Special Topics in Biomedical Science

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Special Topics in Biomedical Science
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Damage to motor systems by disease and injury

• Here are Michael Jordan on the left and Margot
  Fonteyn on the right.
• These are motor behaviors that take years of
  learning and practice.

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Damage to motor systems by disease and injury

• But sometimes that system fails.
• This failure might be from neurodegenerative
  disorders or spinal cord injury.
• Lou Gehrig, the famous baseball player who
  suffered from a motor neuron degenerative disease
  called amyotrophic lateral sclerosis.
• Christopher Reeve suffered a spinal cord injury
  that left him paralyzed.

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Damage to motor systems by disease and injury

• One of the aims of trying to understand the way
  in which circuits control behavior is so that we
  can help neurodegenerative disease and traumatic
  spinal cord and other brain injuries.

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Motor neurons get input from multiple sources

• Remember the main parts of a spinal motor
  circuit.
• Motor neurons innervate muscles, flexor and
  extensor muscles.
• Sensory neurons give feedback information that
  monitors the state of muscle contraction.
• Local circuit interneurons coordinate motor
  output.
• Messages from higher centers in the brain control
  the spinal motor system.

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• The understanding of circuits and the
  understanding of development might come together
  to treat some disease.
• For instance, it may be possible to treat motor
  neuron disease.

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• In many neurodegenerative diseases motor neurons
  are lost.
• Amyotrophic lateral sclerosis is a disease of
  motor neurons where normal motor neurons
  gradually undergo atrophy. They begin to die, the
  muscle itself withers away, and finally motor
  neurons are lost from the spinal cord.

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Using stem cells to create new motor neurons in
mice

• Our knowledge of circuits and of development
  might come together to treat motor neuron
  disease.
• Motor neurons can be distinguished by the
  transcription factors that they express. We can
  label living motor neurons by expressing a marker
  protein.

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• The transcription factor promoter can be used to
  express a green fluorescent protein which will
  label living cells.
• Then all motor neurons would glow green.

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• A mouse embryo in which all motor neurons and
  their axons have been labeled with green
  fluorescent protein.

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Using stem cells to create new motor neurons in
mice

• From this animal it's possible to get stem cells.
• We know how to make motor neurons through the
  developmental pathways.
• We can add small molecule chemicals, including
  hedgehog ligands, to those stem cells and get
  them to become motor neurons.
• Then we grow large numbers.

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• Each of the round clusters contains about 10,000
  cells, about half of which are motor neurons.

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• The motor neurons can be tested for their ability
  to form functional connections.
• They can be transplanted back into the spinal
  cord and then monitored for their ability to send
  axons out of the spinal cord and innervate target
  muscle.

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• Next is a section of the green labeled motor
  neurons in the ventral spinal cord.
• They are sending axons out along all of the major
  axon pathways, and eventually form synaptic
  connections (the blue-white dots at the end of
  the green axons).

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Using skin cells to make patient-specific stem
cells

• Can we make motor neurons from stem cells and get
  them to form functional connections in a human?

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• Collect a small number of skin cells from a
  patient.

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• a population of patient-specific stem cells which
  can be induced to develop into motor neurons by
  the normal developmental signals, as well as the
  local circuit interneurons.

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• Use specialized transcription factors to convert
  those skin cells back to stem cells.

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• A population of patient-specific stem cells

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• which can be made to develop into motor neurons
  by the normal developmental signals, as well as
  the local circuit interneurons.

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• In a patient-by-patient manner, use motor neurons
  and interneurons and any other cell type which is
  relevant to the disease, and reintroduce those
  cells, or use them for drug design to find agents
  that block the progression of the disease and the
  death of motor neurons.

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