Scientists working at the MRC Laboratory of Molecular Biology have founded a spin-out company called Heptares Therapeutics Ltd that aims to design and develop new drugs to tackle diseases involving the nervous system and metabolism. The company will focus on structural studies of a family of proteins present in the cell membrane called G-protein coupled receptors - already an established drug target family.
The pioneering work of LMB scientists Richard Henderson and Chris Tate enabled them to found the company together with Malcolm Weir (Chief Executive Officer) and Fiona Marshall (Chief Scientific Officer). A wider group of MRC scientists, including Gebhard Schertler, and Ed Hulme of the National Institute for Medical research, Mill Hill, London also contributed their expertise. John Berriman is Chairman, and Heptares will be based at Mill Hill in London.
The new drug discovery company has received seed funding from the venture capital firm MVM Life Sciences Partners LLP. Dr Martin Murphy of MVM said:
''Investing in early-stage biotechnologies carries a high risk and so we make relatively few such investments. However, it is clear that if Heptares' technologies can be successfully industrialised as a consequence of our seed-funding, the company has the potential to create the kind of high value necessary to balance such risks".
"The MRC aims to turn basic, long-term research such as this into healthcare that improves human health. A start-up company with first class investors, management and founding scientists like this is one of the ways we can achieve this goal. We're hopeful Heptares will pay dividends to the UK in the future both in terms of economic value but also in tackling disease," said Mike Dalrymple, Acting CEO of MRC Technology.
In a further development, MRC Technology (MRCT) has signed an antibody development agreement with the company Organon, to develop a humanised antibody for use in cancer treatment. The mouse version of the antibody and its cancer-fighting properties were discovered at Organon's research centre in Cambridge, Massachusetts.
The agreement will use the MRCT Therapeutic Antibody Group's long-standing expertise in generating versions of antibodies that are suitable to be used in people.
David Nicholson, Organon Executive Vice President of Global Research and Development said:
"Organon has been stepping up its efforts to discover and develop novel bio-therapeutics for oncology and auto-immune disorders. The collaboration with MRCT on its well-validated antibody humanisation technology is a further step towards becoming effective bio-therapeutic drug hunters."
mrc.ac.uk
суббота, 21 мая 2011 г.
Crammed With Charged DNA, Pressure Rises Inside Virus
It could be an artist's depiction of someone's stomach before and after a rather decadent meal. But it is a 3-D cryoelectron microscope reconstruction of the cross-section of a virus, before and after cramming itself full of its own DNA.
The virus, phi29, has a tiny motor that pumps its DNA into the capsid-outer shell-during the assembly process. The potential energy of the tightly coiled DNA may help phi29 inject its genetic material into the bacterial cells it infects. Now a team led by physicists at the University of California, San Diego has used laser tweezers to measure the forces exerted by the motor as it pushes the DNA into the capsid.
"The virus' motor has to do mechanical work to overcome two factors that create resistance," said Douglas Smith, an assistant professor of physics at UCSD who headed the team that published the discovery this week in the early on-line edition of Proceedings of the National Academy of Sciences. "First, the DNA must be forced to bend. Second, the electrostatic repulsion of the DNA's negatively charged backbone must be overcome. We found that the positively charged ions in the solution are critical to overcoming this repulsion. Without the right combination of positively charged ions, the virus could not force all of its DNA into the capsid."
The researchers discovered that the forces in the capsid are slightly higher than predicted by theoretical calculations. They say this may be because the packed DNA is less ordered than assumed in the calculations.
Other members of research team were Derek Fuller and John Peter Rickgauer at UCSD, and Shelley Grimes, Paul Jardine and Dwight Anderson at the University of Minnesota. The study was supported by grants from the National Institutes of Health, Burroughs-Wellcome Fund, Kinship Foundation and Arnold and Mabel Beckman Foundation.
ucsdnews.ucsd
The virus, phi29, has a tiny motor that pumps its DNA into the capsid-outer shell-during the assembly process. The potential energy of the tightly coiled DNA may help phi29 inject its genetic material into the bacterial cells it infects. Now a team led by physicists at the University of California, San Diego has used laser tweezers to measure the forces exerted by the motor as it pushes the DNA into the capsid.
"The virus' motor has to do mechanical work to overcome two factors that create resistance," said Douglas Smith, an assistant professor of physics at UCSD who headed the team that published the discovery this week in the early on-line edition of Proceedings of the National Academy of Sciences. "First, the DNA must be forced to bend. Second, the electrostatic repulsion of the DNA's negatively charged backbone must be overcome. We found that the positively charged ions in the solution are critical to overcoming this repulsion. Without the right combination of positively charged ions, the virus could not force all of its DNA into the capsid."
The researchers discovered that the forces in the capsid are slightly higher than predicted by theoretical calculations. They say this may be because the packed DNA is less ordered than assumed in the calculations.
Other members of research team were Derek Fuller and John Peter Rickgauer at UCSD, and Shelley Grimes, Paul Jardine and Dwight Anderson at the University of Minnesota. The study was supported by grants from the National Institutes of Health, Burroughs-Wellcome Fund, Kinship Foundation and Arnold and Mabel Beckman Foundation.
ucsdnews.ucsd
New Study Reveals Structure Of The HIV Protein Shell
New research by scientists at The Scripps Research Institute and other institutions provides a close-up look at the cone-shaped shell that is the hallmark of human immunodeficiency virus (HIV), revealing how it is held together - and possible ways to break it apart.
Previously, scientists had known that the genetic material within HIV is enclosed within a shell called the capsid, which is formed by a honeycomb arrangement of about 250 hexagonal protein building blocks. For HIV to infect human cells, the virus binds to cell surface receptors, and then the capsid is delivered into the cytoplasm of the cell.
