Monthly Archives: January 2010

The good doctor

“Haitian history is a chronicle of suffering so Job-like that it inevitably inspires arguments with God, and about God,” wrote George Packer in the January 25th issue of The New Yorker.

Packer then offered a litany of events and circumstances – from slavery, revolt and oppression, to American occupation and neglect, to extreme poverty, political violence, coups, gangs, and hurricanes, “and now an earthquake that exploits all the weaknesses created by this legacy to kill tens of thousands of people.”

Packer could have added that the small island nation had been plagued by endemic diseases including malaria, tuberculosis and, beginning around 1979, HIV/AIDS. Indeed, given a nearly nonexistent healthcare system at the time, Haiti had minimal defenses against the onset of that epidemic.

In 1983, while working for a medical television network aimed at physicians, I learned that the CDC had named Haitians along with three other groups – homosexuals, heroin addicts and  hemophiliacs – as high risk factors for what was then called HTLV infection – the “4H Club,” as some in the mainstream news media benightedly put it.  Ashamed to say that we who should have known better chuckled at this flippancy.

And so, during the period that the disease became increasingly identified with Haitian immigrants tothe U.S., this stigma borne of fear, confusion and racism singled out Haiti as the only country to suffer the consequences – this for a nation in which tourism was the economic backbone.

“It killed tourism in Haiti,” said Dr. Jean W. Pape in a 2006 interview. “Within a year the tourism industry decreased by 80 percent… Goods manufactured in Haiti could not be sold in the U.S.” 

And Haitians in the U.S. found it tougher finding work or selling their homes.

Dr. Jean Pape

Who is Jean Pape? He is a physician and scientist , and a bona fide hero. Honoring “heroes whose actions and courage make the world a better place,” the U.N. has praised Pape’s “achievements, courage and inspiration in contributing to breaking the silence on HIV/AIDS.”

Understanding that a solid research base was needed in Haiti in order to develop the most effective anti-AIDS strategies,  Pape established the Groupe Haitien d’Etudes du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), in 1982. The group integrates patient services, health research, and training in HIV/AIDS and inter-related diseases.

A professor of medicine at Cornell and a professor at the State University of Haiti, Pape also established Cornell’s Tropical Medicine and Infectious Disease Research Unit in Port-au-Prince. 

After completing his medical training at Cornell in 1975, he returned to his native Haiti to study childhood diarrhea.  He noted an increase in adult mortality related to diarrhea and with GHESKIO published the first comprehensive description of AIDS in the developing world in 1983. 

Since the January 12th earthquake,  GHESKIO and the good Dr. Pape has been providing humanitarian assistance and emergency care to literally thousands affected by the disaster and continues to provide life-saving medications to people with HIV/AIDS.

For a glimpse into the harrowing social and medical issues now facing Dr. Pape and GHESKIO, see this January 28, 2010, update he coauthored in The New England Journal of Medicine.

Visit GHESKIO  for a recent NBC Nightly News interview with Dr. Pape.

Les Lang

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TB or not TB

 In the Shakespearean sense, this is a brief yet knotty tale of granulomas, of organized aggregates of immune cells in which things are not what they seem.

 Viewed through the fog of traditional belief, granulomas, the nodules that are a hallmark of tuberculosis, are heroes in stemming growth of the infecting mycobacteria.

 Now it appears that science’s sunlight has dissolved a century of fog.  Analysis of mycobacteria infections in tiny zebrafish embryos reveals that the early granuloma actually facilitates mycobacterial growth.  

Enough of this overwritten drivel!  “The play’s the thing, ” the bard said. 

In brief, new research has discovered the signaling pathway by which a granuloma encourages TB pathogenesis.  And finding how to block that pathway may lead to new therapies for TB and other serious disorders. 

TB bacteria infect host macrophages in a larval zebra fish and prod epithelial cells to produce MMP9, a signaling protein associated with worsening infection. The MMP9 stained green in this mount, while the macrophages in the tubercle stained red. Credit: J.M. Davis and T. Pozos, University of Washington

In a report of the study in Science, on January 22, 2010, John F. Rawls, Ph.D., assistant professor in the UNC departments of cell and molecular physiology and microbiology and immunology,  joined co-authors from the University of Washingtion.

Their study identified a new molecular pathway that infecting mycobacteria use to coerce disease-fighting cells to switch allegiance and work on their behalf.  

Basically, the bacteria residing with immune cells called macrophages secrete the small protein ESAT-6, long implicated in virulence, which then induces nearby epithelial cells to produce the enzyme Matrix Metalloproteinase 9 (MMP9). 

Here the ball really gets rolling, as MMP9 secretion by epithelial cells is ramped up in the vicinity of an infected TB macrophage.  The enzyme’s action draws in uninfected macrophages to join the infected ones, thereby expanding the granuloma. 

Thus, according to the new research, TB bacteria simultaneously suppress the inflammatory action of macrophages to create a safe haven in them, while nudging epithelial cells to signal for the arrival of more macrophages which, in turn, are inducted into granuloma expansion. 

“The implications of these results extend beyond TB to other types of inflammation,” says Rawls. “This novel signaling cascade from bacterium to epithelium to macrophage could represent a common strategy by which other microorganisms or other factors influence the process of inflammation.” 

And so it is hoped that this discovery could help raise the curtain on some exciting innovative therapies that will bring it down on TB, arthritis, and other inflammatory disorders. Fini.

Les Lang

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Of blank slates and embryo development

The DNA contained within each of our cells is exactly the same, yet different types of cells – skin cells, heart cells, brain cells – perform very different functions.

The ultimate fate of these cells is encoded not just in the DNA, but in a specific pattern of chemical modifications that overlay the DNA structure. These modifications, or epigenetic markers as they are called, are stably carried in our genomes — except for at times when the cells change their fate, such as what occurs when the sperm meets the egg. Then they are erased completely. 

