Turning scientific beliefs upside-down

    St. Jude investigators disprove a century-old theory, turning established scientific beliefs on their heads. This exciting discovery may someday have applications for such diseases as Alzheimer’s and Parkinson’s.

    Recently, a century’s worth of ingrained scientific belief was turned upside-down. Just like that.

    Nobody questioned one of the longstanding principles in the field of developmental neurobiology—until a team from St. Jude Children’s Research Hospital disproved it as part of a project to study a completely different topic.

    For more than 100 years, scientists had assumed that neurons in the brain are permanent and cannot divide to produce new neurons. But while studying the genes that contribute to retinoblastoma, Michael Dyer, PhD, and his colleagues were able to coax neurons to make more neurons for the first time. Their discovery disproves the scientific theory that differentiated (or mature) nerves cannot multiply.

    “One of the most exciting things about research is when you are studying one question and come across a completely unexpected discovery that has a much broader impact,” says Dyer, of St. Jude Developmental Neurobiology.

    Analyzing the facts

    Dyer and his colleagues are now analyzing their discovery to figure out why the particular neuron they studied multiplied, whether other neurons can react similarly and if neurons can be manipulated to repeat the same action. If differentiated neurons can be altered so that they temporarily multiply, it could create new treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

    Dyer says this treatment of existing nerves duplicating themselves might be more efficient than inserting stem cells into the brain in an attempt to regenerate lost neurons.

    “There is still a lot of research required to determine if it is possible to control gene activity to make this approach practical,” Dyer explains.

    The discovery also challenges the belief that cancer cells are most aggressive when they are undifferentiated. During the differentiation process, cells lose their primitive, stem-cell–like properties, which include the ability to grow and multiply, and instead develop specialized shapes and functions.

    Dyer says that cancer cells in such diseases as chronic myelogeneous leukemia are less aggressive when they are differentiated.

    The opposite result was discovered in Dyer’s recent research on retinoblastoma.

    “In the model that we were studying, these dividing neurons eventually become tumors, and they go on to form retinoblastoma,” Dyer explains. “The tumors look quite differentiated. They have processes and synapses, and they look like neurons. I would have predicted, based on this cancer model, that they’d be mild tumors, not aggressive. It turns out that it’s exactly the opposite—they’re the most aggressive tumors we’ve ever seen in our model.

    “This really challenges the idea that differentiated means less aggressive and undifferentiated means aggressive.”

    Surprising results

    This development is also important because it could change therapies not only for retinoblastoma but for other tumors where differentiation is induced with the intent of making cells less aggressive.

    The discovery was first reported to Dyer by postdoctoral fellow Itsuki Ajioka, PhD, when Ajioka noticed an increase in the number of nerves in the retina called horizontal interneurons. These specialized neurons were mature and were considered incapable of dividing. When the investigators allowed this cell division to continue, highly differentiated tumors formed that resembled normal horizontal interneurons.

    Since the results were so surprising, Dyer says it took 18 months for the team to confirm the finding by making sure that the nerve cells themselves were dividing and verifying that the increase was not due to a previously undiscovered immature cell.

    Stanislav Zakharenko, MD, PhD, of Developmental Neurobiology heads the lab that performed the project’s microscopy studies.

    “The state-of-the-art resources for research on catastrophic childhood illness made this finding possible,” Dyer said. “St. Jude has some of the world’s leaders in cutting-edge microscopy to visualize neurons and tumors such as our collaborator on the study, Dr. Stanislav Zakharenko.”

    The advanced microscopy services at St. Jude played an important part in this research, as investigators watched the neurons divide in real time with technology not available as recently as a few years ago.

    “There’s nothing like seeing it happen,” Dyer says. “Without that technology, we would not have been able to do what we did or to prove it in that kind of definitive way.”

    Future possibilities

    The team’s discovery could lead to the development of new therapies to treat retinoblastoma that has spread to other parts of the body. Such treatment could result from understanding why differentiated tumors that resemble neurons are aggressive and metastasize, or spread, to the brain, bone marrow and lymph nodes.

    Additional research is necessary to see if these findings could lead to new treatments for diseases such as Alzheimer’s and Parkinson’s—neurodegenerative disorders that occur when differentiated nerves in the brain try to multiply, but instead undergo cell death, a process called apoptosis.

    If researchers can alter the activity of certain genes in differentiated neurons, they might be able to trigger them to multiply temporarily and replace the neighboring neurons that were lost as a result of the disorder.

    “The next step in this research is to determine if we can extend these findings to other types of neurons in the retina and brain,” Dyer says. “If we can induce a variety of neuronal types to divide, then our discovery may have much broader implications for treating neurodegeneration.”

    Reprinted from Promise Autumn 2007

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