Now, in an advance, online issue of the journal Cell published on June 11, 2009, Professor Mark Yeager and colleagues at The Scripps Research Institute, the University of Virginia, and the University of Utah describethe first high-resolution molecular structure of the hexagonal protein building block, called CA, that makes up the HIV capsid. This detailed description may help scientists identify new ways to block HIV infection.
Bringing Down the Capsid
Since HIV/AIDS was first recognized in 1981, several drugs and drug combinations have allowed infected individuals to live longer and healthier lives. However, resistance to the existing drugs has created an urgent need for novel therapeutic strategies.
Current drugs target critical steps in the virus life cycle. For example, protease inhibitors block the protein cleavages that generate viral components - one of them being the protein CA.
Other possible ways to block infection would be to prevent formation of the capsid by blocking assembly of CA molecules or to find a way to disassemble the capsid once it is made.
"Anything that destabilizes the capsid, either by inhibiting assembly or accelerating disassembly should attenuate or even kill the virus," says Owen Pornillos, an investigator in Yeager's lab and first author of the Cell paper.
But to destabilize the capsid, it's necessary to know precisely how it is held together.
Making Crystals
"No one had been able to visualize the CA hexamer at atomic resolution," says Yeager. "Other groups had been able to solve structures of individual regions of CA. But it was not clear from these structures exactly how the CA proteins fit together."
To make the capsid, sets of six CA protein molecules first form hexamers, which then associate with one another to build a honeycomb-like shell comprised of about 250 hexamers. The ends of the shell are closed by insertion of seven and five CA protein pentamers, yielding the characteristic cone-like appearance of the capsid.
In 2007, Yeager's group managed to view the CA hexamers by a type of electron microscopy in which the samples are quick frozen in buffers, which preserves the inherent structure of proteins. That study provided the first glimpse of how CA proteins are arranged in the capsid. (The first author of the 2007 article was Barbie Ganser-Pornillos, Owen Pornillos' wife, who was also involved in the current study.)
In order to view the CA hexamer at even higher resolution, Yeager's group turned to X-ray crystallography. This technique requires growing 3D crystals of a molecule and then scattering a beam of X-rays off the crystals, which are recorded on a detector. Computational methods are then used to interpret the scattering patterns to calculate the position of every atom in the crystallized molecule.
But growing large, 3D crystals of the CA hexamer was no easy feat. The two ends of each CA protein molecule are held together by a "floppy" bridge, which precluded formation of orderly arrays of CA hexamers to form 3D crystals.
To overcome the problem, Pornillos and Yeager turned to molecular biology. They engineered CA proteins that would form sturdy chemical links between them, relying on the 2007 structure as their roadmap to determine exactly where to place the links.
"Our work takes advantage of so-called hybrid methods - molecular biology, biochemistry, electron microscopy, and X-ray crystallography," says Yeager. "These methods are synergistic. The EM results guided the molecular biology to engineer stable CA hexamers that were then amenable to 3D crystallization and X-ray structure analysis at atomic resolution."
The structure they obtained provided a view of the CA hexamer at an unprecedented resolution of two-Г…ngstrom (one Г…ngstrom equals one ten-billionth of a meter).
A Close-Up Look
All proteins are composed of linear chains of amino acids - with one end called the N-terminus and the opposite end the C-terminus - that are folded in three-dimensional shapes. In the CA protein, amino acid chains are twisted into several rods, called a-helices, with extensions - called side chains - that protrude from the main chain to interact with other folded regions of the protein.
The two-Г…ngstrom structure showed the positioning of these a-helices and, for the first time, the location of the atoms in the side chains. "We could precisely delineate all the chemical interactions that stabilize the hexamer," says Yeager.
The center of the CA hexamer is formed by 6 N-terminal ends of the CA protein subunits. The C-terminal domains form a "floppy" belt around this central core, connecting adjacent hexamers. The fact that the belt is not held rigidly in place, helps explain how the honeycomb shape of the capsid forms. "The curvature of the capsid is not constant," says Pornillos. "Now we can see in atomic detail how flexibility in CA makes this happen."
The group discovered another set of interactions critical to stabilizing the capsid - connections between the N-terminal and C-terminal ends of adjacent CA protein molecules in one hexamer. "Think of the fingers of one hand as the N-terminal domain and the palm as the C-terminal," says Yeager. "Imagine the fingers of one hand being cradled in the palm of the other, and so on as if you had six hands in a ring."
Knowing precisely how and where CA proteins interact gives researchers clues on how to interfere with these connections. One approach is to design small molecules that can insert themselves at strategic positions, impeding capsid assembly or making the capsid less stable.
While finding HIV therapies is a main driver for Yeager's work, he points out that it also provides fundamental insights into biology. "Determining the assembly of a relatively simple structure like the capsid of a virus can help us understand how more complex biological structures inside the cell are organized," he explains.
Notes:
In addition to Yeager, Pornillos, and Ganser-Pornillos of Scripps Research and the University of Virginia, co-authors of the paper "X-Ray Structures of the Hexameric Building Block of the HIV Capsid," include Yuanzi Hua and C. David Stout at Scripps Research, and Brian N. Kelly, Frank G. Whitby, Wesley I. Sundquist, and Christopher P. Hill at the University of Utah School of Medicine. For more information, see cell/abstract/S0092-8674(09)00580-7.
This study was funded by the National Institutes of Health and the George E. Hewitt Foundation for Medical Research. Facilities supported by the National Institutes of Health and the U.S. Department of Energy were also used to collect data.
Source:
Keith Mckeown
Scripps Research Institute
Previously, scientists had known that the genetic material within HIV is enclosed within a shell called the capsid, which is formed by a honeycomb arrangement of about 250 hexagonal protein building blocks. For HIV to infect human cells, the virus binds to cell surface receptors, and then the capsid is delivered into the cytoplasm of the cell.
Now, in an advance, online issue of the journal Cell published on June 11, 2009, Professor Mark Yeager and colleagues at The Scripps Research Institute, the University of Virginia, and the University of Utah describethe first high-resolution molecular structure of the hexagonal protein building block, called CA, that makes up the HIV capsid. This detailed description may help scientists identify new ways to block HIV infection.
