All systems go

All systems go

A powerful way of studying biology looks set for take-off

SEVEN years ago, one of the attractions at the now-defunct Millennium Dome in London was what looked like a remarkably detailed video of a beating human heart. People could admire the heart's delicate tracery of blood vessels with the muscle stripped away and hear a display of its electrical activity that would not have disgraced a disco. The voiceover described it as “one of the most powerful tools we have in the fight against disease”, but few of the visitors understood why.

Actually, the beating heart was no simple video. It was, instead, the output of a stupendously complex computer model of a heart, developed over more than 40 years. This model is an example of “systems biology”, an approach that represents a significant shift both in the way biologists think about their field and in how they go about investigating it.

A central tenet of most scientific endeavour is the notion of reductionism—the idea that things can best be understood by reducing them to their smallest components. This turns out to be immensely useful in physics and chemistry, because the smallest components coming from a particle accelerator or a test tube behave individually in predictable ways.

In biology, though, the idea has its limits. The Human Genome Project, for example, was a triumph of reductionism. But merely listing genes does not explain how they collaborate to build and run an organism. Nor do isolated cells or biological molecules give full insight into the causes and development of diseases that ravage whole organs or organisms. A complete understanding of biological processes means putting the bits back together again—and that is what systems biologists are trying to do, by using the results of a zillion analytical experiments to build software models that behave like parts of living organisms.

You can't beat the system

The pharmaceutical industry stands to gain much from this approach. Around 40% of the compounds that drug companies test cause arrhythmia, a disturbance to the normal heart rate. Drugs such as the anti-inflammatory medicine Vioxx and the diabetes treatment Avandia have been linked with an increased risk of heart disease. The result is that billions have been wiped off their makers' share prices.

Not surprisingly, the pharmaceutical industry has sought out Denis Noble of Oxford University, the creator of the beating-heart model, to help. Dr Noble is now part of a consortium involving four drug firms—Roche, Novartis, GlaxoSmithKline and AstraZeneca—that is trying to unravel how new drugs may affect the heart. Virtual drugs are introduced into the model and researchers monitor the changes they cause just as if the medicines were being applied to a real heart. The production of some proteins increases while others are throttled back; these changes affect the flow of blood and electrical activity. The drugs can then be tweaked in order to boost the beneficial effects and reduce the harmful ones.

Systems biology thus speeds up the drug-testing process. Malcolm Young is the head of a firm called e-Therapeutics, which is based in Newcastle upon Tyne. Using databases of tens of thousands of interactions between the components of a cell, his company claims to have developed the world's fastest drug-profiling system. In contrast to the two years it takes to assess the effects of a new compound using conventional research methods, Dr Young's approach takes an average of just two weeks. Moreover, the company has been looking at drugs known to have damaging side effects and has found that its method would have predicted them.

Testing for reactions in this way could also offer a more rigorous route to assessing alternative therapies, such as herbs and clinical nutrition (which seeks to control disease through the use of particular foodstuffs). These remedies are often dismissed as unscientific because they have a multitude of effects on the body that are hard to quantify. Studying multiple effects, however, is precisely what models like the virtual heart are able to do.

Nor need such models be confined to people. In biological terms, mice are better understood than men, and a team in the Netherlands is using a computer model of mouse physiology to investigate the effects of a high-fat diet, by monitoring the concentration of various components of the blood. The team, from a firm called SU BioMedicine, which is based in Zeist, found that the active ingredients of a particular concoction of Chinese herbal medicines have the same effect on blood composition as the anti-obesity drug Rimonabant. The hope is that systems-biology studies like these will eventually trace out the pathways the herbs are affecting.

Such models may also help to pin down the causes of diseases that arise from the interplay of genetic and environmental factors. Andrew Ahn of Harvard Medical School cites the example of diabetes, for which the standard clinical test is a measure of the level of glucose in the blood. But that is a single snapshot in time. Dr Ahn suggests that the way toward a fuller understanding of diabetes is to track glucose levels against other factors such as diet, sleeping habits and psychological health. He proposes to employ a systems-biology model to do so.

Ultimately, the aim is to build an entire virtual human for researchers to play with. But reductionism is still needed to get there. Human bodies are made of cells, and the best way to build a model body might be to construct a general-purpose virtual cell that can be reprogrammed into being any one of the 220 or so specialised sorts of cell of which the human body is composed. That, after all, is how real bodies develop. And a collaboration organised by the European Science Foundation is hoping to do just this, through what it calls the Blue Cell project.

Keeping track of the data needed to carry out systems biology on this scale will be a Herculean task, and may turn out to be the driver of future developments at the heavy-number-crunching end of the computer industry. Dr Noble is in negotiations with Fujitsu, a Japanese computer firm that is developing a machine capable of performing some ten thousand trillion calculations a second. That would make it the world's fastest computer, but it comes with a price tag to match—about a billion dollars. This is a little more than the $6m paid for that fictional bionic man, Steve Austin, even allowing for inflation. But it is only about a quarter of what the Human Genome Project cost. And this time, it might produce some answers that prove immediately useful.

