SETTLING FOR ‘MR. RIGHT NOW’ BETTER THAN WAITING FOR ‘MR. RIGHT’

Evolutionary researchers have determined that settling for “Mr. Okay” is a better evolutionary strategy than waiting for “Mr. Perfect.” When studying the evolution of risk aversion researchers found that it is in our nature – traced back to the earliest humans – to take the safe bet when stakes are high, such as whether or not we will mate. Photo by D.L. Turner

Evolutionary researchers have determined that settling for “Mr. Okay” is a better evolutionary strategy than waiting for “Mr. Perfect.”

When studying the evolution of risk aversion, Michigan State University researchers found that it is in our nature – traced back to the earliest humans – to take the safe bet when stakes are high, such as whether or not we will mate.

“Primitive humans were likely forced to bet on whether or not they could find a better mate,” said Chris Adami, MSU professor of microbiology and molecular genetics and co-author of the paper.

“They could either choose to mate with the first, potentially inferior, companion and risk inferior offspring, or they could wait for Mr. or Ms. Perfect to come around,” he said. “If they chose to wait, they risk never mating.”

Adami and his co-author Arend Hintze, MSU research associate, used a computational model to trace risk-taking behaviors through thousands of generations of evolution with digital organisms. These organisms were programmed to make bets in high-payoff gambles, which reflect the life-altering decisions that natural organisms must make, as for example choosing a mate.

“An individual might hold out to find the perfect mate but run the risk of coming up empty and leaving no progeny,” Adami said. “Settling early for the sure bet gives you an evolutionary advantage, if living in a small group.”

Adami and his team tested many variables that influence risk-taking behavior and concluded that certain conditions influence our decision-making process. The decision must be a rare, once-in-a-lifetime event and also have a high payoff for the individual’s future – such as the odds of producing offspring.

How risk averse we are correlates to the size of the group in which we were raised. If reared in a small group – fewer than 150 people – we tend to be much more risk averse than those who were part of a larger community.

It turns out that primitive humans lived in smaller groups, about 150 individuals. Because resources tend to be more scarce in smaller communities, this environment helps promote risk aversion.

“We found that it is really the group size, not the total population size, which matters in the evolution of risk aversion,” Hintze said.

However, not everyone develops the same level of aversion to risk. The study also found that evolution doesn’t prefer one single, optimal way of dealing with risk, but instead allows for a range of less, and sometimes more-risky, behaviors to evolve.

“We do not all evolve to be the same,” Adami said. “Evolution creates a diversity in our acceptance of risk, so you see some people who are more likely to take bigger risks than others. We see the same phenomenon in our simulations.”

The research was part of an interdisciplinary collaboration with Ralph Hertwig of the Max Planck Institute for Human Development in Berlin.

Also contributing to the study was Randal Olson, graduate student, MSU Department of Computer Science and Engineering and BEACON Center for the Study of Evolution in Action.

Source: Michigan State University

New molecules to burst malaria's bubble

Dr Natalie Spillman. Credit: Alex Maier

Scientists have released details of a raft of new chemicals with potent anti-malarial properties which could open the way to new drugs to fight the disease.

A new paper in PNAS is the third published recently by a group at the Australian National University (ANU). The group has collaborated with scientists from around the globe to uncover potential ammunition in the fight against malaria.

Over 200 million people contract malaria each year, and the parasite that causes the disease has become resistant to most of the drugs currently available.

"The series of papers shows that the malaria parasite has a real Achilles heel, and describe a range of new ways to attack it," said Professor Kiaran Kirk, Dean of the College of Medicine, 
Biology and Environment and one of the scientists involved in the project.

Dr Natalie Spillman, from the Research School of Biology at ANU studied the mechanism by which the parasites are killed.

"The new molecules block a molecular salt pump at the surface of the parasite, causing it to fill up with salt," Dr Spillman said

"This has the effect of drawing water into the parasite, causing it to swell uncontrollably and burst."

