Imaging: From Mice to People
July 5, 2007
Dr. Wilson began with a brief history on medical imaging. He told us that x-rays were discovered in Germany on Nov. 8, 1895. Only a few months later, there was a paper published on the topic, in Jan. 5, 1896. To have a paper published that soon after a discovery is remarkable. Also, the Nobel Prize was awarded relatively quickly after the discovery, in 1901.
Dr. Wilson showed slides of various newspaper clippings showing how Case Biomedical imaging had recently been in the news. There was a slide showing how Case was related to Phillips Medical Systems (the largest in the world), another showing CWRU’s grad program (Dr. Wilson encouraged us to apply!), one describing the creation of the Case Center for Imaging Research, and another with Paul Lauterbur (a CWRU alumni) who won the Nobel Prize in MR imaging two years ago.
There are numerous applications to humans in this field. It can apply in the detection of diseases, in helping to determine stages of diseases, and in therapy. Dr. Wilson discussed how mice are the new laboratory patients and why. In 1998, there were approximately 23 million lab mice in existence, with 50,000 mice on the Case campus alone. The reason mice are chosen is because they are 98% homologous to humans and can be genetically modified at will (e.g. can implement human diseases). The applications to mice in this field are to develop methods for detection and staging of disease and in assessment of therapy. There has been development of smaller MRIs more suitable for mice patients. The only problem with these smaller MRIs is that they are, in fact, more expensive than normal, larger sized MRIs.
Dr. Wilson then discussed the application of bioluminescent imaging of gene expression (inside of living subjects) to mice. The reason why this is such a great procedure, is that they can do it without cutting into the animal. They have genes that are producing proteins. They introduce a reporter gene under the control of a promoter protein. When the gene of interest is expressed, the reporter gene is also expressed. Probe molecules are produced and are visible to optical, radionucleide MRI. The luciferase reporter gene from fireflies is under control of the promoter of the gene of interest. When the expressed luciferase enzyme acts on the probe molecule, luciferin, it creates light.
The light produced is so faint that they must build extremely sensitive equipment even to detect it. They use a liquid nitrogen cooled camera with a light tight box. This collects approximately 90% of the light protons and can image for 1m-6m. When they used this light box they found that they were seeing extra spots. It turned out that they were actually seeing cosmic ray artifacts left over from the Big Bang. They had to create an image processing algorithm to get rid of the spots.
Dr. Wilson is also working on imaging of clusterin (secretory), sCLU. It is unregulated when the cell is stressed by a cyto-toxic agent such as a chemotherapy drug or PDT or by radiation. The first experiment performed was with IR dose response cells on wall plates. They created a transgenic mouse with the luciferase reporter and got stimulation of the reporter gene.
Work is also being completed on the clearance of bacterial pneumonia. Bacterial cells bioluminess and so in vivo (alive) imaging can be conducted. This results in fewer mice in space and repeated imaging from the same mice. Since they use the same mice, they don’t have to kill as many and can receive better data since they are using the same animal as their control.
Dr. Wilson also discussed work on an MRI imaging agent. Paramagnetic nanoparticles are being used since they have different ligands that allow attachment to cancer cells. This is a contrast agent that would provide earlier detection. They refer to them as “smart” MRI agents for molecular imaging and this is a wonderful area of research because it would allow noninvasive techniques for detecting of cancer in humans.
Controlled drug release to a target is another area of research being conducted. A small millirod with a chemotherapy agent can be introduced straight to a tumor. Imaging of these millirods has been done so as to learn how to optimize the amount of agent to use. This is being done so that doctors can spare as much normal tissue as possible during treatment.
Another focus of research is in imaging of stem cell therapies. Stem cells can take on many characteristics and so researchers want to see how they affect the body if injected into mice or humans. Dr. Wilson’s been working on imaging of stem cells, specifically on applications of homing to injuries and proliferation.
Research is being completed on gene therapy of cystic fibrosis. The control is NaI and a small animal scanner is used. Areas of research in imaging related to cancer are mouse models of disease, development of early events, development of MR pulse sequences, EM coils, computer science, 3D rendering, and building of new equipment, etc.
The last topic covered in Dr. Wilson’s presentation was regarding cryo-imaging of frozen mice. This method achieves extremely high resolution and contrast compared to MRI and other similar imaging techniques. This is also a great way to image stem cells, even single cells (e.g. adrenal).
There was a brief question and answer session after the presentation, where several different topics were brought up:
One of the RAs asked how the millirods are inserted during the experimenting. Dr. Wilson responded that they are inserted through a small, hollow needle. Dr. Wilson explained how often they will implant human diseased cells (cancer, etc.) into immunally suppressed mice so it will incubate. He also described how he felt that radiation would be the rate-limiting problem for a Mars human exploration mission. Apparently the normal human field magnet for an MRI is around 1.5 Tesla, whereas a high field magnet for a mouse MRI is around 9 Tesla. The last information Dr. Wilson provided was to say that for PET imaging they need a cyclotron to make drugs, but that it has much better resolution than bioluminescence.