Were Neandertals the Original Redheaded Strangers?

Were Neandertals the Original Redheaded Strangers?

Analysis of a pigmentation gene in Neandertals suggests that the extinct hominids had humanlike skin color patterns

	FRECKLED CAVE DWELLERS:  Hot on the tail of a study showing Neandertals may have been able to speak, a new report reveals that some of the extinct hominids may have been redheads.

When you think of Neandertals, freckles probably aren't the first facial features that come to mind.

But, a new analysis of genetic material from the remains of two Neandertals indicates that some members of the ancient hominid population may well have been pale-skinned redheads. An international team of researchers reached that conclusion after studying a segment of the gene MC1R that controls melanin, which is responsible for skin and hair color. 

"In modern humans, this gene is under a strong selective constraint in Africa, but has experienced a relaxation of this constraint in European populations coming out from Africa 40,000 years ago and, therefore, it has accumulated quite a lot of variation on it," says Carles Lalueza-Fox, an associate professor of animal biology at Spain's University of Barcelona and a co-author of the new study appearing in Science. "I thought that Neandertal's ancestors, having experienced something similar, but half a million years ago, would have accumulated lots of variation in this gene also. But, of course, the mutations were going to be at different places of the gene."

The two Neandertal samples the researchers examined were found in separate locations: Monti Lessini, Italy, and El Sidrón Cave in northern Spain. A 128–base pair fragment of MC1R was isolated from the Italian sample. (For reference, there are estimated to be 250,000,000 base pairs in the entire Neandertal genome.) The researchers found a single base substitution that was unique when compared with the same section of DNA from 3,700 people (indicating that it was not contaminated by human DNA); the Spanish Neandertal sample contained the same mutation.

To determine the skin and hair color this mutation would have caused, the scientists created a copy of the human version of gene with the Neandertal substitution in it and then injected it into a culture of pigment cells. They were particularly interested in observing how the MC1R protein expressed by the altered gene interacted with a second protein—α-MSH—which triggers melanin production.

When the two substances mixed, the researchers say, they had a relatively low level of interaction, indicating that low levels of melanin would be produced—a reaction that mirrors the results in genes of humans with red hair and fair complexions. Pale skin allows those living at higher latitudes and exposed to less frequent and weaker sunlight to more efficiently synthesize vitamin D. (This vitamin helps the body absorb calcium to keep bones strong and healthy; deficiencies can lead to bone disorders such as the childhood disease rickets, which softens bones.)

"Chances are that the gene was full of functional variants in the Neandertal populations that provoked quite a high prevalence of red-haired people," Lalueza-Fox says. "But of course, it still depends on if you are heterozygous [(have two different versions of the gene)] or homozygous for these variants [(like Neandertals and modern Europeans)], so I guess that we should expect the whole range of hair color variation [that is] observed in northern modern Europeans."

Lalueza-Fox says he and his team plan to examine other Neandertal genes to learn more about the species, with eye color, behavior, metabolism, immunity and physiology being of particular interest. As for the findings surrounding MC1R, "It was a big opportunity to have an inference of a trait," he says, "that will never be found in the fossil record." 

Fact or Fiction?: Stress Causes Gray Hair

Fact or Fiction?: Stress Causes Gray Hair

Scientists have a hunch that the gray hairs we dread (or welcome) may arrive sooner with stress

	STRESS AGES:  While no clear link has been found, scientists believe that stress can lead to more gray in your hair.

Legend has it that Marie Antoinette's hair turned white the night before she was guillotined. Presumably the stress of impending decapitation caused her locks to lose color within hours. Extremely unlikely, scientists say, but stress may play a role in a more gradual graying process. 

 The first silvery strands usually pop up around age 30 for men and age 35 for women, but graying can begin as early as high school for some and as late as the 50s for others.  

Graying begins inside the sunken pits in the scalp called follicles. A typical human head has about 100,000 of these teardrop-shaped cavities, each capable of sprouting several hairs in a lifetime. At the bottom of each follicle is a hair-growing factory where cells work together to assemble colored hair. Keratinocytes (epidermal cells) build the hair from the bottom up, stacking atop one another and eventually dying, leaving behind mostly keratin, a colorless protein that gives hair its texture and strength. (Keratin is also a primary component of nails, the outer layer of skin, animal hooves and claws?even rhinoceros horns.)  

As keratinocytes construct hairs, neighboring melanocytes manufacture a pigment called melanin, which is delivered to the keratinocytes in little packages called melanosomes.

