Across the Pond, imaging technology is also shedding light on the way that environmental factors affect DNA and trigger illnesses such as cancer and lung disease.
The link has long been known but what was less clear was the mechanics by which this happened. However, now researchers at the National Institutes of Health in America (NIEHS) have found that the biological machinery that builds DNA can also insert molecules into the DNA strand that is damaged as a result of environmental factors such as ultraviolet exposure, diet, and chemical compounds in paints, plastics, and other consumer products.
Understanding how this happens is important because these damaged molecules trigger cell death that can lead to cancer, diabetes, hypertension, cardiovascular and lung disease, and Alzheimer’s disease. It was an example of the benefits to be gleaned from advances in imaging techniques. In the case of the work carried out at NIEHS, the technique used was on time-lapse crystallography.
The imaging technology allowed researchers to determine that DNA polymerase, the enzyme responsible for assembling the nucleotides or building blocks of DNA, incorporates nucleotides with a specific kind of damage into the DNA strand. Time time-lapse crystallography, which takes snapshots of biochemical reactions occurring in cells, gave the team a unique view of the process. Their work showed that, after the DNA polymerase inserts a damaged nucleotide into DNA, the damaged nucleotide is unable to bond with its undamaged partner, which interferes with the repair function and ultimately leading to several human diseases.
As with the UK dementias project, the information provided by the imaging technology used by NIEHS could have far-reaching implications Samuel Wilson, M.D, senior NIEHS researcher on the team, said: “No one had actually seen how the polymerase did it or understood the downstream implications. The damaged nucleotide site is akin to a missing plank in a train track. When the engine hits it, the train jumps the track and all of the box cars collide.”
Understanding that could lead to new treatments, according to Bret Freudenthal, Ph.D., postdoctoral fellow in the group. Bret said: “One of the characteristics of cancer cells is that they tend to have more oxidative stress than normal cells. Cancer cells address the issue by using an enzyme that removes oxidized nucleotides that otherwise would be inserted into the genome by DNA polymerases. Research performed by other groups determined if you inhibit this enzyme, you can preferentially kill cancer cells.”
- Representative coronal T1–weighted scans in a patient with Alzheimers disease (right), a patient with Dementia with Lewy Bodies (middle) and an age matched healthy person (left).
- The scans reveal increase brain atrophy in both the Alzheimers Disease (AD) and Dementia with Lewy Bodies (DLB) subject compared to control, particularly in the enlarged sulcal spaces.
- Hippocampal atrophy (arrowed) is clearly seen in the AD patient, while the DLB subject and control appear similar.
- Hippocampal atrophy on MRI is a clinical measure used in the evaluation and diagnosis of AD. Healthy DLB AD Magnetic Resonance Imaging (MRI) These data are from the work funded by the Sir Jules Thorn Charitable Trust through their Biomedical Research Award
- Representative Arterial Spin Labeling (ASL) scans where intensity shows cerebral blood flow (upper panel) and the equivalent T2–weighted FLAIR scans highlighting anatomy and periventricular white matter change in a patient with Alzheimers disease (left) compared to an age matched healthy person (right). • The FLAIR scan clearly reveal atrophy with loss of temporal lobe tissue and enlarged ventricle. The ASL blood flow maps show posterior hypoperfusion in the patient.
PET scan showing high uptake and wide distribution of 18FAmyvid in the brain of ‘subject A’ in a dementia imaging study. PET scan showing low uptake and limited distribution of 18FAmyvid in the brain of ‘subject B’ in a dementia imaging study
Why the new technology is so exciting
A key feature in imaging technology is that it provides truly simultaneous imaging of anatomy, physiology and function (from MRI) and of molecular targets (fro
m PET). The standard configuration in PET-CT joins two scanners together, end-to-end. Typically, a CT scan is done first and then the patient bed is moved automatically into the PET gantry. In that case, the decay (positron emission) of an isotope such as 18F is detected following an anti-matter : matter annihilation.
The positron collides with an electron, mass is converted to energy and the two resulting gamma rays trigger scintillation crystals surrounding the patient. PET-MR scanners have the scintillation crystals embedded in the central section of the magnet so that PET measurements can be done throughout the MR imaging examination. This has presented technical challenges in the devices and materials that can be used. Photo-multiplier tubes amplify signals in PET-CT but are not compatible with powerful magnetic fields, so have been replaced by avalanche photodiodes. The material used to make MR detectors can attenuate gamma rays and the absence of CT (X-ray imaging) makes this more difficult to correct.
Apart from the ability to make structural and molecular biology based measurements in patients at exactly the same time (to be exploited by informatics approaches), MRI will be valuable in correcting PET imaging for motion. This will apply in body imaging, to deal with breathing and heart movements, but also in the brain, where experience shows that even control subjects find it difficult to avoid head movements, let alone those patients who may also have movement disorders. On a more practical level, the combination of PET and MRI measurements into a single examination will have a lower radiation exposure, be easier to schedule into treatment studies and more convenient for patients.