Bringing Down the Capsid
Since HIV/AIDS was first recognized in 1981, several drugs and drug combinations have allowed infected individuals to live longer and healthier lives. However, resistance to the existing drugs has created an urgent need for novel therapeutic strategies.
Current drugs target critical steps in the virus life cycle. For example, protease inhibitors block the protein cleavages that generate viral components - one of them being the protein CA.
Other possible ways to block infection would be to prevent formation of the capsid by blocking assembly of CA molecules or to find a way to disassemble the capsid once it is made.
"Anything that destabilizes the capsid, either by inhibiting assembly or accelerating disassembly should attenuate or even kill the virus," says Owen Pornillos, an investigator in Yeager's lab and first author of the Cell paper.
But to destabilize the capsid, it's necessary to know precisely how it is held together.
Making Crystals
"No one had been able to visualize the CA hexamer at atomic resolution," says Yeager. "Other groups had been able to solve structures of individual regions of CA. But it was not clear from these structures exactly how the CA proteins fit together."
To make the capsid, sets of six CA protein molecules first form hexamers, which then associate with one another to build a honeycomb-like shell comprised of about 250 hexamers. The ends of the shell are closed by insertion of seven and five CA protein pentamers, yielding the characteristic cone-like appearance of the capsid.
In 2007, Yeager's group managed to view the CA hexamers by a type of electron microscopy in which the samples are quick frozen in buffers, which preserves the inherent structure of proteins. That study provided the first glimpse of how CA proteins are arranged in the capsid. (The first author of the 2007 article was Barbie Ganser-Pornillos, Owen Pornillos' wife, who was also involved in the current study.)
In order to view the CA hexamer at even higher resolution, Yeager's group turned to X-ray crystallography. This technique requires growing 3D crystals of a molecule and then scattering a beam of X-rays off the crystals, which are recorded on a detector. Computational methods are then used to interpret the scattering patterns to calculate the position of every atom in the crystallized molecule.
But growing large, 3D crystals of the CA hexamer was no easy feat. The two ends of each CA protein molecule are held together by a "floppy" bridge, which precluded formation of orderly arrays of CA hexamers to form 3D crystals.
To overcome the problem, Pornillos and Yeager turned to molecular biology. They engineered CA proteins that would form sturdy chemical links between them, relying on the 2007 structure as their roadmap to determine exactly where to place the links.
"Our work takes advantage of so-called hybrid methods - molecular biology, biochemistry, electron microscopy, and X-ray crystallography," says Yeager. "These methods are synergistic. The EM results guided the molecular biology to engineer stable CA hexamers that were then amenable to 3D crystallization and X-ray structure analysis at atomic resolution."
The structure they obtained provided a view of the CA hexamer at an unprecedented resolution of two-Г…ngstrom (one Г…ngstrom equals one ten-billionth of a meter).
A Close-Up Look
All proteins are composed of linear chains of amino acids - with one end called the N-terminus and the opposite end the C-terminus - that are folded in three-dimensional shapes. In the CA protein, amino acid chains are twisted into several rods, called a-helices, with extensions - called side chains - that protrude from the main chain to interact with other folded regions of the protein.
The two-Г…ngstrom structure showed the positioning of these a-helices and, for the first time, the location of the atoms in the side chains. "We could precisely delineate all the chemical interactions that stabilize the hexamer," says Yeager.
The center of the CA hexamer is formed by 6 N-terminal ends of the CA protein subunits. The C-terminal domains form a "floppy" belt around this central core, connecting adjacent hexamers. The fact that the belt is not held rigidly in place, helps explain how the honeycomb shape of the capsid forms. "The curvature of the capsid is not constant," says Pornillos. "Now we can see in atomic detail how flexibility in CA makes this happen."
The group discovered another set of interactions critical to stabilizing the capsid - connections between the N-terminal and C-terminal ends of adjacent CA protein molecules in one hexamer. "Think of the fingers of one hand as the N-terminal domain and the palm as the C-terminal," says Yeager. "Imagine the fingers of one hand being cradled in the palm of the other, and so on as if you had six hands in a ring."
Knowing precisely how and where CA proteins interact gives researchers clues on how to interfere with these connections. One approach is to design small molecules that can insert themselves at strategic positions, impeding capsid assembly or making the capsid less stable.
While finding HIV therapies is a main driver for Yeager's work, he points out that it also provides fundamental insights into biology. "Determining the assembly of a relatively simple structure like the capsid of a virus can help us understand how more complex biological structures inside the cell are organized," he explains.
Notes:
In addition to Yeager, Pornillos, and Ganser-Pornillos of Scripps Research and the University of Virginia, co-authors of the paper "X-Ray Structures of the Hexameric Building Block of the HIV Capsid," include Yuanzi Hua and C. David Stout at Scripps Research, and Brian N. Kelly, Frank G. Whitby, Wesley I. Sundquist, and Christopher P. Hill at the University of Utah School of Medicine. For more information, see cell/abstract/S0092-8674(09)00580-7.
This study was funded by the National Institutes of Health and the George E. Hewitt Foundation for Medical Research. Facilities supported by the National Institutes of Health and the U.S. Department of Energy were also used to collect data.
Source:
Keith Mckeown
Scripps Research Institute
1 Dose Of New Drug Cures Malaria-Infected Mice
Johns Hopkins University researchers have cured malaria-infected mice with single shots of a new series of potent, long lasting synthetic drugs modeled on an ancient Chinese herbal folk remedy.
The team also has developed several other compounds which defeated the febrile disease in rodents after three oral doses.
These peroxide compounds, containing a crucial oxygen-oxygen unit, promise not only to be more effective than today's best malaria remedies, but also potentially safer and more efficient, said research team leader Gary Posner, Scowe Professor of Chemistry in the Krieger School of Arts and Sciences at Johns Hopkins.
