Wednesday, October 7, 2009

THE SECRETS OF CILIA

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Forty years ago, doctoral student Joel Rosenbaum asked this question: How are cilia, the tiny thread-like appendages protruding from most cells, formed from molecules in the interior of cells?

The answer to this basic biology question asked by Rosenbaum, now professor of molecular, cellular and developmental biology at Yale, has provided new insight into some of most prominent human genetic diseases.

Cilia have become unlikely stars in an unfolding scientific drama that promises new treatments for kidney disease, birth defects, blindness, and neurological and cardiac disorders. They may even be involved in the control of cell division and cancer.

At Yale and labs across the country, scientists are proving that cilia, which exist on almost every mammalian cell, are not just tiny oars that move sperm or keep fluids moving over the surface of tissues in the oviduct or the throat and lungs. These tiny structures play a profound role in sensing the environment outside the cell in many biological processes. Malfunctions of the cilia have now been associated with so many maladies — infertility, obesity, mental deficits, and diseases of the pancreas, liver, heart and kidney — that they have been given their own name: The Ciliopathies.

These unexpected findings, some arising from Rosenbaum's seminal study of cells found in pond scum, have changed our understanding of how biological systems develop from embryos and function in adults. The story illustrates the power of translational research, or how unforeseen insights into our own health can be found within the simplest of organisms.

Rosenbaum's organism of choice to study cilia was the green alga Chlamydomonas, which possess two tiny-hair like flagella, structurally the same as cilia found on nearly all mammalian cells. He wanted to know how proteins in the cytoplasm could travel all the way up to the tip of the cilium, where assembly occurs.

"It was a basic biology question involving molecular motors and transport," Rosenbaum says.

It was not a ‘sexy' area of research, he admits, and he was often asked what possible application to human health his work on cilia might have. His Ph.D. adviser at Syracuse University suggested he tell his inquisitors — and funding agencies — that cilia almost certainly play a role in some forms of blindness. However, it would take decades of lab sleuthing before this connection was firmly established.

During his studies at Yale, Rosenbaum and colleagues such as Paul Forscher, professor of molecular, cellular and developmental biology, and graduate student Keith Kozminski continued to describe the journey of molecules, which like riders on a roller coaster, travelled from the interior of the cell up and down the length of flagella. They named this system, which is responsible for flagellar assembly, intraflagellar transport or "IFT." They also found that when genes that code for the IFT transport proteins are mutated, cilia fail to form.

These findings might have remained of interest to cell biologists alone if not for the technological revolution in genomics over the past 20 years. Now researchers have easy access to catalogues of genes from a variety of species at their computer. Rosenbaum and his colleagues — postdoctoral student Doug Cole, and George Witman and Greg Pazour from the University of Massachusetts (UMass) Medical School — entered a key gene involved in this intraflagellar transport system in Chlamydomonas into the gene bank. They came up with an exact match: a gene found in a mouse model of a disease called polycystic kidney disease (PKD).

"In the lab, we just stared at each other and said, ‘What the hell is going on here?'" Rosenbaum recalls.

What, they wondered, could a gene involved in IFT in green algae possibly have to do with a common and devastating disease, marked by growth of large cysts in the kidney? These cysts are the fourth leading cause of kidney failure and afflict more than 600,000 people in the United States and 12 million worldwide.

Rosenbaum and his colleagues at UMass and Bradley Yoder at the University of Alabama-Birmingham examined the kidneys of mice with PKD by electron microscopy and found their kidney tubules (through which urine flows) lacked cilia — evidence that suggested that this simple appendage might play a role in the disease.

Another part of the puzzle was solved by the lab of Stefan Somlo, now the C.N.H. Long Professor of Medicine, professor of genetics and chief of the Section of Nephrology at the Yale School of Medicine. In 1998, Somlo's team had identified one of two genes known to cause PKD. Rosenbaum approached an initially skeptical Somlo and suggested that PKD was in fact a disease of the cilia. Somlo's skepticism soon vanished when Rosenbaum and his colleagues showed that the protein products of the PKD genes discovered by Somlo were located on the cilia themselves. This finding gave rise to the current "Ciliary Hypothesis of PKD."

But the question remained: How, exactly, were the cilia functioning to cause this devastating disease?

A major breakthrough in answering this question was the finding by researchers at the National Institutes of Health who showed that mechanically bending the cilium of the kidney cell would cause calcium to flow into the cell.

How did this mechanically-induced calcium flow cause PKD? Somlo and Michael Caplan, Yale professor of cellular and molecular physiology, answered this question.

They determined that cilia act like sensors, detecting urine flow through the kidney. When the urine flow decreases, cilia do not bend, calcium does not flow in and a signal is sent to the cell that "not all is right." This in turn signals the formation of more cells. The result is that in mice lacking cilia, excessive cell division causes the cysts in the kidney tubules that are the hallmark of PKD.

