March 25, 2005

Molecular Biology
No Other Way Out for Iron

Infectious Disease
Milestone Reached, But Campaign Against Polio Continues

Developmental Biology
Stem Cell Niche Discovered in Placenta

Medical Practice
Dual Loyalties at Abu Ghraib: Squeezing Ethics out of Care

Leak-patching Protein Shuts Down Tumor Growth, Swelling

Specialization Seen in Chromatin Remodelers

Study Plays Cat and Mouse with Development of the Visual Cortex

Proceedings of the HMS Faculty Council

Donor Funds Labs for Aging Research

MassCURE to Advocate for Regenerative Medicine

Lemelson Prize Awarded for Innovations in Cancer and Stroke

Match Day Links One Third of Fourth-years to Internal Medicine Residencies

Honors and Advances

Consortium Formed for RNA Interference

AIDS and Isolation Among the Navajo

Front Page

Leak-patching Protein Shuts Down Tumor Growth, Swelling

Blood vessels need to be permeable in order to release needed nutrients and important chemical messengers into tissues. But when they get too leaky, fluid can pool in the tissues, causing edema. At Children’s Hospital Boston, Judah Folkman, the Julia Dyckman Andrus professor of pediatric surgery, has focused his research on blood vessels, and his recent findings in the March Cancer Cell suggest that the anti-angiogenic compound caplostatin may also fight aspects of inflammation and counter some conditions caused by leaky vessels.

Caplostatin was developed by the paper’s first author, Ronit Satchi-Fainaro, based on TNP-470, an anticancer compound discovered in Folkman’s lab. TNP-470 had been found in clinical trials to inhibit new blood vessel growth and regress some human tumors, but it was also neurotoxic. Satchi-Fainaro, an instructor in surgery in the Children’s Vascular Biology Program, gave the compound a heavy polymer tail to prevent it from crossing the blood–brain barrier. With 75 times TNP-470’s mass, caplostatin cannot escape normal blood vessels, but microvessels feeding tumors are more leak-prone, so the compound targets tumors nourished by this pathological vasculature. (See Focus, March 19, 2004.)

While quantifying caplostatin’s ability to leak out of vessels, Satchi-Fainaro found that caplostatin and TNP-470 inhibited continued hyperpermeability. Leaked proteins and growth factors are required to build new blood vessels, so when existing microvessels become less permeable, tumors cannot get the nutrients they need to grow. In mice, caplostatin countered the permeability-inducing effects of vascular endothelial growth factor (VEGF), histamine, and platelet-activating factor. Co-author Harold Dvorak, the Mallinckrodt professor of pathology at HMS, codiscovered VEGF in 1983.

Caplostatin and TNP-470 were found to impede permeability triggered by several unrelated pathways, making them effective against multiple angiogenic signals that tumors send to ensure their blood supply. “This is the broadest anticancer agent we’ve worked with. It has worked in every animal tumor model tested so far,” Folkman said. Caplostatin could also be helpful as an adjuvant to the anticancer drug interleukin-2 (IL-2), which often causes pulmonary edema in patients. By preventing vessels in the lungs from leaking, TNP-470 or caplostatin could allow more patients to tolerate treatment; Folkman’s team showed that TNP-470 protected mice from this IL-2 side effect.

If it is validated in clinical trials, the bulked-up compound may find applications well beyond cancer treatment. The Army is interested in using a future FDA-approved caplostatin to treat edemas that often develop when a well-armored soldier survives an explosion.

—Tai Viinikka

Specialization Seen in Chromatin Remodelers

One of the dreams of modern medicine is to turn genes on and off for the good of the patient. The reality is, getting to genes is not easy. Strands of DNA do not lie flat in the nucleus, but instead are coiled tightly around protein spools called nucleosomes. To loosen these strands and make them accessible to gene-triggering transcription factors, the cell sends in chromatin remodeling complexes. The cell has thousands of such complexes, but researchers have discerned at least two main types, SWI/SNF and ISWI. What has not been clear is whether the pair work in similar ways at different locations or carry out their DNA-loosening function in an altogether different fashion.