An article about the team's work appears on the Web in the ASAP section of The Journal of Medicinal Chemistry.
"We are disclosing, for the first time, the curative activity of a new generation of compounds that are long-lasting and therapeutic, even when used by themselves," Posner said. "Older drugs in this family of peroxide antimalarials also are known to be fast-acting, but they are unfortunately short-lived and not curative when used by themselves."
Though they say their results are very promising, the researchers caution that the new compounds must be thoroughly tested for safety and for how they are absorbed, distributed and metabolized in, and eliminated from, rodents' bodies before human tests begin.
Malaria afflicts between 300 million and 500 million people a year, killing between 1.5 million and 3 million, mostly children and mostly in developing nations. The parasite that causes the disease is spread by female mosquitoes feeding on human blood. The most commonly fatal species of the malaria parasite now shows strong resistance to most current treatments, making the development of effective new drugs a worldwide priority.
Since 1992, Posner and his team, which includes collaborator Theresa Shapiro, professor and chair of clinical pharmacology at the Johns Hopkins School of Medicine, have been tackling that challenge by designing a series of peroxide compounds, called trioxanes.
"As a class, these compounds have proven to be unusually valuable in several ways, from their brisk and potent antimalarial activity to their lack of resistance and cross-resistance with other antimalarial agents," Shapiro said.
The Johns Hopkins trioxanes mimic artemisinin, the active agent in a Chinese herbal drug used to treat malaria and other fevers for thousands of years. Artemisinin comes from the Artemisia annua plant, an herb also known by a variety of names including sweet wormwood.
The oxygen-oxygen unit in the peroxides causes malaria parasites essentially to self-destruct. The parasites digest hemoglobin, the oxygen-carrying pigment of red blood cells, and, in the process, release a substance called heme, a deep-red iron-containing blood pigment. When the heme encounters peroxides, a powerful chemical reaction occurs, releasing carbon-free radicals and oxidizing agents that eventually kill the parasites.
But the first generation of trioxane drugs also had a number of shortcomings, including a half-life of less than one hour. (A drug's half-life is the amount of time it takes for half of it to be metabolized.) Posner and team believe that their new compounds address those disadvantages.
"Our semi-synthetic artemisinin-derived compounds successfully overcome the disadvantages of their first-generation predecessors," he said. "Most important is their curative activity after a single, low dose, which is distinctly unusual. But based on our intentional design, they may also have a longer half-life in animals. We also designed them to be more lipophilic, meaning they have an enhanced ability to dissolve in fats and thus to arrive inside malaria-infected red blood cells."
In addition, the new compounds are far less likely to break down into toxic substances when they are metabolized in the test animals' bodies, making them potentially safer than their predecessors.
Although the substance is inexpensive by Western standards, the widespread use of artemisinins in the developing world remains limited, in part by availability and the cost of separating the active ingredient from the Artemisia annua plant. Posner and his team contend that the potency and curative activity of their compounds provide "a substantially more efficient and economical use of the price-setting natural product."
The team's research was supported by the National Institutes of Health and the Johns Hopkins University Malaria Research Institute.
Contact: Lisa De Nike
Johns Hopkins University
The team also has developed several other compounds which defeated the febrile disease in rodents after three oral doses.
These peroxide compounds, containing a crucial oxygen-oxygen unit, promise not only to be more effective than today's best malaria remedies, but also potentially safer and more efficient, said research team leader Gary Posner, Scowe Professor of Chemistry in the Krieger School of Arts and Sciences at Johns Hopkins.
An article about the team's work appears on the Web in the ASAP section of The Journal of Medicinal Chemistry.
"We are disclosing, for the first time, the curative activity of a new generation of compounds that are long-lasting and therapeutic, even when used by themselves," Posner said. "Older drugs in this family of peroxide antimalarials also are known to be fast-acting, but they are unfortunately short-lived and not curative when used by themselves."
Though they say their results are very promising, the researchers caution that the new compounds must be thoroughly tested for safety and for how they are absorbed, distributed and metabolized in, and eliminated from, rodents' bodies before human tests begin.
Malaria afflicts between 300 million and 500 million people a year, killing between 1.5 million and 3 million, mostly children and mostly in developing nations. The parasite that causes the disease is spread by female mosquitoes feeding on human blood. The most commonly fatal species of the malaria parasite now shows strong resistance to most current treatments, making the development of effective new drugs a worldwide priority.
Since 1992, Posner and his team, which includes collaborator Theresa Shapiro, professor and chair of clinical pharmacology at the Johns Hopkins School of Medicine, have been tackling that challenge by designing a series of peroxide compounds, called trioxanes.
"As a class, these compounds have proven to be unusually valuable in several ways, from their brisk and potent antimalarial activity to their lack of resistance and cross-resistance with other antimalarial agents," Shapiro said.
The Johns Hopkins trioxanes mimic artemisinin, the active agent in a Chinese herbal drug used to treat malaria and other fevers for thousands of years. Artemisinin comes from the Artemisia annua plant, an herb also known by a variety of names including sweet wormwood.
The oxygen-oxygen unit in the peroxides causes malaria parasites essentially to self-destruct. The parasites digest hemoglobin, the oxygen-carrying pigment of red blood cells, and, in the process, release a substance called heme, a deep-red iron-containing blood pigment. When the heme encounters peroxides, a powerful chemical reaction occurs, releasing carbon-free radicals and oxidizing agents that eventually kill the parasites.
But the first generation of trioxane drugs also had a number of shortcomings, including a half-life of less than one hour. (A drug's half-life is the amount of time it takes for half of it to be metabolized.) Posner and team believe that their new compounds address those disadvantages.