Hair melanin comes in two shades—eumelanin (dark brown or black) and pheomelanin (yellow or red)—that combine in different proportions to create a vast array of human hair colors. Hair that has lost most of its melanin is gray; hair that has lost all of this pigment is white.  

At any given time, around 80 to 90 percent of the hairs on a person's head are in an active growth phase, which may last anywhere from two to seven years. At the end of this stage, the follicle shrivels, the keratinocytes and melanocytes undergo programmed cell death (apoptosis), and the follicle enters a resting phase, during which the hair falls out.  

To begin building a new hair, the follicle factory must be rebuilt. Fresh keratinocytes and melanocytes are recruited from progenitor cells, also called "stem cells," residing at the bottom of the follicle. For unknown reasons, keratinocyte stem cells have a much greater longevity than the melanocyte stem cells, says David Fisher, professor of pediatrics at Harvard Medical School. "It's the gradual depletion of [melanocyte] stem cells that leads to the loss of pigment," he says.  

Does stress accelerate this demise of the melanocyte population? "It is not so simple," Fisher says, noting that the process of graying is a multivariable equation. Stress hormones may impact the survival and / or activity of melanocytes, but no clear link has been found between stress and gray hair.  

Suspicions—and hypotheses—abound, however. "Graying could be a result of chronic free radical damage," says Ralf Paus, professor of dermatology at the University Hospital Schleswig-Holstein in L・eck, Germany. Stress hormones produced either systemically or locally (by cells in the follicle) could produce inflammation that drives the production of free radicals—unstable molecules that damage cells—and "it is possible that these free radicals could influence melanin production or induce bleaching of melanin," Paus says.  

"There is evidence that local expression of stress hormones mediate the signals instructing melanocytes to deliver melanin to keratinocytes," notes Jennifer Lin, a dermatologist who conducts molecular biology research at the Dana-Farber / Harvard Cancer Center in Boston. "Conceivably, if that signal is disrupted, melanin will not deliver pigment to your hair."  

And general practice physicians have observed accelerated graying among patients under stress, says Tyler Cymet, head of family medicine at Sinai Hospital in Baltimore, who conducted a small retrospective study on hair graying among patients at Sinai. "We've seen that people who are stressed two to three years report that they turn gray sooner," he says. 

Cymet suspects that going gray is "genetically outlined, but stress and lifestyle give you variation of plus or minus five to 10 years." Blonds often appear to go gray later in life because white strands easily hide in a sea of light hair when in fact those who are likely to have the darkest hair (people of African and Asian ancestry) seem to retain their color longer.

In short, scientists are beginning to gather clues that stress can hasten the graying process, but there is no scientific evidence demonstrating a cause-and-effect relationship.  

So what happened to Marie Antoinette? There are at least three possible explanations: She may have suffered from sudden onset of the rare autoimmune disease alopecia areata, which attacks pigmented hairs, causing them to fall out, leaving the white (nonpigmented) strands behind. Or the stress of the situation could have generated a swarm of free radicals in her hair follicles, which traveled along the hair shafts, destroying pigment and creating a bleaching effect. Or maybe she just stopped wearing her wigs—revealing she had gray hair all along. 

Climate Change's Uncertainty Principle

Climate Change's Uncertainty Principle

Scientists say they can never be sure exactly how extreme global warming might become, but that's no excuse for delaying action  

	UNCERTAIN FUTURE:  Because small changes in things like snow cover or greenhouse gas concentrations lead to big climate effects, scientists will never be certain how bad global warming could be.

The Intergovernmental Panel on Climate Change in its first report in 1990 predicted that temperatures would warm by 0.5 degree Fahrenheit (0.3 degree Celsius) per decade if no efforts were made to restrain greenhouse gas emissions. But the panel of scientists and other experts was wrong: By 2001, the group estimated that average temperatures would increase by 2.7 to 8.1 degrees F (1.5 to 4.5 degrees C) in the 21st century, and they raised the lower end to 3.6 degrees F (2 degrees C) this year in their most recent report. In essence, neither this international team of experts nor any other can say with any certainty just how bad global warming may get.

There is a simple explanation for this, says atmospheric physicist Gerard Roe of the University of Washington (U.W.) in Seattle: Earth's climate is extremely sensitive. In other words, small changes in various physical processes that control climate lead to big results. "If nothing else changed by [warming], a doubling of carbon dioxide would ultimately lead to a temperature change of about 1.2 [degrees] C," [(2.1 degrees F)] Roe says. "In fact, because of internal processes within the climate system, such as changing snow cover, clouds and water vapor in the atmosphere, our best estimate is that the actual warming would be two to four times larger than that."

Some of these feedback processes are poorly understood—like how climate change affects clouds—and many are difficult to model, therefore the climate's propensity to amplify any small change makes predicting how much and how fast the climate will change inherently difficult. "Uncertainty and sensitivity are inextricably linked," Roe says. "Some warming is a virtual certainty, but the amount of that warming is much less certain."