Although the process of developing the new compounds into clinical drugs is complex and lengthy, Professor Kirk is optimistic the findings will lead to new treatments.

"It's very early days, but these pump-blocking compounds have some of the most promising anti-malarial potential we've seen," he says.

Aspects of the work were carried out with groups at Griffith University, Monash University and the Menzies School of Health Research in Darwin.

"This is a good example of a long-term, international drug development program in which Australian groups have played a key role," he said.

Source: Australian National University

Promising compound rapidly eliminates malaria parasite

A new report says that the rapid action of (+)-SJ733 will likely slow malaria drug resistance. Credit: Peter Barta, St. Jude Children's Research Hospital

An international research collaborative has determined that a promising anti-malarial compound tricks the immune system to rapidly destroy red blood cells infected with the malaria parasite but leave healthy cells unharmed. St. Jude Children's Research Hospital scientists led the study, which appears in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS).

The compound, (+)-SJ733, was developed from a molecule identified in a previous St. Jude-led study that helped to jumpstart worldwide anti-malarial drug development efforts. Malaria is caused by a parasite spread through the bite of an infected mosquito. The disease remains a major health threat to more than half the world's population, particularly children. The World Health Organization estimates that in Africa a child dies of malaria every minute.

In this study, researchers determined that (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable.

Planning has begun for safety trials of the compound in healthy adults.

Laboratory evidence suggests that the compound's speed and mode of action work together to slow and suppress development of drug-resistant parasites. Drug resistance has long undermined efforts to treat and block malaria transmission.

"Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," said corresponding author R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude."

Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, revealed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium.

The sequencing effort was led by co-author Joseph DeRisi, Ph.D., a Howard Hughes Medical Institute investigator and chair of the University of California, San Francisco Department of Biochemistry and Biophysics. Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite.

Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size. They also became more rigid and exhibited other alterations typical of aging red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of aging red blood cells.

Another promising class of antimalarial compounds triggered the same changes in red blood cells infected with the malaria parasite, researchers reported. The drugs, called spiroindolones, also target the ATP4 protein. The drugs include NITD246, which is already in clinical trials for treatment of malaria. Those trials involve investigators at other institutions.

"The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognize and rapidly eliminate infected cells," DeRisi said. "This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed."

Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said.

Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults. The drug development effort is being led by a consortium that includes scientists at St. Jude, the Swiss-based non-profit Medicines for Malaria Venture and Eisai Co., a Japanese pharmaceutical company.

Source: St. Jude Children's Research Hospital

Researchers ferret out a flu clue

Professor Michael Jennings, Deputy Director of the Institute for Glycomics. Credit: Image courtesy of Griffith University

Research that provides a new understanding as to why ferrets are similar to humans is set to have major implications for the development of novel drugs and treatment strategies.

Published in the journal Nature Communications, the research is a collaboration between Professor Michael Jennings and other researchers from the Institute for Glycomics, Griffith University and collaborators at the University of Queensland and the University of Adelaide.

The team has shown for the first time that ferrets share a mutation that was previously thought to be unique to humans, among the mammals. This helps to explain why the molecular characteristics of ferrets so uniquely mimic human susceptibility, severity and transmission of influenza A virus strains.

Professor Michael Jennings, Deputy Director of the Institute for Glycomics, says these findings open up a completely novel approach to tackling human diseases from influenza through to cancer.

"For over 80 years we've known that ferrets are uniquely susceptible to human influenza A virus, but the precise reason was unknown," Professor Jennings said.

"We have shown that ferrets have a mutation in a gene required to make a crucial sugar called sialic acid. Most animals can make two types of sialic acid. Ferrets, like humans can make only one. Different flu strains have preferences for the type of sialic acid they bind to cause infection. Because ferrets can only make the human form of this sugar, they are naturally "humanized" for the receptors recognised by human strains of the flu virus."