"What really happened here is that apparently unrelated fields of research coalesced into something unexpected," Somlo says.

Rosenbaum explains that the similarity of cilia found in pond scum to those in human and mouse kidneys offered the biggest clue. "When you observe similarity in structure, there is likely a similarity in function," he says.

Rosenbaum notes that those lab mice with PKD not only lacked cilia in the kidneys, but in other cells as well. And these mice had other health problems. Revelations of cilia's role in a host of diseases began pouring out from labs at Yale and around the globe.

Dr. Martina Brueckner, associate professor of pediatrics and genetics at Yale and a pediatric cardiologist, found defects in cilia can lead to severe heart defects in children. Brueckner's lab in the late 1990s was investigating why some children are born with hearts on the right side of their chest rather than the correct position on the left. In this condition, the heart and other organs in the developing fetus cannot tell right from left. In severe cases when these organs end up misaligned along the left and right sides of the body, many children die before the age of five.

To Brueckner's great surprise, the culprit for this form of congenital heart disease turned out to be a gene coding for a part of the cilium in embryonic cells. These cilia actually move in an unusual way and direct the flow of fluid from left to right — acting almost like traffic cops by helping direct cells to form organs along a left-right axis. In the case of mice with heart abnormalities closely resembling those found in humans with abnormal left-right development, the cilia were no longer able to direct this left-right flow and the proper body asymmetry was not formed.

"We had no idea when we started where this was going," Brueckner says. She also suspects that cilia found in heart cells may be responsible for orchestrating other important cardiac functions.

Working independently from Rosenbaum's lab, but in the same department, a team of Yale scientists discovered a potential treatment that slows the formation of PKD cysts. Craig Crews, associate professor of chemistry, molecular, cellular and developmental biology and of pharmacology, was interested in the chemistry of triptolide, a potent biochemical compound found in a Chinese medicinal herb called "Thunder God Vine" which has been used for centuries as a treatment for cancer, inflammation and autoimmune disease. Crews and Somlo found that the compound reduced cysts in mice containing one of the mutant PKD genes.

The insight that malfunctioning cilia might trigger cyst formations has led to some interesting possibilities for research on cancer, which is marked by uncontrollable cell division. Scientists wondered: Was it possible that cancer somehow destroyed cilia to promote proliferation? Several labs are now investigating this possibility. It is based on a 50-year-old observation that cells with cilia do not divide until the cilia are lost.

Now, the profound effects of cilia are being recognized in many other areas of research. For instance, a Yale team led by neuroscientist Pasko Rakic recently described how cilia play a role in creating molecular signals that spur creation of neurons in an area of the brain involved in mood, learning and memory.

Ironically, Rosenbaum and his colleagues at UMass are also finding evidence that cilia may indeed be involved in a form of blindness, just as his Ph.D. adviser suggested more than 40 years ago.

Rod cells in the retina are crucial to sight. They are formed from cilia, and these cilia play a key role in transporting molecules that repair the rods as they age. If material does not reach these key portions of the rod cells (called "rod outer segments"), they die and blindness can result.

It turns out that the transport mechanism that delivers these key materials to rod cells is the same intraflagellar transport system Rosenbaum studied in the green algae Chlamydomonas. In one form of sight loss, called Joubert's Syndrome, scientists have now identified a genetic defect that causes a blockage at the base of the cilium that prevents transport of these repairing molecules and have identified the particular part of the cilium that is defective. Using gene therapy to correct the defect, scientists have now succeeded in restoring sight in some animals with Joubert's Syndrome.

In 40 years since Rosenbaum began his lonely study of these microscopic marvels, cilia have taken a place among science's most fascinating and rewarding structures.

(Photo: Yale University)

Yale University

FABRICS THAT FIGHT GERMS AND DETECT EXPLOSIVES GO TO MARKET

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Fabrics with embedded nanoparticles to detect counterfeiting devices, explosives and dangerous chemicals or to serve as antibacterials for hospitals, law enforcement or the hospitality industry are just a few of the products that a new company, launched by two Cornell researchers, will produce.

iFyber LLC, begun in fall 2008, uses technology developed through a cross-campus collaboration by fiber science professor Juan Hinestroza and Aaron Strickland, a research associate in the Department of Food Science. The company, which will commercialize this research was launched and funded by KensaGroup LLC in collaboration with the Cornell Center for Technology Enterprise and Commercialization.

The key to iFyber's technology is the ability to deposit nanocoatings on natural and synthetic fibers with nanoscale precision, Hinestroza explained.

