70% of the country has flooded on extreme years. As climate change continues to melt the ice caps, sea level rises further. Flooding not only wrecks infrastructure and drowns people, but also hampers agricultural production by increasing soil salinity. The 1970 Bhola cyclone produced a storm surge that killed half a million people in the low-lying Ganges Delta that encompasses present day Bangladesh². The cyclone was an extreme event but—according to time series analyses by NASA climatologist James Hansen and colleagues—extreme weather anomalies occurred 10 times more frequently between 1980 and 2010 than during the preceding 30 years^3,4. These changes can be attributed to human-caused climate change^3,4, which implies that Bhola-type catastrophes are fair game in the foreseeable future. And there is more. Bangladesh has 54 rivers that originate upstream in India. As climate change reduces the mass of Himalayan glaciers that feed these rivers, unpredictable flows will threaten the agricultural potential of both countries. Yet India, who already is building a security fence along its border with Bangladesh, clearly has the upper hand. As rivers dry and agricultural production crashes, India potentially could decide to hoard that water and keep desperate Bangladeshi migrants outside their fence. At an estimated 1050 Bangladeshis per square kilometre (according to 2010 statistics), most in abject poverty, the potential for diminished Himalayan glaciers and rising sea levels to promote regional chaos is not small⁵. Similar tensions could arise from the drying of rivers shared between India and Pakistan, two nations who happen to have nuclear weapons⁶. No wonder the US Military is interested in climate change.

The Indian subcontinent is not unique. It is not a big stretch to predict that resource scarcity, which is directly linked to climate, will cause armed conflicts to become more frequent around the globe^6-8. To understand why, allow me to digress into the world of evolutionary theory and behavioural ecology. When we return to war in a few paragraphs, it will be with new fundamental insights.

During the 1980s, Marc Mangel, Colin Clark, John McNamara and Alasdair Houston pioneered mathematical models of animal behaviour that are state-dependent. That is, these models predict how an animal’s current ‘state’, namely age and body condition, influence antipredator and feeding behaviours that affect the future reproductive potential of that individual^9,10. Central to this idea is the trade-off that antipredator behaviour may keep prey from getting eaten, but it also slows down the rate at which prey can feed and limits where and when they can eat. A mountain sheep watching out for wolves cannot put its head down to chomp on grass, a rockfish hiding inside rocky crevices is safe from larger fish that want to eat but also misses out on meal times, and a grasshopper that circumvents the rough neighbourhood of predatory spiders may give up access to the best goods. So natural selection has honed animal decisions into that happy medium that behavioural ecologists call ‘optimal’, those which allow for a ‘reasonable’ chance of not getting killed and a ‘reasonable’ chance of finding enough food to stay in good shape and reproduce^11,12. Yet, what is ‘reasonable’? The answer is not static. It varies with the animal’s age, body condition, and current experience of available resources, all which affect the reproductive success that each individual animal might expect during its remaining lifespan^9,10,13.

Imagine a young animal in good shape and surrounded with ample resources. This animal can look forward to the possibility of many reproductive bouts during its remaining lifespan. Given its many reproductive assets that are worth protecting into the future, it is ‘reasonable’ for this animal to aim for lots of safety while feeding just enough to not lose that good body condition. This animal can even allow body condition to dip down to a point from which it can bounce back up by increasing feeding rates—which implies greater exposure to predators—but only slightly thanks to the many available resources. Now imagine an older animal during a drought. Skinny and worn out, it might get another chance at reproduction, perhaps its last, but only if it improves its body condition by getting some really good meals. Between a rock and hard place, with few reproductive assets that are worth protecting into the future, it may as well risk greater exposure to its predators with the expectation of feeding on the quality foods that might allow one more reproductive bout. If it gets killed, at least it tried. Beats hiding and starving. It also beats staying alive without reproducing, which—unless the animal can help relatives survive and reproduce or is young enough to expect future chances that make up for lost reproductive time—is the same as dead, in evolutionary terms.

Models of state-dependent behaviour predict that resource declines and associated losses of body condition should increase risk-taking and predation rates for individuals attempting to avoid imminent starvation or other net losses of reproductive potential. I find these models to be visually beautiful, and love the way the equations dance their way over the page. But beyond abstract beauty, these models are a useful map of the real world. In the 1990s, Bradley Anholt and Earl Werner exposed bullfrog tadpoles to predation risk from larval dragonflies under contrasting levels of food abundance. Tadpoles experiencing low food levels moved one and half times more frequently and at higher speeds than tadpoles experiencing high food levels. Higher movement rates under food scarcity, which reflect greater foraging effort, also increased exposure to predators and caused a near-doubling of predation rates, despite predator densities remaining constant¹⁴. These and later experiments suggest that synergisms between resources and predators are fundamental to population and community processes, and that behavioural decisions by prey are inherent to these synergisms. And these processes scale-up to vast landscapes. Wildebeests in poor body condition, for instance, spend more time in habitats with better food and higher predation risk and, consequently, get killed more often by lions than wildebeests in better condition that use safer habitats with less food¹⁵.

Seeking to generalize these ideas to other ecosystems, in 2000 I travelled to Shark Bay, Western Australia, where I spent much of my time jumping off skiffs to capture and tag green turtles. During that study, my colleagues and I noticed great variation in the body condition of individuals. Green turtles in good condition had a convex underside and large fat reserves around the neck, while those in poor condition had a concave underside and flapping skin around skinny necks. I was working with Mike Heithaus, who had been studying tiger sharks in the area for three years and had started the turtle project. Over the course of the study, which eventually spanned seven years of data¹⁶, we discovered that turtles in poor body condition were more likely to be found over shallow seagrass banks, where the best quality food for these herbivores are found. But the interior of seagrass banks also are dangerous. Here a turtle encountering a tiger shark can escape only in two dimensions, horizontally, and lacks the option to bolt down into deep water. In contrast, the edges of sea grass banks, where turtles in good body condition were more likely to be found, have lower quality sea grasses but are safer because turtles can escape sharks in three dimensions, horizontally and towards the deep. Seasonal variation highlighted how body condition, food, and predator presence combine to affect risk-taking decisions. Turtles in really good condition ventured towards the interior of sea grass banks only during winter, when shark densities predictably were at their annual low point, while turtles in the worst body condition always used the interior of seagrass banks. Even during the season of low shark abundance, turtles in good body condition stayed closer to the bank edge than their skinnier counterparts¹⁶. When I look at the graphs of that study, it is almost as if those beautiful modeling equations had danced off the page and onto the seagrass banks.

The theory of state-dependent behaviour, supported by observations in real ecosystems, can have profound implications for ecological conservation because humans influence the global distribution and abundance of resources used by all living things¹⁷. Models I have developed, for example, predict that overfishing can force harbour seals and Steller sea lions in western Alaska to increase the frequency of their deep foraging dives at the cost of increased exposure to Pacific sleeper sharks in deep water. These deep dives not only increase time exposed to danger in the deep, but because deeper dives also tend to be longer than shallower ones, they also demand a longer period of oxygen recovery at the surface which increases risk of predation from shallow water predators, such as transient killer whales^18,19. Through these changes in feeding behaviour, overfishing may indirectly increase predation rates on both harbour seals and Steller sea lions, potentially contributing to declining trends for some populations^20-22. Another prediction is that climate change, which affects resource availability, can indirectly alter rates of mortality experienced by animals¹⁷. Among other applications, this prediction might help us anticipate and perhaps mitigate conflicts between humans and some large carnivores, such as polar bears. Under normal conditions of sea ice, polar bears are successful hunters of seals surfacing at breathing holes on the ice pack. When the ice is good, the bears stay fat and healthy, and can afford to stay clear from human settlements. Yet the option for polar bears to avoid humans is diminishing as climate change reduces the permanence of the ice pack. In western Hudson Bay, earlier break-up of sea ice during spring has increased the period in which polar bears fast on land unable to access seals. At the same time, there are more hungry polar bears in search of human-related foods showing up at settlements, and therefore getting killed more often by humans in self-protection²³.