"Our semi-synthetic artemisinin-derived compounds successfully overcome the disadvantages of their first-generation predecessors," he said. "Most important is their curative activity after a single, low dose, which is distinctly unusual. But based on our intentional design, they may also have a longer half-life in animals. We also designed them to be more lipophilic, meaning they have an enhanced ability to dissolve in fats and thus to arrive inside malaria-infected red blood cells."
In addition, the new compounds are far less likely to break down into toxic substances when they are metabolized in the test animals' bodies, making them potentially safer than their predecessors.
Although the substance is inexpensive by Western standards, the widespread use of artemisinins in the developing world remains limited, in part by availability and the cost of separating the active ingredient from the Artemisia annua plant. Posner and his team contend that the potency and curative activity of their compounds provide "a substantially more efficient and economical use of the price-setting natural product."
The team's research was supported by the National Institutes of Health and the Johns Hopkins University Malaria Research Institute.
Contact: Lisa De Nike
Johns Hopkins University
Knuckle-Walking Evolved At 2 Different Times
A detailed examination of the wrist bones of several primate species challenges the notion that humans evolved their two-legged upright walking style from a knuckle-walking ancestor.
The same lines of evidence also suggest that knuckle-walking evolved at least two different times, making gorillas distinct from chimpanzees and bonobos.
"We have the most robust data I've ever seen on this topic," said Daniel Schmitt, a Duke University associate professor of evolutionary anthropology. "This model should cause everyone to re-evaluate what they've said before."
A report on the findings will appear online during the week of Aug. 10 in the research journal Proceedings of the National Academy of Sciences.
The research, led by post-doctoral research associate Tracy Kivell, was supported by the Natural Sciences and Engineering Research Council in her native Canada, General Motors' Women in Science and Mathematics, and the University of Toronto, where Kivell did her Ph.D. work.
The debate over the origins of human bipedalism began during Charles Darwin's lifetime and continues vigorously to this day, commonly dividing into two competing models, the researchers explained.
One model "envisions the pre-human ancestor as a terrestrial knuckle-walker, a behavior frequently used by our closest living relatives, the African apes," they wrote in the PNAS report. The other model traces our two-legged walking to earlier tree-climbing, a mode of locomotion that is used by all living apes.
Supporters of the knuckle-walking origin think we and African apes evolved from a common knuckle walking ancestor. That connection, they contend, is still evident in wrist and hand bone features shared by African apes and by fossil and living humans.
But Kivell found otherwise when she began comparing juvenile and adult wrist bones of more than 100 chimps and bonobos, our closest living primate kin, with those of gorillas.
Significantly, two key features associated with knuckle walking were present in only 6 percent of the gorilla specimens she studied. But she found them in 96 percent of adult chimpanzees and 76 percent of bonobos. In all, she looked at specimens from 91 gorillas, 104 chimps and 43 bonobos.
Kivell and Schmitt suggested that one explanation for the absence of these features in gorillas is that they knuckle-walk in a fundamentally different way from chimps and bonobos. Gorillas stride with their arms and wrists extended straight down and locked in what Kivell called "columnar" stances that resemble how elephants walk. By contrast, chimps and bonobos walk more flexibly, "with their wrists in a bent position as opposed to being stacked-up," she said. "And with their wrists in bent positions there will be more stresses at those joints."
As a result, chimp and bonobo wrists have special features that gorillas lack -- little ridges and concavities that serve as "bony stops" to keep their wrists from over-bending. Gorillas don't need those, she added.
"When we first got together to work on this study that (difference) really jumped out in living color," Schmitt said.
"Then we sat down together and asked: 'What are the differences between them?' Schmitt said. "The answer is that chimps and bonobos spend a lot of time in the trees. And gorillas do not."
Chimpanzees and bonobos have a more extended-wrist way of knuckle-walking which gives them added stability on branches, the researchers concluded. In contrast, gorillas' "columnar" style of knuckle-walking is consistent with ground transport.
Indeed, "from what we know about knuckle-walking among wild populations, gorillas and adult chimpanzees will both knuckle-walk about 85 percent of the time that they're moving," Kivell said. "But chimpanzees and bonobos are more arboreal than gorillas. So they're doing a lot more of it in the trees."
Kivell and Schmitt think this suggests independent evolution of knuckle-walking behavior in the two African ape lineages.
Some scientists point to features in the human anatomy as our own vestiges of a knuckle-walking ancestry. One notable example is the fusion a two wrist bones that could provide us extra stability, a feature we share with gorillas, chimps and bonobos.
But some lemurs have that feature too, and they do a variety of different movements in the trees but do not knuckle-walk, Kivell said.
Altogether, the evidence leans against the idea that our own bipedalism evolved from a knuckle-walking ancestor, the pair wrote. "Instead, our data support the opposite notion, that features of the hand and wrist found in the human fossil record that have traditionally been treated as indicators of knuckle-walking behavior in general are in fact evidence of arboreality."
In other words, a long-ago ancestor species that spent its time in the trees moved to the ground and began walking upright.
There are no fossils from the time of this transition, which likely occurred about seven million years ago, Kivell and Schmitt said. But none of the later fossils considered to be on the direct human line were knuckle-walkers.
Source:
Monte Basgall
Duke University
The same lines of evidence also suggest that knuckle-walking evolved at least two different times, making gorillas distinct from chimpanzees and bonobos.
"We have the most robust data I've ever seen on this topic," said Daniel Schmitt, a Duke University associate professor of evolutionary anthropology. "This model should cause everyone to re-evaluate what they've said before."
A report on the findings will appear online during the week of Aug. 10 in the research journal Proceedings of the National Academy of Sciences.
The research, led by post-doctoral research associate Tracy Kivell, was supported by the Natural Sciences and Engineering Research Council in her native Canada, General Motors' Women in Science and Mathematics, and the University of Toronto, where Kivell did her Ph.D. work.
The debate over the origins of human bipedalism began during Charles Darwin's lifetime and continues vigorously to this day, commonly dividing into two competing models, the researchers explained.