A fertilized egg prior to division. Two nuclei (one from the egg and one from the sperm) are visible in the center. Photo courtesy: Stan Beyler, PhD, UNC A.R.T. lab)

Researchers at the UNC School of Medicine have discovered a protein complex that appears to play a significant role in erasing these epigenetic instructions on sperm DNA, essentially creating a blank slate for the different cell types of a new embryo to develop. The protein complex – called elongator – could prove valuable for changing cell fate, such as converting cancer cells to normal cells, as it may be able to reactivate tumor suppressor genes by removing the epigenetic modifications that often prevent them from curbing the proliferation of cancer cells. 

The discovery may also have implications for stem cell research by providing a tool to quickly reprogram adult cells to possess the same attributes as embryonic stem cells, but without the ethical or safety issues of cells currently used for such studies. The results of the study appear on-line in the Jan. 6, 2010issue of the journal Nature

“The implications of such research have always been clear, and that is why for years researchers have tried to identify a factor responsible for erasing these epigenetic markers,” said senior author Yi Zhang, Ph.D., Howard Hughes Medical Institute Investigator and Kenan Distinguished Professor of Biochemistry and Biophysics at UNC. He is also a member of the UNC Lineberger Comprehensive Cancer Center. 

Epigenetic markers are essentially chemical tags attached to the genomes of each cell, determining which genes will be turned on or off and, ultimately, what role that cell type will have in the body. One way this comes about is through DNA methylation, a process by which methyl groups are stamped onto cytosines — one of the four bases of DNA — to produce a characteristic pattern for a particular cell. 

During fertilization, the paternal genome derived from the sperm is actively demethylated, removing these methyl tags quickly before cell division, while the maternal genome is demethylated passively. The new methylation pattern will be reestablished at a later stage. 

“Several previous studies have identified factors that can perform gene-specific DNA demethylation, but ours is the first to link a protein complex to global DNA demethylation that correlates to germ cell to somatic cell transition,” Zhang said. 

For further details, click here.

Les Lang

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Fish gotta swim, bacteria gotta…walk

The ability to swim comes as naturally to bacteria as it does to fish. In the wet, microbes propel themselves through fluids using a whip-like extension called a flaggella.

But when on solid surfaces, the little beasties also can walk, twitching along using little fibrous legs called pili.  And when they adhere to host tissue, including that of  homo saps like you and me, the pathogenesis of bacterial infection, its establishment and spread elsewhere in the body, largely depends on bacterial ability to walk. 

Now what if it were possible to prevent infection by stopping bacteria in their tracks? New research at the  University of North Carolina at Chapel Hill appears to have taken a major step in that direction.

The UNC researchers have discovered that a single atom can control how bacteria walk.  By resolving the structure of a protein involved in the motility of the opportunitistic human pathogen Pseudomonas aeruginosa, the scientists identified a spot on the bacteria, that when blocked, can indeed stop  bacterial motility cold.  

“When it comes down to it, a single atom makes all the difference,” said senior study author Matthew R. Redinbo, Ph.D., Professor of Chemistry, Biochemistry and Biophysics at UNC. His findings appear in the Dec. 28, 2009, early online edition of the Proceedings of the National Academy of Sciences.

The binding and release of a single atom (shown in light blue) to a bacterial protein is necessary for microbial walking and infection.

For the last few years, Redinbo and his team has been working in close collaboration with Matthew C. Wolfgang, Ph.D., an Assistant Professor of Microbiology and Immunology and a member of the Cystic Fibrosis/Pulmonary Research and Treatment Center at UNC, trying to figure out how bacteria’s tiny legs or pili function.

The researchers began to look at one of the many types of pili, called type IV pili. Type IV pili are basically long, dense fibers that bacteria assemble (extension) or disassemble (retraction) quite quickly.

“These pili act as grappling hooks – the bacteria extend the fibers out, the fibers attach or stick to a surface, and then retracted back into the bacteria, pulling it along,” said Wolfgang. “This crawling movement is called twitching motility, and without it Pseudomonas, a common cause of hospital-acquired pneumonia would never be able to move from the lung tissue into the bloodstream, where the infection becomes lethal.”

The researchers knew that inside the cell lie the tiny little motors – called ATPases – that drive the extension and retraction of the pili. One of these ATPases is the extension motor, which sticks the bacteria’s leg out. The other ATPase is the retraction motor, which pulls it back in. But what wasn’t clear was how the two motors were coordinated so that pushing and pulling didn’t occur at the same time. That is what Redinbo and Wolfgang set out to discover.

First, they resolved the crystal structure of the Pseudomonas PilY1 protein, which other research had shown was necessary for the creation of pili. They made large amounts of the protein, coaxed it out of solution so that it formed a crystal, and then put the crystal under intense x-ray beams through a process called x-ray diffraction that resulted in a series of spots.

Based on the spots, the researchers calculated what the protein looked like. When they studied the structure, one particular site – the binding site of a calcium atom – looked like it could be important for the function of the protein. So the researchers began to tinker with the site, looking to see if the changes they made affected the protein’s behavior.

When they changed the protein so it could no longer bind calcium, the bacteria couldn’t make any legs. When they fooled the protein into thinking it was forever bound to calcium, the bacteria made legs but couldn’t retract them, essentially becoming paralyzed. The results suggested that the protein has to bind calcium to make legs, but it also has to be able to let go of the calcium to pull the legs back in.

“We found it pretty remarkable that the binding of a single atom to a protein that is outside the cell is sufficient to tell these motors that are inside the cell to either stop pushing or stop pulling,” said Redinbo.

He says they are currently using a combination of genetics and biochemistry to figure out how this long-distance communication is possible.

 

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