So no matter at what scale of the animal world we chose to look at—from little tadpoles at risk from dragonfly larvae (or even smaller predators and prey) to wildebeest at risk from lions and polar bears at risk from humans—prey organisms play it cool and safe whenever food is easily accessible and body condition is good. Taking away some of that food limits the choice to avoid risk. Taking away most of it heats up the stakes, virtually eliminating the choice to play it safe.

Which brings us back to war. Why does it pervade human history? Clearly there is no single answer to that question. But one thing that the paleoclimate and historical records do tell is that humans are not exempt from our own form of state-dependent behaviour. Historically, climate-driven resource shortages have influenced the decision by hungry societies to initiate wars that might never have occurred had human populations been well fed. A team of geographers pieced together evidence suggesting that during the Little Ice Age, which occurred between the 15^th and 19^th century, there was a strong relationship between dips in global temperatures and an increase in the numbers of wars occurring world-wide. Consistent with theory on state dependent behaviour, drops in agricultural production and rising food prices appear to have been the factors mediating climatic stress and war²⁴. And the Little Ice Age is not an isolated fluke. Recent analysis of a data set spanning from 1950 to 2004 shows that in 93 tropical countries strongly affected by El Niño Southern Oscillation (ENSO)—an oceanographic cycle that influences global climate, alternating between warmer and drier El Niño phases and moister and cooler La Niña phases—armed civil conflicts were twice as likely to arise during El Niño than during La Niña²⁵. In contrast, in 82 temperate countries where ENSO effects are weak, the timing of armed conflicts was unrelated to ENSO²⁵. The lack of temporal relationship between conflict and ENSO in those 82 countries is critical from the standpoint of scientific inference because it controls for the possibility that some unknown variable co-occurred with ENSO world-wide²⁵. Although ENSO and the Little Ice Age do not necessarily provide a road map for future effects of human-caused climate change, these quantitative analyses do provide strong evidence that the general relationship between climatic stress and war, with resource and economic scarcity as likely mediating factors, is real. In addition, there is growing qualitative evidence suggesting that volatility has risen in dry regions of Africa and other resource-stressed parts of the world, as the frequency of drought or other unfavourable conditions, linked to human-caused climate change, reduces resources and fuels ethnic violence⁸. In all of these cases it would be wrong to call climate change the direct cause of conflict. But there is good reason to think of climate change and resource scarcity as strong winds that fan the flames of state-depending behaviour, increasing the willingness by people to engage in armed conflict⁸. According to Chris Huhne, UK’s Secretary of State for Energy and Climate Change who was recently quoted in Nature Climate Change, ‘Climate change is a threat multiplier. It will make unstable states more unstable and conflict more likely.’⁷

Humans. Us who change the Earth’s climate. Us who, against evolutionary odds, extend compassion beyond our kin. Us who create global instititutions such as the United Nations which, for all their faults, were born from a desire to promote peace. Us who are capable of marvellous intelligence and unbelievable stupidity. For us, the past need not be a mirror for the future. But it sure is an ominous warning.

Twyla Bella, during the early 1990’s, your mother and I were in our 20s. It was an era of freedom, adventure and intellectual exploration. My Dall’s sheep study, part of my master’s thesis, had brought us to Kluane National Park in the Yukon, where we experienced a living, breathing landscape with its full component of large carnivores. During March mornings, with temperatures dipping to minus 20 Celsius, we would be scanning the slopes with our spotting scopes, watching how Dall’s sheep behaved to manage the conflicting demands of finding food and not getting killed by wolves and coyotes²⁶. Later, in April, we encountered our first grizzly bear of the season, adding to the list of predators that Dall’s sheep had to avoid. In May, with lambs recently born, the mothers had to be extra vigilant for golden eagles that may knock their young off the cliffs and then pickup the meal at the bottom. Our stay was meant to last a few months but turned into a year. The study ended, my thesis was defended, and we settled for the long term in the southwest Yukon, alternating our time between research contracts (history for Gail, ecology for me), Gail’s emerging career in modern dance, and exploring the vastness of the Yukon and neighbouring Alaska coast. Blasting through remote glaciers on skis. Running rivers in kayaks. Blissfully unaware that, in a parallel universe, genocides were unfolding in the former Yugoslavia and Rwanda.

Some years later, I descended from that cloud and confronted images of Rwanda’s Kagera River clogged with mutilated corpses; eight hundred thousand people hacked to death with machetes in 100 days²⁷. For a time, these images took hold of me. How could such extreme horror come to be? Resource scarcity was not the direct cause—myriad historical and socio-political factors can take credit for that. But according to economists studying Northwest Rwanda during the years leading to the genocide, land degradation and resource scarcity were the dry hot wind that fanned tensions between the Tutsi, who controlled a majority of resources in rural areas, and the Hutu, who were increasingly needy for those resources²⁸. The economists emphasise that ‘the prevailing state of extreme land hunger created a troubled environment which made the most desperate people (particularly young people with only bleak prospects) ready to seize any opportunity to change their present predicament or reverse the present order of things.’ They also point out that ‘extreme scarcity of land resources and lack of non-agricultural employment opportunities did not (directly) cause the civil war which was triggered off by macro-political forces cynically playing upon ethnic divisions in order to maintain themselves in power. Yet, there can be no doubt that the strained situation engendered by economic scarcities goes a long way towards explaining why violence spread so quickly and so devastatingly throughout the countryside’²⁸. Resource scarcity, it seems, pushed individuals already at the edge into an abyss where they could dehumanize their neighbours into mere ‘cockroaches’ obstructing access to land. Once inside the abyss, horrors such as that recounted by Dr. James Orbinski, head of mission for Médicins Sans Frontièrs during the Rwandan genocide, became routine²⁹:

One night, after many long hours of surgery, a girl of about nine told me how she had escaped murder at the hands of the killing squads. The squads were part of an organized government plan to erase the existence of the Tutsi people from Rwanda. Through an interpreter, the girl told me, “My mother hid me in the latrines. I saw through the hole. I watched them hit her with machetes. I watched my mother’s arm fall into my father’s blood on the floor, and I cried without making noise in the toilet.”

A day in June 2006 at Annie Lake, Yukon: the place known as Désdélé Méné to the Carcross-Tagish people who call this region their ancestral home. You, Twyla Bella, are two and half years old. The ice melt still recent. The water surface calm. Rugged mountains all around. Dall’s sheep lambs visible up high among the crags. Common loons on the lake. Wolf scats in the nearby forest. This valley, our home for the last 11 years. The placenta that you and Gail shared while you were in the womb is buried at the shore of the nearby Watson River. Being broken down by detritivores, its essence now drifts into the river that connects with Bennett Lake and the other Southern Lakes, The Yukon River, and eventually The Arctic Ocean. The physical bond with your mother has become indistinguishable from the land, the flowing waters.

Twyla Bella, fate has been good to us. Happy historical accidents have placed us in a vastly different world from that of Rwanda in 1994. But, given that we are the descendents of Jews who left Europe just before the Holocaust—with all relatives that remained, save four survivors, dying in Nazi concentration camps—the fate of that Rwandan girl is not completely unrelatable to our family history. Worse: fates comparable to that of the Rwandan family continue to play themselves out today in many places where resource scarcity pushes people with existing grievances into the abyss^7,8.

