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<tr><td><p style="font-size:12px" align=center><i>Attributions: Erik Ersland, Alexa Garcia, Christian Richardson</i></p></td></tr>

<tr><td><p style="font-size:12px" align=center><i>Attributions: Erik Ersland, Alexa Garcia, Christian Richardson</i></p></td></tr>

<tr><td align=center> <img src="https://static.igem.org/mediawiki/2014/0/06/MIT_future_homepage.png"> </td></tr>

<tr><td align=center> <img src="https://static.igem.org/mediawiki/2014/0/06/MIT_future_homepage.png"> </td></tr>

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Our system to detect and treat Alzheimer’s disease would potentially be a therapeutic for human patients. As such, we know that there needs to be a designated method of delivering the system into the human body. This is no trivial consideration: the necessary delivery method could have implications at many stages in the research and development process.  

Our system to detect and treat Alzheimer’s disease would potentially be a therapeutic for human patients. As such, we know that there needs to be a designated method of delivering the system into the human body. This is no trivial consideration: the necessary delivery method could have implications at many stages in the research and development process.  

In the early stages of our research, we contacted several professionals in the field of neuro-biology and Alzheimer’s disease. Through several <a href="https://2014.igem.org/Team:MIT/2014.igem.org/Team:MIT/Interviews">remote and face-to-face conversations</a>, we discussed and developed several potential delivery methods for the system we hoped to created. For the purpose of our system, there were two types of cells in the brain that we could consider as targets for modification: neurons and microglia.

In the early stages of our research, we contacted several professionals in the field of neuro-biology and Alzheimer’s disease. Through several <a href="https://2014.igem.org/Team:MIT/2014.igem.org/Team:MIT/Interviews">remote and face-to-face conversations</a>, we discussed and developed several potential delivery methods for the system we hoped to created. For the purpose of our system, there were two types of cells in the brain that we could consider as targets for modification: neurons and microglia.

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Neurons are the main cells affected by Alzheimer’s disease. Direct modification of neurons would be beneficial, since beta-amyloid production occurs within these cells. Delivery to neurons can take two routes.  We could use a viral vector to directly modify existing neurons.  This may be done by minimally invasive neurosurgery to bypass the blood brain barrier which also reduces the chance of an adverse immune response to the viral vector.  It may also be possible to inject into the spine which would not require surgery.  A very promising possibility is that bone marrow and possible blood borne cells <a href="http://www.scientificamerican.com/article/neurons-from-bone-marrow/">may naturally cross the blood brain barrier and become neurons.</a>  This would allow clinicians to remove a sample of the patients bone marrow and modify its genome using bench top methods which are much safer than in vivo methods.  These modified cells can then be screened for quality assurance then transplanted back into the patient.  Enough cells may colonize the brain and bone marrow to cause effective delivery, but if not, irradiation can be used to kill some or all of the patients existing bone marrow and the new cells will replace them, similar to how bone marrow transplants are performed on cancer patients.  New and experimental methods are being developed, such as lipid rafts and replicons, which may offer safer or more effective delivery methods.

Neurons are the main cells affected by Alzheimer’s disease. Direct modification of neurons would be beneficial, since beta-amyloid production occurs within these cells. Delivery to neurons can take two routes.  We could use a viral vector to directly modify existing neurons.  This may be done by minimally invasive neurosurgery to bypass the blood brain barrier which also reduces the chance of an adverse immune response to the viral vector.  It may also be possible to inject into the spine which would not require surgery.  A very promising possibility is that bone marrow and possible blood borne cells <a href="http://www.scientificamerican.com/article/neurons-from-bone-marrow/">may naturally cross the blood brain barrier and become neurons.</a>  This would allow clinicians to remove a sample of the patients bone marrow and modify its genome using bench top methods which are much safer than in vivo methods.  These modified cells can then be screened for quality assurance then transplanted back into the patient.  Enough cells may colonize the brain and bone marrow to cause effective delivery, but if not, irradiation can be used to kill some or all of the patients existing bone marrow and the new cells will replace them, similar to how bone marrow transplants are performed on cancer patients.  New and experimental methods are being developed, such as lipid rafts and replicons, which may offer safer or more effective delivery methods.