Source: Griffith University

Flu virus key machine: First complete view of structure revealed

The complete structure allows researchers to understand how the polymerase uses host cell RNA (red) to kick-start the production of viral messenger RNA. Credit: © EMBL/P.Riedinger

Scientists looking to understand -- and potentially thwart -- the influenza virus now have a much more encompassing view, thanks to the first complete structure of one of the flu virus' key machines. The structure, obtained by scientists at EMBL Grenoble, allows researchers to finally understand how the machine works as a whole, and could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics.

If you planned to sabotage a factory, a recon trip through the premises would probably be much more useful than just peeping in at the windows. Scientists looking to understand -- and potentially thwart -- the influenza virus have now gone from a similar window-based view to the full factory tour, thanks to the first complete structure of one of the flu virus' key machines. The structure, obtained by scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, allows researchers to finally understand how the machine works as a whole. Published in two papers in Nature, the work could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics.

The machine in question, the influenza virus polymerase, carries out two vital tasks for the virus. It makes copies of the virus' genetic material -- the viral RNA -- to package into new viruses that can infect other cells; and it reads out the instructions in that genetic material to make viral messenger RNA, which directs the infected cell to produce the proteins the virus needs. Scientists -- including Cusack and collaborators -- had been able to determine the structure of several parts of the polymerase in the past. But how those parts came together to function as a whole, and how viral RNA being fed in to the polymerase could be treated in two different ways remained a mystery.

"The flu polymerase was discovered 40 years ago, so there are hundreds of papers out there trying to fathom how it works. But only now that we have the complete structure can we really begin to understand it," says Stephen Cusack, head of EMBL Grenoble, who led the work.

Using X-ray crystallography, performed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, Cusack and colleagues were able to determine the atomic structure of the whole polymerase from two strains of influenza: influenza B, one of the strains that cause seasonal flu in humans, but which evolves slowly and therefore isn't considered a pandemic threat; and the strain of influenza A -- the fast-evolving strain that affects humans, birds and other animals and can cause pandemics -- that infects bats.

"The high-intensity X-ray beamlines at the ESRF, equipped with state-of-the-art Dectris detectors, were crucial for getting high quality crystallographic data from the weakly diffracting and radiation sensitive crystals of the large polymerase complex," says Cusack. "We couldn't have got the data at such a good resolution without them."

The structures reveal how the polymerase specifically recognises and binds to the viral RNA, rather than just any available RNA, and how that binding activates the machine. They also show that the three component proteins that make up the polymerase are very intertwined, which explains why it has been very difficult to piece together how this machine works based on structures of individual parts.

Although the structures of both viruses' polymerases were very similar, the scientists found one key difference, which showed that one part of the machine can swivel around to a large degree. That ability to swivel explains exactly how the polymerase uses host cell RNA to kick-start the production of viral proteins. The swivelling component takes the necessary piece of host cell RNA and directs it into a slot leading to the machine's heart, where it triggers the production of viral messenger RNA.

Now that they know exactly where each atom fits in this key viral machine, researchers aiming to design drugs to stop influenza in its tracks have a much wider range of potential targets at their disposal -- like would-be saboteurs who gain access to the whole production plant instead of just sneaking looks through the windows. And because this is such a fundamental piece of the viral machinery, not only are the versions in the different influenza strains very similar to each other, but they also hold many similarities to their counterparts in related viruses such as lassa, hanta, rabies or ebola.

The EMBL scientists aim to explore the new insights this structure provides for drug design, as well as continuing to try to determine the structure of the human version of influenza A, because although the bat version is close enough that it already provides remarkable insights, ultimately fine-tuning drugs for treating people would benefit from/require knowledge of the version of the virus that infects humans. And, since this viral machine has to be flexible and change shape to carry out its different tasks, Cusack and colleagues also want to get further snapshots of the polymerase in different states.

"This doesn't mean we now have all the answers," says Cusack, "In fact, we have as many new questions as answers, but at least now we have a solid basis on which to probe further."

Source: European Molecular Biology Laboratory (EMBL)