One model "envisions the pre-human ancestor as a terrestrial knuckle-walker, a behavior frequently used by our closest living relatives, the African apes," they wrote in the PNAS report. The other model traces our two-legged walking to earlier tree-climbing, a mode of locomotion that is used by all living apes.
Supporters of the knuckle-walking origin think we and African apes evolved from a common knuckle walking ancestor. That connection, they contend, is still evident in wrist and hand bone features shared by African apes and by fossil and living humans.
But Kivell found otherwise when she began comparing juvenile and adult wrist bones of more than 100 chimps and bonobos, our closest living primate kin, with those of gorillas.
Significantly, two key features associated with knuckle walking were present in only 6 percent of the gorilla specimens she studied. But she found them in 96 percent of adult chimpanzees and 76 percent of bonobos. In all, she looked at specimens from 91 gorillas, 104 chimps and 43 bonobos.
Kivell and Schmitt suggested that one explanation for the absence of these features in gorillas is that they knuckle-walk in a fundamentally different way from chimps and bonobos. Gorillas stride with their arms and wrists extended straight down and locked in what Kivell called "columnar" stances that resemble how elephants walk. By contrast, chimps and bonobos walk more flexibly, "with their wrists in a bent position as opposed to being stacked-up," she said. "And with their wrists in bent positions there will be more stresses at those joints."
As a result, chimp and bonobo wrists have special features that gorillas lack -- little ridges and concavities that serve as "bony stops" to keep their wrists from over-bending. Gorillas don't need those, she added.
"When we first got together to work on this study that (difference) really jumped out in living color," Schmitt said.
"Then we sat down together and asked: 'What are the differences between them?' Schmitt said. "The answer is that chimps and bonobos spend a lot of time in the trees. And gorillas do not."
Chimpanzees and bonobos have a more extended-wrist way of knuckle-walking which gives them added stability on branches, the researchers concluded. In contrast, gorillas' "columnar" style of knuckle-walking is consistent with ground transport.
Indeed, "from what we know about knuckle-walking among wild populations, gorillas and adult chimpanzees will both knuckle-walk about 85 percent of the time that they're moving," Kivell said. "But chimpanzees and bonobos are more arboreal than gorillas. So they're doing a lot more of it in the trees."
Kivell and Schmitt think this suggests independent evolution of knuckle-walking behavior in the two African ape lineages.
Some scientists point to features in the human anatomy as our own vestiges of a knuckle-walking ancestry. One notable example is the fusion a two wrist bones that could provide us extra stability, a feature we share with gorillas, chimps and bonobos.
But some lemurs have that feature too, and they do a variety of different movements in the trees but do not knuckle-walk, Kivell said.
Altogether, the evidence leans against the idea that our own bipedalism evolved from a knuckle-walking ancestor, the pair wrote. "Instead, our data support the opposite notion, that features of the hand and wrist found in the human fossil record that have traditionally been treated as indicators of knuckle-walking behavior in general are in fact evidence of arboreality."
In other words, a long-ago ancestor species that spent its time in the trees moved to the ground and began walking upright.
There are no fossils from the time of this transition, which likely occurred about seven million years ago, Kivell and Schmitt said. But none of the later fossils considered to be on the direct human line were knuckle-walkers.
Source:
Monte Basgall
Duke University
New Tissue-Engineering Research Focuses On Vocal Cords
Damaged or diseased vocal cords can forever change and even silence the voices we love, from a family member's to a famous personality's.
Julie Andrews, who starred in such classics as The Sound of Music, is among the professional singers who have undergone surgery to remove callus-like growths that can form from overuse of these two small, stretchy bands of tissue housed in the larynx, or voice box. Sadly, Andrews may never fully recover her singing voice after surgery on her vocal cords in 1997.
Engineering pliable, new vocal cord tissue to replace scarred, rigid tissue in these petite, yet powerful organs is the goal of a new University of Delaware research project. It is funded by a five-year, $1.8 million grant from the National Institutes of Health's National Institute on Deafness and Other Communication Disorders.
Xinqiao Jia, UD assistant professor of materials science and engineering, is leading the project. Jia's research focuses on developing intelligent biomaterials that closely mimic the molecular composition, mechanical responsiveness and nanoscale organization of natural extracellular matrices--the structural materials that serve as scaffolding for cells. These novel biomaterials, combined with defined biophysical cues and biological factors, are being used for functional tissue regeneration.
Randall Duncan, associate professor of biological sciences and mechanical engineering at UD and an expert in cellular biomechanics and signal transduction, is a co-investigator on the project. He will assist the interdisciplinary research team in determining how vocal cord cells respond to mechanical forces, which is the first step in engineering functional vocal cord tissue. Duncan is actively involved in Jia's career development as her senior mentor at UD.
Rodney Clifton, professor of engineering at Brown University and a member of the National Academy of Engineering, is providing the project with a unique testing capability, using a device he invented that can measure the mechanical properties, or elasticity, of tissue samples at human speech frequencies. Jia began working with Clifton a few years ago when she was a postdoctoral researcher and he was a visiting scientist at the Massachusetts Institute of Technology.
Also collaborating on the project is Dr. Robert Witt, a head and neck oncologist at Christiana Care Health System, in Newark, Del. Witt will provide clinical expertise in vocal cord pathology. The research partnership was established through the Center for Translational Cancer Research, which is directed by Mary C. Farach-Carson, professor of biological sciences and material sciences at UD.
According to Jia, the vocal cords are more accurately defined as "vocal folds." Each vocal fold is a laminated structure consisting of a pliable vibratory layer of connective tissue, known as the lamina propria, sandwiched between a membrane (epithelium) and a muscle. These flexible folds of tissue, coated in mucous to keep them moist, operate like an elevator door and must come together to produce a sound.