“These proteins are involved in helping cells stay committed to the right pathway.”

It now appears that the two complexes function quite differently. ISWI-based complexes unwrap DNA at the edges, where the strand enters and exits the nucleosome. SWI/SNF-based complexes are more versatile. They open up DNA as it coils around the whole spool. These findings by Hua-Ying Fan, Robert Kingston, and their colleagues, which appear in the March Molecular Cell, appear to be tailored to the needs of the cell. “When you unpackage DNA, sometimes you only need to partially unpack it,” said Kingston, HMS professor of genetics at Massachusetts General Hospital. “In other cases you would need to completely unpackage it. Sometimes there will be regions of DNA in the cell that are right in the middle of the nucleosome that need to be opened up to get a gene turned on properly.”

Fan, an HMS research fellow in genetics, Kingston, and their colleagues homed in on the difference by taking the two kinds of complexes apart and swapping their central motor, or ATPase-containing, proteins. Powered by ISWI’s motor, the normally versatile SWI/SNF was able to part the DNA strand only at its edges. The findings suggest that the motor units are responsible for carrying out the two types of unwinding functions—something the researchers did not know when they began. “We got lucky,” said Kingston.

The idea of turning on genes for therapeutic purposes is the cherished goal of gene therapy, though the field has been tarnished by the deaths of several people in clinical trials. “If it ever comes back into fashion, that would be one place that these findings would be useful,” said Kingston.

The burgeoning field of stem cell biology is another. Stem cells need to turn on genes—and keep them on—in order to differentiate into particular types of cells. “These proteins are involved in helping cells stay committed to the right pathway,” Kingston said.

—Misia Landau

Study Plays Cat and Mouse with Development of the Visual Cortex

Anyone who has worked to learn a language as an adult has struggled to reshape the brain’s connections. One key scientific window into how experience molds the brain is the development of the mammalian visual cortex, which must receive inputs from both eyes during a critical period to enable binocular vision. Carla Shatz, the Nathan Marsh Pusey professor of neurobiology at HMS, and her colleagues devised a technique for following development in the visual cortex of mammals by looking at expression of the Arc gene. Their results were published in Nature Neuroscience in March.

“The work in the lab is directly related to childhood learning and disorders of development. You can’t fix problems like autism or dyslexia without a basic understanding of normal brain development.”

Researchers think the brain initially develops according to a fixed program and then enters a stage at which it is shaped by sensory experience of the environment. Once this stage ends, the brain becomes less malleable. For instance, in mice, if one eye is disabled during the critical period for plasticity in the visual cortex, between 25 and 35 days of age, neural connections rearrange to make the working eye dominant. Other species and other brain functions are shaped in similar ways, though the molecular machinery behind plasticity during the critical period is not known.

Researchers in Shatz’s lab used the expression of the Arc gene to identify areas that became more or less active in response to visual experience or deprivation. (It is not clear what Arc’s function is, but about 30 minutes after a visual stimulus, its expression increases several orders of magnitude in areas of the visual cortex receiving input from the stimulated eye.)

The Arc-induction method yielded information about plasticity in three dimensions across the whole visual cortex, and this led to some surprising results in mice. “We really did not expect to find a longer critical period than had been previously reported,” Shatz said. Arc induction revealed a mouse critical period that started earlier and continued much later than was found using other methods. Previous techniques had only monitored the surface layers of the visual cortex or a small area responsible for binocular vision.

In a more visual species, the findings were different. “In cat, there were no surprises so far. It confirmed 50 years of data,” said Patrick Kanold, a co–first author of the paper and research fellow in neurobiology. The researchers plan to use genetic techniques in mice to zero in on molecular mechanisms of plasticity during critical periods, then work back to more complex mammals, including humans.

“The work in the lab is directly related to childhood learning and disorders of development. You can’t fix problems like autism or dyslexia without a basic understanding of normal brain development,” said Shatz. Now that the Arc method has proven a useful complement to established techniques, she prom-ises more molecular findings on plasticity in the future.

—Tai Viinikka