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Microglia are another potential cell target.  Microglia are the immune cells of the brain, <a href="http://www.ncbi.nlm.nih.gov/pubmed/20552234">and have been show to break down beta amyloid at some level natively</a>.  Microglia are recruited from precursor cells in the blood in response to inflammation in the brain.  Inflammation is caused by beta amyloid in Alzheimer's Disease or can be stimulated by irradiation (and the brain is appreciably more resistant to radiation than the rest of the body due to the slow division rate of neurons).  Like neurons, microglia would be engineered ex vivo and delivered back into the patients blood.  Microglia may be safer because they are not involved in brain function directly and, unlike neurons, the brain can continue to function after populations of them die.  This means wer could potentially include a kill switch in the modified cells in case there are undesirable side effects.

Microglia are another potential cell target.  Microglia are the immune cells of the brain, <a href="http://www.ncbi.nlm.nih.gov/pubmed/20552234">and have been show to break down beta amyloid at some level natively</a>.  Microglia are recruited from precursor cells in the blood in response to inflammation in the brain.  Inflammation is caused by beta amyloid in Alzheimer's Disease or can be stimulated by irradiation (and the brain is appreciably more resistant to radiation than the rest of the body due to the slow division rate of neurons).  Like neurons, microglia would be engineered ex vivo and delivered back into the patients blood.  Microglia may be safer because they are not involved in brain function directly and, unlike neurons, the brain can continue to function after populations of them die.  This means wer could potentially include a kill switch in the modified cells in case there are undesirable side effects.

While contemplating our potential delivery mechanisms, we also took into consideration that some methods might be more publicly acceptable than others. In the end, as a therapeutic, our system would be effective only if patients were willing to receive it.  

While contemplating our potential delivery mechanisms, we also took into consideration that some methods might be more publicly acceptable than others. In the end, as a therapeutic, our system would be effective only if patients were willing to receive it.  

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Considering our research, the opinions of professionals and the results of our public opinion survey, we decided to pursue a system intended for delivery into neurons. This option allows for more targeted and effective delivery of our system, and (theoretically) a more potent effect on the symptoms of Alzheimer’s disease.  The biochemistry of Alzheimer's Disease is also better understood in neurons and neuron based test beds are more widely available.

Considering our research, the opinions of professionals and the results of our public opinion survey, we decided to pursue a system intended for delivery into neurons. This option allows for more targeted and effective delivery of our system, and (theoretically) a more potent effect on the symptoms of Alzheimer’s disease.  The biochemistry of Alzheimer's Disease is also better understood in neurons and neuron based test beds are more widely available.

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Our system is based mostly on the interactions of proteins and miRNA molecules. The proteins used may function in either neurons or microglia. In order to switch our system functionality from a neuron environment to a microglial environment, it would require modifying the <a href="https://2014.igem.org/Team:MIT/miRNA">miRNA</a> sensed for and <a href="https://2014.igem.org/Team:MIT/Treatment">used in our various modules</a>. However, it must be noted that, although our system is meant to target neurons, in the event that this method becomes undesirable, it is quite possible to (in theory, simply) modify the system to target microglial precursor cells.

Our system is based mostly on the interactions of proteins and miRNA molecules. The proteins used may function in either neurons or microglia. In order to switch our system functionality from a neuron environment to a microglial environment, it would require modifying the <a href="https://2014.igem.org/Team:MIT/miRNA">miRNA</a> sensed for and <a href="https://2014.igem.org/Team:MIT/Treatment">used in our various modules</a>. However, it must be noted that, although our system is meant to target neurons, in the event that this method becomes undesirable, it is quite possible to (in theory, simply) modify the system to target microglial precursor cells.

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