 

Roe and his U.W. co-author, atmospheric physicist Marcia Baker, argue in Science that, because of this inherent climate effect, certainty is a near impossibility, no matter what kind of improvements are made in understanding physical processes or the timescale of observations.

"Once the world has warmed 4 degrees C [(7.2 degrees F)] conditions will be so different from anything we can observe today (and still more different from the last ice age) that it is inherently hard to say when the warming will stop," physicists Myles Allen and David Frame of the University of Oxford wrote in an editorial accompanying the article. "If the true climate sensitivity really is as high as 5 degrees C [(9 degrees F)], the only way our descendants will find that out is if they stubbornly hold greenhouse gas concentrations constant for centuries at our target stabilization level."

Therefore, waiting for more scientific certainty before acting is a mistake, Roe says. "People are comfortable with the idea that stock markets, housing prices and the weather are uncertain, and they are used to making decisions on that basis," he notes.

But this also means that targets such as stabilizing atmospheric concentrations of CO₂ at 450 parts per million (nearly double preindustrial levels) to avoid more than a 3.6 degree F (2 degree C) temperature rise are nearly impossible as well. There is no guarantee that such a target would achieve its stated goal. "Policymakers are always going to be faced with uncertainty and so the only sensible way forward to minimize risk is to adopt an adaptive policy," argues climatologist Gavin Schmidt of the NASA Goddard Institute of Space Studies, "which adjusts emissions targets and incentives based on how well, or badly, things are going."

It also means that scientists and other experts are going to have to monitor measures other than just atmospheric concentration of greenhouse gases to catch catastrophic climate change developing. "It is essential that we designate the harbingers of abrupt and significant changes or, perhaps more importantly, the triggers and thresholds that could commit the planet to these changes well before their tell-tale signs appear," says economist and IPCC author Gary Yohe of Wesleyan University in Middletown, Conn. "We cannot accept the adaptive design completely without having confidence in our abilities to determine exactly what to monitor."

The IPCC has taken a crack at that, identifying 26 "key vulnerabilities" in its most recent assessment, ranging from declines in agricultural productivity to the melting of ice sheets and polar ice cover as well as determining how to judge if they are spiraling out of control. Disappearing Arctic ice is already helping to amplify global warming beyond what the IPCC had predicted in the past. "We already know about as much as we are going to about climate system's response to greenhouse gases," Roe says. "We already have the basis for making the decisions we need to make."

 

Mass Extinctions Tied to Past Climate Changes

Mass Extinctions Tied to Past Climate Changes

Fossil and temperature records over the past 520 million years show a correlation between extinctions and climate change

	FOSSIL RECORD:  Analyzing the fossil record and past temperatures shows that a warming world is bad for the number of different plants and animals on Earth.

Roughly 251 million years ago, an estimated 70 percent of land plants and animals died, along with 84 percent of ocean organisms—an event known as the end Permian extinction. The cause is unknown but it is known that this period was also an extremely warm one. A new analysis of the temperature and fossil records over the past 520 million years reveals that the end of the Permian is not alone in this association: global warming is consistently associated with planetwide die-offs.

"There have been three major greenhouse phases in the time period we analyzed and the peaks in temperature of each coincide with mass extinctions," says ecologist Peter Mayhew of the University of York in England, who led the research examining the fossil and temperature records. "The fossil record and temperature data sets already existed but nobody had looked at the relationships between them."

Pairing these data—the relative number of different shallow sea organisms extant during a given time period and the record of temperature encased in the varying levels of oxygen isotopes in their shells over 10 million year intervals—reveals that eras with relatively high concentrations of greenhouse gases bode ill for the number of species on Earth. "The rule appears to be that greenhouse worlds adversely affect biodiversity," Mayhew says. 

That also bodes ill for the fate of species currently on Earth as the global temperatures continue to rise to levels similar to those seen during the Permian. "The risk of future extinction through rapid global warming is primarily expected to occur through mismatches between the climates to which organisms are adapted in their current range and the future distribution of those climates," Mayhew and his colleagues write in Proceedings of the Royal Society B: Biological Sciences, though it may also be that warmer temperatures lead to less hospitable seas, he adds.

That is not to say that global warming was the cause of this Permian wipeout or that all mass extinctions are associated with warmer worlds—witness the disappearance of 60 percent of different groups of marine organisms during the cooling at the end of the Ordovician period roughly 430 million years ago. But these scientists argue that the evidence of a link between climate change and mass extinctions gives reason to be concerned for the future. "We need to know the mechanism behind the associations and we need to know if associations of this sort also occur in shorter-term climatic fluctuations," Mayhew says. "That will help us decide if this is really a worry for the next generation or if the threat is merely a distant future threat."