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Watching brain tumor stem cells grow

June 29 -- I spent a recent afternoon with a gram of glioblastoma tumor cells in a third floor laboratory at the Feinstein Institute for Medical Research. After 22 years covering all things brain for Newsday, a daily newspaper in New York, hard science coverage was winding down and I was offered a great opportunity to share space with scientists at the Feinstein. I would be a science writer-in-residence. Basically, I hang out with scientists and write about what they do. It’s a science writer’s dream job. So on this given day, it was a glioblastoma that would take me to the laboratories of Marc Symons and Maria Ruggieri. They are scientists who run their own laboratories, and they are also married. Glioblastoma multiforme is the research project that brought the couple together as scientific collaborators.

                   More than 40,000 people in the United States will be diagnosed with a primary brain tumor this year. Glioblastoma multiforme is the most malignant type, and there are traditional treatments but nothing seems to stop the growth of these deadly tumors. The hope for Symons and his colleagues is to figure out how these tumors behave – and then find ways to stop them in their tracks. In other words, they want to cure brain cancer.

                  For years, they had been using stocked lines of brain tumor cells, but after so much growth and regrowth it was hard to know if these cells still resembled the original brain cancer cells. The team needed fresh brain tumor cells. Cells they could rely on. This was recently made possible through the new Tissue Donation Program at North Shore-Long Island Jewish Health System. Patients and volunteers can offer up blood and spit and in the case of surgical procedures a bit of leftover tissue. These samples are culled for DNA for genetic studies and the tissue cells are used for a variety of studies. It is one of the only such tissue banks in the area.

                 Dr. David Chalif is a brain surgeon who asked one of his patients whether he would be willing to donate spare brain tumor tissue to science. The patient agreed. On the day of the operation, a young investigator named Salvatore Zavarella, who is a medical student with hands set on brain surgery, was invited into the operation to wait for the tumor. The tumor was large, and David Chalif cut around its edges and removed the tumor in its entirety. A chunk was taken to pathology and a large piece was placed in a tube and handed to Sal. Still dressed in his surgical scrubs, he rushed back to Symon’s lab. Earlier that morning, I met Marc and Maria over tea in a shared kitchen at the research institute. They told me they were waiting for the tumor – and they would separate the cells and grow them up in an attempt to unravel the puzzle of glioblastomas.

               Like Pavlov’s dog, I salivated. Wasn’t this exactly in my job description? Find a glioblastoma and follow its trail…

              “Can I come watch, please?” I begged.

               Marc and Maria are the perfect fit – both physically in their tall, thin frames and in their quietly enthusiastic and open personalities. “Of course, why not,” they said in unison.

              A few hours later (I took in a lecture on schizophrenia while I was waiting) Amanda Chan, a scientist in the lab who is running the study, came to fetch me.

             “We’re racing with time to get these brain tumor stem cells into the incubator,” said Amanda. Sal laid out the pink tissue, still firm, under lamps at a lab bench. Carefully, like a seasoned chef (or surgeon-to-be) he began cutting away at the cells, separating blood from tumor. The tumor sits in is a mix of a liquid medium and blood. When glioblastomas infiltrate the brain, they leech onto the blood supply. The blood makes the tumor cells sticky and Sal keeps adding saline and glucose to the mix to have a better handle on separating the cells. He works fast, deftly slicing up the tissue to rescue the tumor cells. There are plenty of these tumor stem cells for research, the scientists surrounding the bench agree. Plenty to crack the code on brain tumors, Symons said.

               Lines of these cells could eventually be used to identify genes involved in the growth of these glioblastoma cells. The brain tumor cells also offer an opportunity to test experimental therapies to see how they respond in a test-tube or in a small animal model.

Less than 30 minutes later, the brain tumor cells, still pink with blood cells, are spinning down in a centrifuge. After a few minutes, Sal’s back at the bench trying to separate the brain tumor cells from the mix of blood cells – eventually making a pure culture of pristine and deadly brain tumor cells.   