World War II, all wars past, current and future, may seem far away from this valley, yet I am not so naïve as to ignore the fact that warring raids punctuated the relationship between the original Carcross-Tagish inhabitants of this place and their Chilkat neighbours of the Alaska coast. Even the Inuit, arguably among the most egalitarian societies that have ever existed, were no strangers to bloody feuds over resources. Yet I like to believe that humans have the capacity to take ownership of our history, both evolutionary and otherwise, and transcend it while acknowledging our origins. Sure, we are vulnerable to evolutionary drives, such as those that govern state-dependent behaviour. But we are not necessarily bound by them³⁰. My father, your abuelo, was born into a dysfunctional household, raised with violence and amidst mental illness. He could have reincarnated into dysfunction but chose not. If he could muster that much self awareness, then it is a sign that people can learn to recognize our vulnerability to evolutionary drives while choosing to not act on them. If that awareness was to propagate, then perhaps society might treat climate change as the world emergency that it is³¹ and act in ways that respect intergenerational justice.

We place the canoe on the water. Your friend, only slightly older, helps you into it. A glimmer, to my biased eyes, of W. Eugene Smith’s ‘A Walk To Paradise Garden’. The best hopes for humanity emerging from the aftermath of the worst of humanity. We glide on the canoe towards the wetland where we will collect medicinal herbs, coltsfoot and wormwood. Plants that strengthen our bond to the Earth.

Love,

Alejandro

References

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2            Mirza, M. M. Science for Adaptation to Climate Change: The Case of Bangladesh. Annual Meeting of the American Association for the Advancement of Science (2012).

3            Hansen, J. Human-Made Climate Change: A Scientific, Economic, and Moral Issue. Annual Meeting of the American Association for the Advancement of Science (2012).

4             Hansen, J. E., Sato, M. & Ruedy, R. Perceptions of Climate Change:The New Climate Dice. http://arxiv.org/ftp/arxiv/papers/1204/1204.1286.pdf  (In review).

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17            Frid, A. & Heithaus, M. R. in Encyclopedia of Animal Behavior Vol. 1  (eds Breed M.D. & Moore J.)  366-376 (Academic Press, 2010).

18            Frid, A., Dill, L. M., Thorne, R. E. & Blundell, G. M. Inferring prey perception of relative danger in large-scale marine systems. Evolutionary Ecology Research 9, 635-649 (2007).

19            Frid, A., Heithaus, M. & Dill, L. Dangerous dive cycles and the proverbial ostrich. Oikos 116, 893-902 (2007).

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21            Frid, A., Baker, G. G. & Dill, L. M. Do Shark declines create fear-released systems? Oikos 117, 191-201 (2008).

22            Frid, A., Burns, J., Baker, G. G. & Thorne, R. E. Predicting synergistic effects of resources and predators on foraging decisions by juvenile Steller sea lions. Oecologia 158, 775-786, doi:10.1007/s00442-008-1189-5 (2009).

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29            Orbinski, J. An Imperfect Offering: Humanitarian Action in the Twenty-First Century.  (Doubleday Canada, 2008).

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31            Hansen, J. Storms of My Grandchildren.  (Bloomsbury, USA, 2009).

Staphylococcus aureus, the bacteria commonly known as Staph, uses our skin as its natural habitat.  The beast attacks when our immune system is weak, causing an aggressive pneumonia which progress rapidly and causes extensive lung tissue damage.  Staph can also cause a plethora of other nasty conditions such as necrotic faciitis, better known as the disfiguring and deadly “flesh eating disease.”  Although antibiotics were once effective against Staph infections, new antibiotic resistant strains of Staph pose serious new threats.  In order to remedy this situation, scientists need to identify new points of intervention, and this will need to start with understanding how Staph invasion proceeds.

To put it simply, our body is like a building, with cellular “bricks” held together by a “cement” of various molecules, including one called E-cadherin.  At the surface where lung tissue meets our breath, the top cell layer forms a barrier which allows gas exchange with underlying blood vessels without the blood gushing out.  This barrier maintains tissue integrity and offers first line defense against microbes.

During infection, Staph damage cells by producing molecules called hemolysin, belonging to a group called pore forming cytotoxins (PFT).  As the name suggests, PFTs plug themselves into cells to cause cell contents to leak out, much like the old BC Place with punctured dome.  Hemolysin molecules in Staph function like barrel staves, with seven of these staves forming a whole barrel, and are critical for Staph to cause disease.

Although hemolysin damages cells, this process is slow and regional – the collective barrier remains largely intact. Scientists have suspected that another activity is responsible for the rapid and extensive tissue damage we see in Staph pneumonia and necotic faciitis.  A research group from the University of Chicago recently reported that for rapid, devastating disease progression Staph needs to hijack one of our own cell components – a molecule called ADAM10.  ADAM10 resides on the surface of our cells and releases molecules that serve as messages from one cell to another.  It is similar to tying messages on kites and releasing them by cutting the string, hoping the wind takes them to your target.  In this case, ADAM10 is the “scissors.”

The researchers discovered that PFT staves are attracted to ADAM10 as if ADAM10 is a piece of Velcro, allowing the staves to form barrels and insert into the barrier cells more efficiently, and thus faster leakage and ionic imbalance between the cell and outside environment.  The ionic imbalance pushes ADAM10 into overdrive and, in a cutting frenzy, it cuts molecules that it normally does not, one of which is the aforementioned E-cadherin “cement” that holds our cells together.  Loss of E-cadherin causes a breach of the protective barrier and body fluids then gushes out and interferes with air exchange.  This allows Staph to invade deeper into the body and blood stream, and so begins a deadly downward spiral.

Since the ADAM10 “scissors” seem to play such an important role, what would happen if the scissor function was blocked?  The team tested this by using the ADAM10 inhibitor, a drug that jams up the “scissors.”  The result was dramatic: blocking the scissors minimized barrier disruption and far fewer mice died from infection. Knocking down  ADAM10 effectively takes the punch away from Staph infections.  What is even more exciting is that since PFTs are not exclusive to Staph, infections by other pathogens that use PFT may also be treatable this way.

Unfortunately it will likely be quite some time before we see ADAM10 inhibitors available from our family doctors.  In these experiments scientists injected the inhibitor before Staph infection and we don’t know yet whether the approach will be effective post-infection treatment. This is especially important because early Staph pneumonia is frequently misdiagnosed as common flu.  Next steps will also include efficient drug delivery methods and assessment of side effects. This does not take away from the merit of the study, though.

These findings also have a broad significance beyond Staph infections. Many other pathogens hijack our own molecules in similar fashion, so knocking down host function instead of eliminating pathogen as we see here could prove useful against a range of antibiotic resistant infections.  This approach makes antibiotic resistance less relevant as we are raising the bridge and keeping the enemies at the moat.

* Inoshima et al. 2011. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nature Medicine,  2011 Sep 18. V17, pp.1310-4.

Neil Swart and Andrew Weaver crunched the numbers for answers. In a recent paper published in Nature Climate Change (Vol 2, pages 134–136, 2012), these climatologists from the University of Victoria estimate that global warming caused by the burning of all proven reserves of coal would be 0.92 degrees Celsius. Utilizing all of Canada’s oil sands, infamous for their local environmental impacts and intense energy requirements during extraction, would increase global temperatures by 0.03 degrees Celsius. Gas and conventional oil, in combination, would add another 0.40 degrees Celsius of warming.

Oil sands supporters could easily misconstrue the above results as a victory. After all, coal would bear the lion’s share of the total (68%) while  Canada’s oil sands contribute only 2%. Media headlines inspired by the study were unsurprising: “Coal, not oil sands, the true climate change bad guy, analysis shows” (The Globe and Mail and Winnipeg Free Press); “Coal, not oil sands, causes global warming: study” (CTV); “Coal, not oil sands, the real threat to climate, study finds” (Toronto Star). But are these the study’s conclusion or wishful thinking?