When you talk or sing, the folds may vibrate more than 100 times a second from the air that is forced up from the lungs through the trachea. However, excessive use or abuse of the voice can lead to scarring of the vocal fold lamina propria, which disrupts their natural pliability, resulting in hoarseness and other symptoms of vocal dysfunction.
"The reduction of vocal-fold scarring remains a significant therapeutic challenge," Jia said.
Jia and her colleagues want to explore two parallel tissue-engineering approaches to regenerate the lamina propria. One method focuses on injecting gelatin-like materials, composed of soft, strong and long-lasting hydrogels, into damaged tissue to improve its pliability and prevent scar formation.
In the second approach, the scientists want to form functional tissue from a combination of vocal fold connective tissue cells (fibroblasts), artificial extracellular matrix, and biological cues and mechanical stimuli that capture the mechanical and biological characteristics of the natural organs.
"In order to grow a functional tissue in vitro, you need to provide the cells with a biological and physical environment that is as close to that of the natural tissue as possible," Jia said.
To mimic the complex and rigorous movement experienced by vocal fold tissue, the researchers have constructed a bioreactor capable of delivering well-defined vibrational and tensile stresses.
The device, which Jia designed, simulates the demanding, high-frequency environment in which vocal fold cells live, vibrating back and forth at up to 100 hertz (100 times a second). Not only do the vocal folds collide as they open and close, driven by air from the lungs, they also must be able to elongate as the pitch of the voice changes, a movement that occurs at a much slower frequency of 1-2 hertz (1-2 times a second), according to Jia.
"The combination of vocal fold fibroblasts, elastic and bioactive artificial extracellular matrices, and a dynamic bioreactor offers an exciting opportunity for in vitro tissue engineering of vocal fold lamina propria," Jia noted.
Earlier this year, Jia received the National Science Foundation's Faculty Early Career Development Award. The highly competitive award is bestowed on those scientists deemed most likely to become the academic leaders of the 21st century.
Jia received her bachelor's degree in applied chemistry and master's degree in polymer chemistry and physics from Fudan University in Shanghai, China, and a doctoral degree in polymer science and engineering from the University of Massachusetts at Amherst.
Before joining the UD faculty in 2005, Jia worked as a postdoctoral researcher with Robert Langer, a pioneer in tissue engineering at the Massachusetts Institute of Technology. Langer recently was awarded the National Medal of Science, the nation's highest honor for science and technology.
University of Delaware
150 S. College Ave.
Newark, DE 19716
United States
udel
Julie Andrews, who starred in such classics as The Sound of Music, is among the professional singers who have undergone surgery to remove callus-like growths that can form from overuse of these two small, stretchy bands of tissue housed in the larynx, or voice box. Sadly, Andrews may never fully recover her singing voice after surgery on her vocal cords in 1997.
Engineering pliable, new vocal cord tissue to replace scarred, rigid tissue in these petite, yet powerful organs is the goal of a new University of Delaware research project. It is funded by a five-year, $1.8 million grant from the National Institutes of Health's National Institute on Deafness and Other Communication Disorders.
Xinqiao Jia, UD assistant professor of materials science and engineering, is leading the project. Jia's research focuses on developing intelligent biomaterials that closely mimic the molecular composition, mechanical responsiveness and nanoscale organization of natural extracellular matrices--the structural materials that serve as scaffolding for cells. These novel biomaterials, combined with defined biophysical cues and biological factors, are being used for functional tissue regeneration.
Randall Duncan, associate professor of biological sciences and mechanical engineering at UD and an expert in cellular biomechanics and signal transduction, is a co-investigator on the project. He will assist the interdisciplinary research team in determining how vocal cord cells respond to mechanical forces, which is the first step in engineering functional vocal cord tissue. Duncan is actively involved in Jia's career development as her senior mentor at UD.
Rodney Clifton, professor of engineering at Brown University and a member of the National Academy of Engineering, is providing the project with a unique testing capability, using a device he invented that can measure the mechanical properties, or elasticity, of tissue samples at human speech frequencies. Jia began working with Clifton a few years ago when she was a postdoctoral researcher and he was a visiting scientist at the Massachusetts Institute of Technology.
Also collaborating on the project is Dr. Robert Witt, a head and neck oncologist at Christiana Care Health System, in Newark, Del. Witt will provide clinical expertise in vocal cord pathology. The research partnership was established through the Center for Translational Cancer Research, which is directed by Mary C. Farach-Carson, professor of biological sciences and material sciences at UD.
According to Jia, the vocal cords are more accurately defined as "vocal folds." Each vocal fold is a laminated structure consisting of a pliable vibratory layer of connective tissue, known as the lamina propria, sandwiched between a membrane (epithelium) and a muscle. These flexible folds of tissue, coated in mucous to keep them moist, operate like an elevator door and must come together to produce a sound.
When you talk or sing, the folds may vibrate more than 100 times a second from the air that is forced up from the lungs through the trachea. However, excessive use or abuse of the voice can lead to scarring of the vocal fold lamina propria, which disrupts their natural pliability, resulting in hoarseness and other symptoms of vocal dysfunction.
"The reduction of vocal-fold scarring remains a significant therapeutic challenge," Jia said.
Jia and her colleagues want to explore two parallel tissue-engineering approaches to regenerate the lamina propria. One method focuses on injecting gelatin-like materials, composed of soft, strong and long-lasting hydrogels, into damaged tissue to improve its pliability and prevent scar formation.
In the second approach, the scientists want to form functional tissue from a combination of vocal fold connective tissue cells (fibroblasts), artificial extracellular matrix, and biological cues and mechanical stimuli that capture the mechanical and biological characteristics of the natural organs.
"In order to grow a functional tissue in vitro, you need to provide the cells with a biological and physical environment that is as close to that of the natural tissue as possible," Jia said.
To mimic the complex and rigorous movement experienced by vocal fold tissue, the researchers have constructed a bioreactor capable of delivering well-defined vibrational and tensile stresses.