"We're using a chemical process to uniformly deposit nanoscopic particles onto the surface of a fabric," he said. "These particles can change the properties of the fabric."

Among the custom properties of the treated fibers are simultaneous water and oil resistance, antimicrobial behavior and electrical conductivity. The company's proprietary coating process allows the nanoparticles to adhere to curved fiber surfaces and crevices with a uniform distribution of particles using traditional textile processing equipment.

"There is significant potential to use this technology in a wide range of applications," said Strickland, director for research and development of iFyber.

To date, the company has received two Small Business Innovative Research Grants from the U.S. Department of Defense for developing custom fabrics using nanotechnology. One project is to develop a material that can detect and identify leaks in chemical warfare suits used by the U.S. Air Force. The second is to create novel antibacterial wound dressings and surgical sutures for the U.S. Navy.

In addition, undergraduate students from Cornell's School of Hotel Administration, under the direction of Professors Robert Kwortnik and Michael Sturman, conducted a preliminary market analysis on using the technology to create antibacterial bedding and linens for the hospitality industry. "We are awaiting further market analysis before moving into the linen market," he said.

(Photo: Cornell University)

Cornell University

MAGNETISM OBSERVED IN A GAS FOR THE FIRST TIME

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For the first time, MIT scientists have observed ferromagnetic behavior in an atomic gas, addressing a decades-old question of whether it is possible for a gas to show properties similar to a magnet made of iron or nickel.

The MIT team observed the behavior in a gas of lithium atoms cooled to 150 billionth of 1 Kelvin above absolute zero (-273 degrees C or -459 degrees F). The work, reported in the Sept. 18 issue of the journal Science, was led by Wolfgang Ketterle, the John D. MacArthur Professor of Physics, and by David E. Pritchard, the Cecil and Ida Green Professor of Physics. If confirmed, the MIT result may enter the textbooks on magnetism, showing that a gas of elementary particles known as fermions does not need a crystalline structure to be ferromagnetic.

For decades, it has been an open question whether it is possible for a gas or liquid to become ferromagnetic. Ferromagnetic materials are those that, below a specific temperature, are strongly magnetized even in the absence of a magnetic field. In common magnets such as iron and nickel that consist of a repeating crystal structure, ferromagnetism occurs when unpaired electrons within the material spontaneously align in the same direction.

Electrons, and also neutrons and protons, are elementary particles classified as fermions. Atoms and molecules that consist of an odd number of fermion particles are considered composite fermions. Since all fermions have some properties similar to electrons, they can be used to simulate the behavior of electrons in a ferromagnet. In this work, the researchers studied the fermionic atom lithum-6, which consists of three protons, three neutrons and three electrons.

Just like electrons, these lithium-6 atoms act like little magnets that can align in the same direction under certain circumstances. In nature, fermionic liquids or gases exist as electron gases, in liquid helium-3 and in neutron stars.

"All liquid or gaseous fermion systems in nature don't have strong enough interactions to become ferromagnetic," explains physics graduate student Gyu-Boong Jo, a member of the research team. "But for the lithium atoms, we can use tricks of atomic physics to adjust the interactions between the atoms to arbitrary strength, by simply changing an external magnetic field."

In their experiment, the MIT team trapped a cloud of ultracold lithium atoms in the focus of an infrared laser beam. When they gradually increased the repulsive forces between the atoms, they observed several features indicating that the gas had become ferromagnetic. The cloud first became bigger and then suddenly shrunk. When the atoms were released from the trap, they suddenly expanded faster.

This and other observations agreed with theoretical predictions for a phase transition to a ferromagnetic state. "The evidence is pretty strong," says Pritchard, "but it is not yet a slam dunk. They started to form molecules and may not have had enough time to develop regions of aligned atoms large enough for us to see."

Ketterle adds that he and his colleagues have many ideas how to study this new form of matter more closely: "One thing is certain: We have made an important discovery, which will advance our understanding of magnetism."

Christophe Salomon, research director at France's National Center for Scientific Research, says the findings provide convincing evidence that fermionic gases display the same type of ferromagnetism found in solid crystal materials. To fully prove the case, he says, "It would be nice to see direct observation of ferromagnetism - that all the spins are parallel."

The MIT research is part of a program studying novel magnetic materials — which have important applications in data storage, nanotechnology and medical diagnostics — and the interplay between magnetism and superconductivity.

The work is a continuation of earlier research on Bose-Einstein condensates, a form of matter in which particles condense and act as one big wave. Ketterle received the 2001 Nobel Prize for the discovery and study of this long-sought new form of matter. "We still use the same refrigerator as we used to study Bose-Einstein condensates," says Ketterle. "But the science is very different. Ten years ago, I would have never thought that I would study magnetism today."

(Photo: Patrick Gillooly)

MIT

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