What Swart and Weaver actually said is that there are no good guys; consumption of coal and oil sands and gas and conventional oil must be phased out as soon as possible. Given that humans have already warmed the Earth by 0.8 degrees Celsius, burning the proven reserves of all fossil fuels, oil sands included, would create a world that is at least 2.15 degrees Celsius warmer than pre-industrial times and push civilization into unprecedented climatic challenges.

This estimate is very conservative for at least four reasons. First, Swart and Weaver exclude emissions from oil sands production, which are greater than for conventional fossil fuels, and thus underestimate the total emissions by about 17%. Second, if we include fossil fuel reserves that are not yet economically viable to extract in the calculations, the result is a world that is over four degrees warmer than pre-industrial times. Third, Swart and Weaver consider only the warming that would result directly from burning fuels; they do not consider indirect mechanisms in which relatively small temperature rises unleash other processes that accelerate further warming. For instance, warming in the Arctic and Subarctic already has reduced sea ice and began to melt permafrost. The indirect consequences are that melting is releasing underground greenhouse gases and the dark unfrozen ocean is now absorbing solar radiation that sea ice once reflected back to space. Finally, oil sands extraction physically removes peat wetlands that store large amounts of sequestered carbon. According to a study published in the Proceedings of the National Academy of Science (PNAS 2012 doi:10.1073/pnas.1117693108) by University of Alberta ecologists Rebecca Rooney, Suzanne Bayley and David Schindler, “Landscape changes caused by currently approved mines will release between 11.4 and 47.3 million metric tons of stored carbon and will reduce carbon sequestration potential by 5,734–7,241 metric tons [per year].” Current plans by oil companies for land reclamation will fail to restore the land’s capacity to store carbon.

As Swart states in his public summary of the Nature Climate Change paper, “To keep warming below 2°C will require a rapid transition to non-emitting renewable energy sources, while avoiding commitments to infrastructure that supports fossil fuel dependence.” [My emphasis.] Given the scientific evidence, it is reasonable to expect the Canadian government to already be engaged in policy shifts that promote the timely phase out of oil sands production and the implementation of alternative energies. Instead, Prime Minister Harper and his Conservative government are aggressively seeking the approval of the Northern Gateway pipeline in British Columbia. Such a project would commit Canada to the extensive exploitation of the oil sands reserve. It would also show complete disregard for the 2009 Copenhagen accord, which recognized the scientific view ‘that the increase in global temperature should be below 2 degrees Celsius.’

A devil’s advocate might argue something like this. ‘We could just burn the oil sands, bear the pain of a 0.03 degrees Celsius temperature rise (plus more warming from production emissions and the release of peat carbon stores), and leave coal in the ground.’ Given that coal does have the greater potential contribution to global warming, in the most optimistic of worlds this argument might be akin to providing safe injection sites for drug addicts as a harm reduction strategy. In our world, however, that same argument implies that the rest of the world should be happy to grant Canada a monopoly while leaving their fossil fuels and money in the ground. Contrary to Harper’s policy of derailing international negotiations on climate change, analysts like Gwynne Dyer (author of Climate Wars) and NASA climatologist James Hansen (author of Storms Of My Grandchildren) point out that without international cooperation in which all nations work together to concurrently phase out fossil fuel production, this is just not going to work.

Oil sands production, therefore, is inseparable from broader issues of equity. Canadians represent half a percent of the global population. According to calculations that Swart provides on his website, if everyone in the world developed their resources and produced emissions at the same per capita rate as Canada, within a few decades the worlds climate would hugely exceed the two degree Celsius warming threshold agreed to in the Copenhagen Accord. Canada’s current efforts to limit warming clearly are inferior to its fair share and will be further diminished if we continue to exploit the oil sands.

Which brings us back to what Swart and Weaver actually concluded: consumption of coal and oil sands and gas and conventional oil must be phased out as soon as possible. This is not a pipedream. According to climatologists like Andrew Weaver and economists like Simon Fraser University’s Mark Jaccard, a rising price on carbon emissions would go a long way towards dethroning fossil fuels. In his 2009 testimony to the US House of Representatives, James Hansen details how a gradually rising federal carbon fee on fossil fuels at their source would ensure that clean energy (such as wind, solar and geothermal) could compete with fossil fuels within a short time frame. Hansen argues that the carbon tax would succeed in reducing emissions if all revenues were returned as monthly dividends to citizens, thus ensuring that everyone can afford the transition to a decarbonized economy and increasing financial reward for those who burn less fuel.

Yet even carbon taxes with teeth and a decarbonized economy would not make everything immediately rosy. Our consumption of fossil fuels already has caused atmospheric carbon dioxide to rise from a pre-industrial 280 parts per million (ppm) to 390 ppm today. All that excess carbon dioxide will remain in the atmosphere for centuries. The bad news, therefore, is that even an immediate cease to fossil fuel consumption will not stop global temperatures from continuing to rise for many decades. To stabilize the climate at the conditions under which civilization evolved, Hansen argues, atmospheric carbon must be reduced to 350 ppm or lower, a task that will require mass reforestation, agricultural practices that promote carbon sequestration in the soil, and some level of geo-engineering. Climatic challenges affecting food production and stable shorelines, therefore, will increase over the next several decades, even under the best case scenario.

Yet that bad news is pure sunshine compared to the alternative of not decarbonizing right now. Atmospheric carbon dioxide currently is increasing at annual rate of 2 ppm. If nothing changes, we will reach 450 ppm in about 30 years. According to paleoclimatic analyses by Hansen and colleagues, the last time Earth’s atmosphere exceeded 450 ppm of atmospheric carbon—35 million years ago—the planet was almost entirely ice-free and sea levels were radically higher than today. Considering that most of humanity lives in low-laying coasts, this is a recipe for refugee waves and social unrest of a global scale.

So let’s keep cool and leave most of the remaining coal, oil sands and other bad guys in the ground. As the father of an 8 year-old, I see no reasonable alternative.

Laura von Rosk is an artist who likes to get outside. She hikes and paddles and asks lots of questions about how things work. Laura paints imaginary landscapes, glowing images of places from fragments of memory, many from the Adirondack Mountains where she lives.

Three years ago the two met while working together on an exhibition that merged art, science, and underwater archeology at the Lake George Arts Project’s Courthouse Gallery, where Laura is the gallery director. Sam is a diehard enthusiast of art/science fusion.

This past winter, Laura spent three months in Antarctica as an assistant on Sam’s research expedition. They have recently returned and The Crux tracked them down with a few questions. (All photos are by Laura von Rosk unless otherwise noted; mouse over photo for legend and attribution).

The Crux: Sam, what are “forams” and what is it that fascinates you about these creatures?

Bowser: Forams (foraminifera) are a diverse and extremely abundant group of protists (single-celled critters with a nucleus). The most familiar ones build hard shells made of mineral particles cemented together by adhesive substances, or by secretion of calcium carbonate. Those that inhabit the world’s oceans play important roles in the marine food web. Those that secrete shells of calcium carbonate help buffer atmospheric levels of carbon dioxide, in a nutshell by turning the gas into rock. So in the context of global climate change, it’s important that we learn everything we can about their basic biology.

The Crux: What is so special about the ones that live on the bottom of an Antarctic bay, under the ice? Can’t you just study the ones in Lake George?

Bowser: The species that live in freshwater are almost unknown, so it’s hard to mount a research program on Lake George forams. We have detected their genetic signature in lakes and ponds, but we haven’t isolated these critters yet. By contrast, the ones living at our study site in Antarctica are huge – some can fit in your palm – and are easy to work on in the lab. For example, I can dissect a nucleus out of one species by hand. Try doing that with Chlamydomonas ;-} [Editor's note: This is not going to happen.]