The device, which Jia designed, simulates the demanding, high-frequency environment in which vocal fold cells live, vibrating back and forth at up to 100 hertz (100 times a second). Not only do the vocal folds collide as they open and close, driven by air from the lungs, they also must be able to elongate as the pitch of the voice changes, a movement that occurs at a much slower frequency of 1-2 hertz (1-2 times a second), according to Jia.
"The combination of vocal fold fibroblasts, elastic and bioactive artificial extracellular matrices, and a dynamic bioreactor offers an exciting opportunity for in vitro tissue engineering of vocal fold lamina propria," Jia noted.
Earlier this year, Jia received the National Science Foundation's Faculty Early Career Development Award. The highly competitive award is bestowed on those scientists deemed most likely to become the academic leaders of the 21st century.
Jia received her bachelor's degree in applied chemistry and master's degree in polymer chemistry and physics from Fudan University in Shanghai, China, and a doctoral degree in polymer science and engineering from the University of Massachusetts at Amherst.
Before joining the UD faculty in 2005, Jia worked as a postdoctoral researcher with Robert Langer, a pioneer in tissue engineering at the Massachusetts Institute of Technology. Langer recently was awarded the National Medal of Science, the nation's highest honor for science and technology.
University of Delaware
150 S. College Ave.
Newark, DE 19716
United States
udel
Discovery Of Mechanism For Postpartum Depression In Mice May Lead To Better Treatments
Researchers have pinpointed a mechanism in the brains of mice that could explain why some human mothers become depressed following childbirth. The discovery could lead to improved treatment for postpartum depression. Supported in part by the National Institute of Mental Health, of the National Institutes of Health, the study used genetically engineered mice lacking a protein critical for adapting to the sex hormone fluctuations of pregnancy and the postpartum period.
"For the first time, we may have a highly useful model of postpartum depression," said NIMH Director Thomas R. Insel, M.D. "The new research also points to a specific potential new target in the brain for medications to treat this disorder that affects 15 percent of women after they give birth."
"After giving birth, female mice deficient in the suspect protein showed depression-like behaviors and neglected their newborn pups," explained Istvan Mody, Ph.D., of the University of California at Los Angeles, who led the research. "Giving a drug that restored the protein's function improved maternal behavior and reduced pup mortality."
Mody and Jamie Maguire, Ph.D., report on their findings in the July 31, 2008 issue of Neuron.
Researchers had suspected that postpartum depression stemmed from the marked fluctuations in estrogen and progesterone that accompany pregnancy and childbirth. Yet manipulating the hormones experimentally triggers depression only in women with a history of the disorder. The roots of their vulnerability remain a mystery.
Evidence suggested that the hormones exert their effects on mood through the brain's major inhibitory chemical messenger system, called GABA, which dampens neural activity, helping to regulate when a neuron fires.
Mody and Maguire discovered that a GABA receptor subunit fluctuated conspicuously during pregnancy and postpartum in the brains of female mice, hinting that it might have pivotal behavioral effects. To find out, they used mice lacking the gene for this subunit and studied them in situations that can elicit responses similar to human depression and anxiety.
Much like human mothers suffering from postpartum depression, the genetically altered mouse mothers were more lethargic and less pleasure-seeking than normal mice. They also shunned their pups and failed to make proper nests for them.
This abnormal maternal behavior was reversed and pup survival increased after the researchers gave the animals a drug called THIP that acts on the receptor in a way that specifically restores its function in spite of the reduced number of subunits.
"Improper functioning of the subunit could impair the GABA system's ability to adapt to hormone fluctuations during the highly vulnerable post partum period," explained Maguire. "Targeting this subunit might be a promising strategy in developing new treatments for postpartum depression."
Reference:
Maguire J, Mody I. GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008 Jul 31;
The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website, nimh.nih/.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
Source: Jules Asher
NIH/National Institute of Mental Health
"For the first time, we may have a highly useful model of postpartum depression," said NIMH Director Thomas R. Insel, M.D. "The new research also points to a specific potential new target in the brain for medications to treat this disorder that affects 15 percent of women after they give birth."
"After giving birth, female mice deficient in the suspect protein showed depression-like behaviors and neglected their newborn pups," explained Istvan Mody, Ph.D., of the University of California at Los Angeles, who led the research. "Giving a drug that restored the protein's function improved maternal behavior and reduced pup mortality."
Mody and Jamie Maguire, Ph.D., report on their findings in the July 31, 2008 issue of Neuron.
Researchers had suspected that postpartum depression stemmed from the marked fluctuations in estrogen and progesterone that accompany pregnancy and childbirth. Yet manipulating the hormones experimentally triggers depression only in women with a history of the disorder. The roots of their vulnerability remain a mystery.
Evidence suggested that the hormones exert their effects on mood through the brain's major inhibitory chemical messenger system, called GABA, which dampens neural activity, helping to regulate when a neuron fires.
Mody and Maguire discovered that a GABA receptor subunit fluctuated conspicuously during pregnancy and postpartum in the brains of female mice, hinting that it might have pivotal behavioral effects. To find out, they used mice lacking the gene for this subunit and studied them in situations that can elicit responses similar to human depression and anxiety.
Much like human mothers suffering from postpartum depression, the genetically altered mouse mothers were more lethargic and less pleasure-seeking than normal mice. They also shunned their pups and failed to make proper nests for them.
This abnormal maternal behavior was reversed and pup survival increased after the researchers gave the animals a drug called THIP that acts on the receptor in a way that specifically restores its function in spite of the reduced number of subunits.
"Improper functioning of the subunit could impair the GABA system's ability to adapt to hormone fluctuations during the highly vulnerable post partum period," explained Maguire. "Targeting this subunit might be a promising strategy in developing new treatments for postpartum depression."
Reference:
Maguire J, Mody I. GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008 Jul 31;
The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website, nimh.nih/.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.
Source: Jules Asher
NIH/National Institute of Mental Health
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