             Later, Amanda will put the cells in a solution to dissolve the extracellular matrix and single cells are beginning to stand apart from one another. The cells were placed in lab dishes filled with two growth factors that selectively amplify stem cells. If things go right, a few days from now the cells will grow into spheres, beautifully and mysteriously shaped circles that may someday yield clues to brain tumors.

          The team is happy. Three days later, peering into a microscope, the cells look like spheres, dotted with surrounding blood cells that should eventually die off. They have to be careful. The spheres, which are made up of brain tumor stem cells, can come together and grow too big.  Amanda had to separate the spheres, which were developing nicely, to grow new plates of stem cells.  The team also studies another tumor type, medulloblastoma -- the most common childhood brain tumor in colaboration with Dr. Steven Schneider and Mark Mittler at Schneider Children's Hospital.

           Marc Symons is giddy with excitement when he stares into the microscope. After they watch the cells, and show them off, they return the growing brain tumor stem cells to the incubator, where they will grow some more. “These guys are looking perky,” said Marc. “When stem cells are happy, they stretch their arms.” He’s right. I look down onto the plate of the potentially fatal tumor cells – and there are the protrusions, tiny wisps of wings, rounding the edges of the spheres. Symons tells me this is the way that these tumors move about. The legs of the beast. 

Parkinson's study in BRAIN identifies new network

• The disease that causes tremors, rigidity and slowed movements in a million Americans also targets another brain network that regulates cognitive thought and the ability to carry out everyday tasks. David Eidelberg, M.D., head of the Center for Neurosciences at the Feinstein Institute for Medical Research, and his colleagues measured and quantified this network of brain regions during a 5 year study of newly diagnosed Parkinson’s patients who agreed to be followed several times over the course of the study. This is the first longitudinal study of Parkinson’s disease using a brain scan to follow these Parkinson’s network over time. The new report appears in an online version in the journal Brain, and will be published soon in a print version.

• The technology is now precise enough to diagnose the two brain networks – one that regulates movement and the other cognition – in individuals, and Dr. Eidelberg said that it could be used to assess the degenerative disease process and the person’s response to treatments. The study also shows that the standard drugs used to treat Parkinson’s alter the areas that are involved in movement but not those that regulate cognition. The network that grows abnormal over time includes an called the pre-frontal cortex, known as the brain’s executive secretary; organizing, planning and carrying out tasks in order of importance. It’s the same region that is hard-hit in mild cognitive impairment, the precursor to Alzheimer’s dementia. But Eidelberg said that the symptoms in the two diseases are quite different. But thinking that medicines used for Alzheimer’s might help normalize this network, the scientists gave Parkinson’s patients 8-weeks of treatment. It didn’t work.

• “We really don’t know precisely what’s going on in this newly-identified network, but we can begin to ask questions and figure it out,” said Dr. Eidelberg.  “We don’t even know whether this network can be fixed.”

• In 1999, the researchers recruited 15 patients with early stage Parkinson’s and signed them on to get brain scans at different points throughout the study. Some were on medicines and some were not. The first networks to be identified were no surprise: The basal ganglia, thalamus and brain stem that regulate movement. The scans they used measured glucose metabolism – the brain’s fuel – and identified areas in this motor network that showed decreased metabolic activity and some areas that had increased metabolic activity. Over time, the cognitive network became apparent. And as the disease progressed and symptoms worsened, this network also took its toll.

• “The circuits are like a fingerprint of the disease,” Dr. Eidelberg said. “As the disease gets worse, the fingerprint is much easier to identify.”  The circuits are the same in all Parkinson’s patients, he added. They are now testing other treatments, including deep brain stimulation, to see if it can impact on the cognitive network. “The cognitive problems are real and have to be addressed,” he added. “The medicines for Parkinson’s don’t seem to do anything to alter these networks and we need new ones to target these symptoms.”

• He said that the networks could be used as biomarkers to diagnose the disease. The scientists have also developed mathematical computer models to determine how fast the disease will progress. “These scanning techniques may be helpful in determining what treatments work and what don’t.”  Check out the Michael J. Fox Parkinson's Disease Foundation story at http://www.michaeljfox.org/newsEvents_parkinsonsInTheNews_article.cfm?ID=220