The Crux: What do you hope to learn? Can you show us some pictures?

Bowser: Early in my career, I studied the cell biology of forams, particularly their motility and cytoskeleton. Needing to grow them in the lab, I also studied their ecology and found that almost all of them are voracious carnivores, eating anything they can grasp with their sticky pseudopods (including juvenile shrimp and brittle stars). Now I’m interested in the early evolution of forams, and would like to learn how they may have changed the landscape over the past 600 million years.

A fascinating piece of this research is the question “why do they build their shells?” The answer seems obvious:protection. But the shell is also a “tool” used by the foram for other purposes, like obtaining food and dispersing gametes.

[Aside from Von Rosk: I love that the answer is not obvious.  It reminds me that there been countless unexpected discoveries in science that have changed the world, and perceptions of our place in it.]

We’re also “mining” their genomes for unique proteins we can put to use in medicine and biotechnology. I also have this crazy idea that we can use them to build nanodevices, but I’ll keep that a secret for now.

The Crux: In what ways do you think art is important to science and vice versa?

Bowser: I think the “right brain/left brain” paradigm of creativity is a crock. Maybe that’s because I’m a lefty, so my brain connections are not canonical? Science is art, and art is science, and like the two cerebral hemispheres the two belong together. But being pragmatic scientists must do a better job of communicating their passion for research and their findings to the public. I’ve written essays for popular magazines and given countless talks about our work, but the most powerful approach I’ve come across is to touch the hearts of audiences through art and music. Not my art, and certainly not my music! But by collaborating closely with “real” artists – with no strings attached (pun intended) so we are free to explore ideas heartily, the resulting work often portrays the beauty and mysteries that scientists explore. (As a bonus, I get to work with some brilliant artists!)

For artists, I think that science provides a practical way to ensure that art education budgets aren’t totally destroyed by fiscal zealots. We are in desperate need of nurturing creativity in schools, and by combining art and science curricula we can do both. It’s that simple.

The Crux: Laura, you’ve recently experienced something that few people ever get to experience. And I am not talking about visiting Antarctica. I am talking about living in close quarters with scientists for three months. What was that like? And what are your thoughts on the foram research?

Von Rosk: Scientists are just like the rest of us.  Even though these scientists are passionate about forams (more on that later) they occasionally need a break from their research work.

We went nuts taking photos on our trip the Herbertson Glacier.  I love this photo that has us all snapping away – including me, with my shadow.

This trip almost didn’t happen, because of various equipment complications, and the late hour. I am so glad we pushed through that! Irritations about camp life completely vanished during this “family vacation.”

We were surrounded by glaciers: The Ferrar Glacier, Herbertson Glacier, Double Curtain Glacier, and others. The landscape worked its “magic” on us.  Our quirky personalities were now really shining through.  I warmly remember not only the beauty of the landscape, but how each of us reacted to what was around us, and to each other – revealing the best about ourselves, and our individual passions, as we together, and separately explored the glaciers, pressure ridges, the sun, and the cold.

We got back to camp around 2 am.  I remember stopping a few times as we approached camp to take photos.   It was still very light at 2 am on that date, but the shadows were different.  Camp looked different.

At home in the Jamesway tent  we sat talking around the table.  We were up late together — this time because we shared our “vacation,” and not because one of us needed to re-fuel the hotsie and generator.

We all came together as a group during the research dives.   This is serious business.  I had some training in assisting divers, but before this trip, never under such extreme conditions.  This is one reason I was hired, and I thought I was ready for it. But being in Antarctica, and knowing the dangers, watching my team-mates go under the ice filled me with fear.  It took a couple of weeks to shake off that internal fear.  You wait at the dive hole at the end of the scheduled dive time to see bubbles at the “safety stop.”  Those moments are clear in my mind. I was completely in the present. When I was tending alone, waiting for them to surface, I thought about things I haven’t thought about in years, or, more often, things I had never thought about.  When I was tending with other mates we talked deeply, or we were just completely goofy – which, in a way, is the same. But always in our minds, our mates are below the ice.

Learning about people, and trying to live in harmony is a process – and Team Bravo 043 was fortunate to have 3 months together to figure it out, in an incredibly beautiful, but often intimidating environment.  I remember Sam (with years of New Harbor camp experience) saying more than once: “this place can bring the best and/or worst out in a person… watch each other’s backs.”

The Crux: Can you tell us a bit about your experience of the science?

Von Rosk: The visual experience of looking at foraminifera for the first time under a microscope was different, but on the same level as what happened when that C-17 plane landed on the Ross Sea Ice shelf.

Both the landing and the science were like being transported out of my physical body into history.  At first I travelled back in recent human history, then at the microscope I was taken much further back in earth’s history.  Getting off the plane on October 4, 2011, I was in awe.  Here I was, standing in the same place where some of my heroes stood over 100 years ago…. Scott, Amundsen, Shackleton, Mawson and many others.

Above: Midwinter’s Day at Cape Evans, photographed by Ponting, 22 June, 1911. Seated from left, Debenham, Oates, Meares, Bowers, Cherry-Garrard, Scott at the head, Wilson, Simpson, Nelson?, Lt. Evans, Day?, and Taylor. Standing at left, Wright and Atkinson; at left, Gran. (More of Scott’s photos are here).

Team Bravo 043 at Explorers Cove, Antarctica, November 27, 2011. Sam Bowser, Hilary Hudson, Danielle Woodward, Andy Gooday, Laura Von Rosk, Cecil Shin.

It was never a space I imagined I would find myself in. There I was on the ice runway, with real and present full sun on my face, the Antarctic wind, and the temperature cold enough that if you stayed still for even a very short time you would start to hurt (freeze).

Seeing and researching forams spiraled me into completely unknown territory.  Here are these singled celled organisms, and somewhere in time and space we share an ancestor?  It is hard to imagine. We share the same planet, at least I get that. Knowing facts about foraminifera is one thing, but being actively engaged in the research, discoveries, conversations, and opinions of 3 scientists who have studied them for decades is like landing on another planet!  I gradually learned some of their alien language, and was able to converse in a limited way, but I only touched the tip of the “iceberg.”

The Crux: Laura, can you summarize for us what you learned about forams? What they mean to you and what you think of the research that the team is doing?

Von Rosk:  I can’t speak as a scientist, but I will say that forams are as beautiful, unique and varied in their form and architecture as mollusks (or mushrooms, wildflowers, birds or humans), yet so little is known about them.  Ever ask someone at a dinner party about foraminifera?

Until a couple of years ago I didn’t know much about them – it took me a while before I was sure I was pronouncing the word “foraminifera” correctly.  But now, when I hear the word, I see many pictures in my mind.  And it is fun to say these words: Astrammina triangularis (sounds so elegant), Notodendrodes antarctikos, (is a fun mouthful), Cibicides refulgens (say it 5 times fast!).  When you know its name, and can identify the foram visually – it simply changes networks in your brain.  When you attach a name to something you start a process that I imagine is similar to learning a new language.

When you examine something (under a microscope for example) you enter another world.  Although I was not seeing life forms in situ under microscope – it is still a new world. It is a new landscape, viewed from above, with a rich variety of worms, snails, tiny urchins, shells, bones and colorful grains of sand (that in themselves may hold clues to a particular core sample).

What is found in a particular sediment sample may hold clues to foram biology, as well as possible changes in the environment in Explorers Cove (and the polar environment), but I leave that work to the scientists. I just say “hey, what’s this?” or “why does this seem different from that?”… then they start conversing like aliens from planet Zoogomina from the 7^th Galaxy of the Foramifizonodozoid Universe – but I sense from their body language something is important here.

As a painter I crave that sense of discovery.  There can be hours of self-doubt in the studio.  But by pursuing and pushing on, something happens every once in a while, and something new and different appears.  Searching for forams is almost like doing a painting in reverse.

Picking from the tray is not only a visual pattern seeking exercise – through this delicate work you can sense the structure, substance, bulk, and texture of these creatures.  The feel of picking up hard and solid Astrammina rara is quite different then picking the delicate Notodendrodes antarctikos.  Sam has referred to Astrammina triangularis as a jeweled pillow – a perfect description!  They seem fragile, yet the shell is knit/glued/formed so tightly together.  When poked with picking tweezers I can sense a puffy pillow (but not as puffy as tunicates).

Silver saccammina are fragile in a different way – poke too hard and you crack the shell (and leave the silver single celled ball without a home).

They say it was a bad year for Astrammina rara.  But one day I counted 60+ from one sample.  I found a bunch of gold nuggets!

Notodendrodes antarctikos was not as abundant.  Finding them was such a treat!  Maybe it’s similar to a birder with a “life list”.

Antarctica and forams are forever linked for me.  Observing living creatures that can survive and thrive in Antarctic waters is mind bending (the water temperature is 28^oF). In my mind forams are linked to the air I breathe, the ocean, ice, limestone, Weddell seals, pteropods, echinoderms, snails, polychaetes, pycnogonids, ophiuroids, tunicates, Mt Erebus, glaciers, friends, skidoos, scuba divers, helicopters, steak dinners, lemon ginger tea and much more. I am grateful for the many new neuronal pathways that have sprung up as a result of being immersed in this research expedition.

The Crux: Are you going to start painting microscopic life? Glaciers? Dive holes?

Von Rosk: It was thrilling to be part of this project.  I look forward to helping the team translate and communicate their findings to the public at large.  Living in Antarctica, and viewing life under the microscope is not the day-to-day world I live in – but it gave me something, which I hope will manifest in the work I do.  What that looks like or how I do not know.  The manifestation of the experience in my art may be subtle beyond clear recognition or definition.  But I did paint those three things you mentioned…

***

Von Rosk: Did you know that Sam is also a serious science fiction movie nerd?  It makes sense. I see the connection – entering the unknown.

Bowser: Sci Fi movies certainly sparked my imagination as a kid. They were also comforting: scientists usually saved the world.

Imagine walking up a steep hill when suddenly you feel dizzy and develop a crushing pain in your chest. Heart attack! The next thing you know, you are in an ambulance on the way to the hospital. It turns out that the pain in your chest isn’t a heart attack, but something called angina – an indicator that your heart is beating too slowly. This is a problem because your heart is unable to pump enough oxygen to the body to keep up with your everyday activities. The only solution is to implant an artificial pacemaker to increase your heart rate.

Unfortunately, pacemakers come with problems. Major surgery is required to embed them in your chest and once in place, they can only be set to maintain a specific heart rate, making exercise difficult. And, of course, occasionally the batteries need replacing, that too requires surgery. Did you know that you already have a pacemaker? We all have a natural pacemaker that keeps our heart beating on time.

We all have a group of cells in our heart that controls our heart rate. Within this group of cells is a protein called the Pacemaker. During exercise, like walking up a hill, your heart rate increases because the adrenaline in your body makes a special molecule called cAMP that binds to the Pacemaker protein. During relaxation your heart rate slows down because less cAMP is made therefore less cAMP binds to the Pacemaker protein. Now what’s interesting is when the Pacemaker protein and cAMP come together, this reaction gives off heat. Although the amount of heat is very small, it is key to figuring out important elements of the interaction. The heat measurements tell me how the two molecules interact and will give me clues to designing a new heart rate increasing drug. My research is important and novel because I have figured out a way to measure this heat that could not be measured before.

So far I have measured this heat using a machine that tells me how strongly cAMP binds to the pacemaker protein. I have also swapped in and swapped out different pieces of the pacemaker protein to figure out which pieces bind stronger to cAMP and which pieces bind weaker to cAMP. From this information, I hope to create a road map for Pacemaker protein drug development so a person suffering from low heart rates will have an alternative to pacemaker implantation surgery.

********

A version of this piece was the script for Sarah’s entry in the Three Minute Thesis Competition at the University of British Columbia. Details about the competition can be found here.

Currently, one of the standard methods of treatment for blood disorders is autologous hematopoietic stem cell transplantation (ASCT; commonly known as bone marrow transplant), but limitations in our ability to scale up hematopoietic stem cells mean that ASCT is not a viable treatment option for many patients with the most devastating blood disorders. Sauvageau is also working on this problem, and is considered to be a pioneer in this field.

I know a bit about Sauvageau’s work; I’ve met him on a couple of occasions and heard him speak at the 2009 Stem Cell Network annual meeting, where he received the Till & McCulloch Award. I know, for instance, that he received notoriety in 2004 when he and Keith Humphries identified the role of the TAT-HOXB4 protein in the formation and expansion of hematopoietic stem cells. I know that Sauvageau can trace his research lineage directly back to James Till and Ernest McCulloch, who famously identified stem cells in the blood system back in 1961. (They too were working on ASCT, then a relatively new technique whose mechanism for reforming the blood system after radiation therapy was poorly understood.)  I also know that Sauvageau has some new, as yet unpublished, data that has some people buzzing about the implications.

And I’ve been told that he generally prefers not to talk to media, which I fear is exactly the category I’ve been lumped into.

I arrive at the Institute 15 minutes ahead of our scheduled meeting and dump my wind-destroyed umbrella into the trash. My clothes are sodden and plastered uncomfortably to my legs. This, I realize, is my reward for trying to catch a cab in downtown Montréal during lunch hour in the rain. When I present myself at Sauvageau’s office, however, I am kindly told that he’s been called into another meeting for at least the next hour. Thankfully, I am met by two of his lab personnel, who would be pleased to show me through the labs and allow me to do some filming in the meantime.

Jalila Chagraoui, research associate and Iman Fares, PhD candidate are members of the Sauvageau team working on a new translational grant focused on identifying small molecules and proteins for hematopoietic stem cell expansion. It’s a week before the holiday break and everyone is busy. You can see it as soon as you step foot in the lab, where some students are focused on bench work, others are discussing a particular research protocol and a technician is busy with the high throughput screening equipment.  It’s not unlike many other labs I’ve visited, but here there is a certain energy behind it all.  I’d like to call it determination, but there’s more to it: enthusiasm; intensity, and a sense of camaraderie.

Fares, a relative newcomer to the lab (some, like Chagraoui, have been there for upwards of 10 years), has just finished dissecting some mice for a current experiment and offers an animated account of her role in finding a new and very promising drug target for stem cell expansion. Fares’ passion and excitement are infectious and with good reason – there is real potential here – this is the work I had heard whispers about, but Fares delicately suggests that I should talk to Sauvageau about it in more detail.

What strikes me in the lab tour and through my conversation with Chagraoui and Fares is the incredible speed with which this research has been accomplished. Since adopting the rapid screening (high throughput) technologies most commonly used in the pharmaceutical industry, many branches of molecular and genetic biology have made astounding leaps in a very short time.  The key is the ability to mix functional experiments (such as RNAi testing combined with deep screening through the high throughput machines) to dissect entire networks that are involved in a single cellular behaviour.

I leave the lab with greater understanding, but even more to ask about. Back down at the office, however, I am regretfully told that Dr. Sauvageau will be unavailable until very late in the afternoon. I debate the merits of canceling my return train to Ottawa in order to wait, but in the end, I head back into the storm (sans umbrella) with my list of festering questions and the promise of another meeting time.

It’s a good thing persistence pays off.

When I do get the chance to speak with Sauvageau many days later, I start by commenting on the ease with which all his trainees and technicians worked in the space and asking him about his perceived role as a mentor and leader.

Sauvageau quickly gives the credit to his team. “I’m surrounded by a bunch of really good people, and I’m not saying this just to be nice to them. They choose one another when we interview them, and they train one another. They ensure the stability and the passage of the know-how between postdocs and students and I think that’s a key point.”

But Sauvageau worries that this crucial element of his lab culture may be in jeopardy.  This is the reality of a research system where less money is available to increasing numbers of researchers and it has led some funding agencies to place caps on their grants.

“It’s a deep, profound trend we’re seeing now and I feel badly for the funding agencies that are just trying to please as many people as possible,” says Sauvageau. “One thing I love about research is that it’s based on merit. You fund people who propose the most original work, but once you start spreading the money around and trying to please everyone I don’t think you’re accomplishing what science is all about.  It’s sad the way the system is evolving.”

Sauvageau contends that labs that have larger infrastructures may have difficulty surviving in a system where there is a maximal amount of money in the lab.

For his own work, infrastructure is critical. The lab includes more than just sophisticated equipment; it includes people with specific skills – bioinformatitians and statisticians, for example, in addition to the more traditional complement of lab personnel.  These diverse skills are essential to the success of the sophisticated research being conducted. “You need to be aware that you can make a mistake and for this you need to be sitting beside someone who knows what you don’t,” he explains.

“Scientific culture has to be maintained at the highest level so I would argue that as a country we need to invest in places where unique resources are available on site.”

Until that fateful day arrives, there’s work still to be done. In fact, this is the reason Sauvageau can be hard to pin down for people like me. Contrary to the rumours I had heard, I don’t think it’s because he doesn’t want to talk about science to the media or the public – he is gracious, eloquent and clearly passionate about the work he does. He’d just rather be doing it than talking about it.

“I think we’re in a very privileged moment in scientific history right now where we have the means and the technology to understand things very deeply. For example, when people like ourselves are interested in the self-renewal of cells, we now have chemical tools, high throughput technology that allows you to do genome-wide experiments and really identify the determinant that regulates the process. When things go awry such as in leukemia, you can use these technologies to completely see the genetic anomalies that are involved and you can even start to put people together who will try to get at the bottom of this and come up with new strategies for cure.”

As I’m talking with him, Sauvageau has a new set of data in front of him that he’s quite excited about – a follow up to the work Fares spoke about earlier.

“I’m working on a bunch of leukemia that we sequenced recently and it took our bioinformatic team only a few months to really get the necessary tools together for understanding the basis behind this disease,” he explains in reference to the data. “This table illustrates the complete set of genetic anomalies in human acute T  lymphoblastic leukemia. It’s beautiful!”

The genetic mutations are not identical from patient to patient – there were 565 anomalies among 12 patients to be exact – but what this data shows is that the pathway is exactly the same. It gives strong evidence to support a deeper investigation of this pathway for therapeutic targets. The fact that the Sauvageau lab has already identified two possible chemical compounds, among many thousands, only intensifies the excitement.

There are so many numbers and combinations at play – to me it seems incredible that they would be able to narrow it down so precisely. So I ask him if he believes in luck.

“I believe in data analysis. If you do a lot of experiments and don’t analyze them properly, you’ll never find the gold mine hidden within. And in the era of high throughput, where people generate so much data, you must be careful about not trashing it too quickly, because sometimes it is the method of analysis that allows you pinpoint a critical pathway.  For example: in this sequencing project you can see the twelve leukemias that we sequenced and the hundreds of anomalies, and if you look at them on your spreadsheet they make no sense. But if you bring this data into programs that allow you to find networks, you suddenly see that it’s all the same groups, and then your data makes sense.”

“It’s extremely exciting and I predict to you that unless the system collapses, which is not impossible, we’re going to see major things in this country in the next ten years.”

All the more reason to work hard and talk less. Given the possibilities, I wouldn’t mind spending more time in the rain.

This article is appearing simultaneously on Numéro Cinq, a literary magazine that keeps an eye on science.

Last week at the World Economic Forum Harper bemoaned the “less-than-optimal results” from our investments in science, a “significant problem for our country” (Vancouver Sun, January 28, 2012). Yikes! These statements sound bizarre. The scientific work that goes on in this country is highly respected around the world and Harper knows that. Does he perceive that we’ve been too slow to turn discovery into product?

Whatever the perceived problem is (and that isn’t clear) a drastic misdirected fix — such as a cut in funding for Science and Technology in the upcoming budget — could lead to serious unintended consequences. What is urgently needed is a shift in the allocation of funding within Science and Technology.

Over the past ten years there has been a dramatic decline in funding to basic biomedical researchers in Canadian Universities. Many excellent Canadian scientists – highly trained, intelligent, hard-working scientists with creative ideas that could lead to the next big breakthrough – are running their labs on fumes. Graduate students and postdoctoral fellows who would normally receive stipends to work in these labs are turning to other careers. As a result, Canadian labs engaged in basic research are doing fewer experiments.

What exactly is basic research? It is research directed at fundamental questions about how cells work. Scientists use model organisms, such as fruit flies, yeast and green algae to discover how cells divide or how they communicate with one another to build a complex multicellular organism. Basic research is not directed at understanding a specific disease, and it may not have any immediate impacts, but there is a long list of important medical advances that have arisen from basic research. You can read about a few of them here.

Meanwhile, under the Harper government there has been a dramatic increase in funding for applied and translational research, industry partnerships and commercialization at the expense of basic research.* There is not a distinct line between basic and translational research; it is a continuum. Scientists poke and prode discoveries from the most basic research with progressively more targeted goals in mind. It is the last stages of this process that are easiest to squeeze (or try to squeeze) into political timetables.

I don’t believe that the Harper government is on a mission to kill basic research in Canada. Its imminent demise is more likely the unintended consequence of giving too much of science’s slice of pie to the targeted phases of scientific research. Basic research is slow and unpredictable; it requires long-term stable funding.

Basic researchers know how to tighten their belts. They are familiar with tight funding cycles. Unfortunately we are approaching a critical point where people can no longer hold on and wait for things to get better. The current situation is threatening to become severe enough that recovery could take decades.

— Lynne Quarmby

 ———–

*Thanks to Lisa Craig for providing data documenting the shifting in funding priorities in Canada:

Ten years ago about 33% of the applications submitted to the Canadian Institutes for Health Research (CIHR) were funded. Success rates are currently hovering at a low of 17%. In 2001, 91% of CIHR funding for operating grants went to open operating grants (OOGs), which fund a broad spectrum of basic health research for hundreds of labs across the country (see http://www.cihr-irsc.gc.ca/e/43812.html). The remaining 9% went to strategic initiatives mandated by CIHR. The amount of funding dedicated to strategic grants has been steadily increasing: in 2010, 33% of CIHR operating funds went to strategic grants, while the OOGs were reduced to 67%. The breakdown for 2010 is as follows: 43.5% of CIHR’s total budget went to OOGs and 33.5% went to a combination of Catalyst, Team Grants, RCTs, Commercialization/Industry Partnerships, Knowledge Translation and Other.

It’s that season again and the relentless struggle against extra pounds is about to intensify. Why do many of us find it difficult to consume only the calories that our bodies need? The struggle feels deeper than the social and psychological issues that are much discussed.  Indeed, appetite control is in our cells and in our genes and like many systems in our bodies, it can get out of tune.

It is more rule than exception that serendipity in science reveals unexpected insights. Research on how green algae swim combined with studies of how round worms smell and how fish can change the colour of their skin, opened doors that are leading to a new molecular understanding of appetite regulation. At the recent meeting of the American Society for Cell Biology held in Denver, Dec 3-7, Nicolas Berbari, Bradley Yoder and colleagues from the University of Alabama at Birmingham reported new studies on mice that are helping us understand how our sense of satiety can go awry. And if you are an optimist like me, the work offers hope to those of us discouraged by relentless calorie counting.

The hormone leptin is an important signal of satiety. It travels in our blood stream, crosses the blood-brain barrier, and when it reaches a tiny region of the brain known as the hypothalamus, it binds to another molecule on the surface of neurons, the leptin receptor. The molecular interaction between leptin and its receptor in the hypothalamus triggers a cascade of biochemical and neurological activity that gives us a feeling of satiety.   People (or mice) who are unable to produce leptin become obese because they overeat – their brains don’t seem to notice the leptin signal that is trying to tell them that they have consumed enough.

We know that there is more to the story because most overweight and obese people (and mice) make abundant amounts of leptin and genes for the leptin receptors are normal. Why then don’t we all receive a nice robust satiety signal? The answer lies in the architecture of the cell.

About a dozen years ago, researchers studying how microscopic algae swim made the then-surprising discovery that these cells build their swimming appendages in the same way, using the same molecules, as mammalian cells build hair-like appendages known as cilia. The researchers discovered that when cilia are not built properly, mice developed polycystic kidney disease. (I tell the story of this discovery here.)

Since then research on model organisms has revealed that cilia serve as cellular antennae, processing and integrating signals that are ultimately transduced into  cellular responses. Among these studies, experiments on how tiny round worms sense their environment helped show that proper placement of the molecular machinery for molecular recognition and signal transmission in the cilia is essential for correct interpretation of signals.  We now know that defective cilia cause a range of pathologies including polycystic kidneys, retinal degeneration and polydactyl (extra fingers and toes). The so-called ciliopathies manifest as different diseases, depending upon the specific lesion(s).

One such disease is Bardet-Biedl syndrome (BBS), a rare genetic disorder characterized by polycystic kidneys, blindness, polydactyl, learning disabilities and obesity. Although BBS is clearly a ciliopathy, how defective cilia could cause obesity was not understood. That BBS patients present with several cilia-associated symptoms indicated that cilia might play an important role in processing satiety signals in the hypothalamus, causing these patients with defective cilia to become obese.

Are cilia required for receipt and interpretation of the leptin signal by hypothalamic neurons? The surprising answer is that they are not. As principle investigator Bradley Yoder puts it, “we were barking up the most obvious tree but it turned out to be the wrong tree.” It remains controversial whether the leptin receptor has anything to do with cilia, but Berbari, Yoder and their team have shown that leptin can signal normally in cilia-defective mice.

Because cilia serve as antennae for the signals that cells send to one another to produce the many diverse cells that make up our various tissues, The researchers used sophisticated molecular technology to mess up the cilia only after mice had developed normally. Soon after the experimenters induced ciliary defects in the mice, the animals began overeating and became overweight.

At first it looked as though cilia mediated leptin signalling because the overweight mice became insensitive to leptin. The hormone did not suppress the appetites of mice without cilia. The surprising result came when the researchers put the overweight mice on a calorie-restricted diet.

When the dieting mice lost weight, they regained their sensitivity to leptin. Weight loss restored leptin signalling in the mice, even though they still lacked cilia. These surprising new data clearly show that weight gain caused the leptin-insensitivity. Cilia loss can lead to obesity, which in turn leads to loss of sensitivity to leptin. In other words, something about being obese caused  the appetite suppression system to stop working.  This is interesting in that it may help explain the slippery slope of weight gain, but it still leaves us without an answer to the central question: what is it about cilia loss that leads to weight gain in the first place?

The short answer is that we still don’t know. The more interesting answer is that it may have something to do with how fish change skin colour to camouflage themselves.

Melatonin Concentrating Hormone (MCH) is so-named because scientists discovered it as the molecule that triggered the skin cells of fish (and other animals) to redistribute their pigment melanin. Whether we see the skin as dark or light depends upon whether there is a tight dot of melanin at the centre of the cell (leaving the cell light) or distributed throughout the cell, giving the cell a dark colour. (This YouTube video shows the skin cells of an octopus using this technique to change colour).

It turns out that although we mammals can’t change the colour of our skin, we use MCH as a hormone in a variety of other ways.  MCH regulates anxiety, depression, sleep, and the reward response. In earlier work, Berbari had shown that the receptor for MCH localizes to the cilia of hypothalamic neurons, making it a candidate for the cause of obesity in cilia defective mice.

Whereas leptin is an appetite suppressor, MCH stimulates appetite. Because cilia are signal processing centres, sometimes their role is to keep a signal in check, to moderate transmission of the message. Signals are not properly processed If receptors cannot localize to the cilia, as happens when the cilia are not properly assembled. A cell might not “hear” the message or, hormones binding to receptors that are on the surface of the cell body and not concentrated in a cilium might trigger a persistent and uncontrolled message.  Given that MCH stimulates appetite and cilia-defective mice gain weight, the researchers hypothesized that in cilia-defective mice, MCH would over-stimulate the hypothalamic neurons.

Berbari, Yoder and their colleagues discovered that the cilia defective mice are hyper-responsive to MCH antagonism. Administration of a drug that turns the MCH pathway off causes the cilia-defective mice to lose  more weight than their wild-type brethren. We don’t yet know whether the excessive weight loss is due to effects of MCH on the satiety system in the hypothalamus or to cilia-related modulation of one of the other effects of this complex hormone.

To tease apart the complex physiological systems involved in satiety regulation scientists will use genetic studies on model organisms, such as mutations that cause fish to become obese. And as ever, the most important breakthroughs will likely arise from the least likely avenues of exploration, because that is how science works.

Meanwhile, Yoder’s group has given a boost to my plans for continuing to battle those extra pounds: perhaps if I lose some weight my leptin signaling will become more effective and it will become easier to resist those tasty morsels.

]]> http://blog.quarmby.ca/obesity-unexplained/feed/ 6 http://blog.quarmby.ca/should-we-spend-tax-dollars-studying-fruit-flies-worms-and-pond-scum/ http://blog.quarmby.ca/should-we-spend-tax-dollars-studying-fruit-flies-worms-and-pond-scum/#comments Sat, 10 Dec 2011 19:43:38 +0000 Lynne http://blog.quarmby.ca/?p=688 Continue reading →]]>

The relatively new fields of genomics and systems biology aspire to an era of personalized medicine. This approach treats the human body as a black box – the inputs combine genetic and environmental information and the outputs are personal health outcome predictions. These approaches are exciting and have tremendous potential to revolutionize healthcare. Ah, if only we were black boxes.

The true power of these new approaches to medicine arise from a molecular understanding of how the body works. I have a new essay on Numéro Cinq on the model organisms that scientists use to understand the molecular interactions that make us who we are.

A Feeling for the Model Organism
December 5, 2011

Chlamydomonas is my favorite “model organism.” It is a small green alga that is one of a handful of unlikely organisms that serve science by acting as proxies for the human body. Scientists don’t pick so-called model organisms for exceptional evolutionary achievement and there is no scientific catwalk of gorgeous creatures. Some scientists do exclaim over the beauty of these creatures, but really. Pond scum? Writhing white round worms? Slime mold? The truth is, model organisms are a haphazard lot that scientists select from the teeming crowds because of quirks that make them useful for laboratory research. They are useful and as we work with them we come to know them.

Click here to continue reading A Feeling for the Model Organism