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© 2011, 2012 Health Futures Digest
New understanding of the genetics of immune system cells could lead to better-targeted therapies for some major diseases, including diabetes, lupus (note advances in lupus treatments covered elsewhere in this issue), and rheumatoid arthritis. New genetic understandings also open up new avenues of potential cancer therapies. For example, the discovery that genetically damaging an already damaged – cancer-causing – cell kills the cancer suggests an obvious new approach.
Increased understanding of the proteomics of non-small cell lung cancer suggests a better way than drugs currently under development to overcome the cancer’s notorious resistance to chemotherapy.
Another significant breakthrough has been made toward a potential cure for cancer, through manipulation of a single gene. As is so often and so frustratingly the case, the breakthrough was made in mice, not humans.
Cancer is not the only war in which genetics is playng a major role: Neurodegenerative disease is also in the cross-hairs, as another gene linked to susceptibility to Alzheimer’s is found, along with potential preventatives and cures for Parkinson’s and stroke. However, the cures may be ready before our ability to apply them. We first need to be able to diagnose the diseases, if not before they strike, then at least very soon afterwards. But there is progress in that regard, too, as evidenced by the development of a simple genetic test for lung cancer (still some years from validation and approval.)
Despite all these advances, it is in one sense almost back to the drawing board for geneticists, with the discovery that we do not, after all, differ by only a half percent of our genomes, but by at least 12 percent.
Whitehead Institute and Dana-Farber Cancer Institute scientists have mapped the genome of T-cells and discovered genetic links thought to be important in auto-immune diseases, where the body’s immune system attacks normal tissue by mistake. They identified 30 genes in the cell that appear to be influenced by a gene known to be important in controlling a special type of “regulatory” T-cells that prevent ordinary T-cells from mistakenly damaging normal tissue when fighting invaders.
Another of the 30 genes has already been linked by other studies to type 1 diabetes, lupus, Grave’s disease, and rheumatoid arthritis, so the discovery strengthens the evidence that this is the mechanism that is going wrong in these diseases. The work may help produce new therapies for autoimmune disease.
Yet Another New Approach to Cancer
University of California at San Diego researchers have discovered that mice with abnormal numbers of chromosomes (a condition known as aneuploidy) become more cancer-prone with age. Yet, when additional genetic errors were introduced, they became less prone.
Mice that lacked a tumor suppressor gene were more susceptible to cancer, as expected, but if they also had a high rate of aneuploidy, tumor growth was again slowed.
It seems that increasing the level of genetic damage in aneuploid mice kills tumor cells, which opens up new avenues for cancer therapies in humans. For example, a drug might be developed to induce aneuploidy in new cells.
Cancer Research UK researchers have identified a number of key proteins that appear to influence the development of resistance to chemotherapy in small cell lung and other cancer patients. They found that in addition to the protein FGF-2 (already known to induce resistance), another protein – S6K2 – was present in higher levels in drug-resistant cancer samples, and that patients who relapsed after treatment had higher levels of S6K2 in their tumors.
A researcher told the BBC News: “This suggested that chemotherapy initially killed lots of cancer cells, but cells with S6K2 were able to survive and pass on their resistance. New cancer cells therefore also had increased levels of S6K2 and the tumor became increasingly resistant to treatment.”
Another said drugs already in development that can block the action of FGF-2 carried a risk of side effects because the protein also plays important functions in healthy cells. Given that S6K2 has fewer functions than FGF-2 in healthy cells, “if we can develop new drugs that stop it working, it may be a better way to reverse drug resistance.”
Cold Spring Harbor Laboratory and MIT researchers have made various types of tumor start to shrink in mice by reactivating p53 genes, which are mutated or inactivated in most human cancers. Even when only briefly reactivated, the gene dramatically reduces the size of the tumors, in some cases by 100 percent. It did not harm normal cells.
The mechanism behind the regression appeared to vary depending on the type of tumor. Lymphoma cells were coaxed to commit suicide, while sarcoma cells started to grow old and lose their ability to divide. In normal cells, p53 activates DNA repair mechanisms and prevents cells with damaged DNA from dividing. If DNA damage is irreparable, p53 induces apoptosis (the cell destroys itself.) When p53 is turned off by mutation or deletion, cells are much more likely to become cancerous, because they will divide uncontrollably even if their DNA is damaged.
The researchers used engineered mice that had the gene for p53 turned off. But they also included a genetic “switch” that allowed the researchers to turn p53 back on after tumors developed.
The findings could potentially provide a powerful way of treating the disease in humans.
An international study of more than 6,000 people has led to the identification of versions of a gene called SORL1 that appear to raise the risk of developing the most common form of Alzheimer’s disease – modestly, though the researchers don’t yet know exactly by how much.
If confirmed, the finding is “a substantial step forward in our understanding of the genetics of Alzheimer’s disease” and could help lead to new treatments, as experts told Malcolm Ritter of the Associated Press.
A gene called APOE has already been firmly linked to susceptibility to the common form of Alzheimer’s, and some 20 others are thought to be promising candidates.
Preventatives for Alzheimer’s, Stroke
Researchers at the Buck Institute for Age Research have concluded from two animal studies that simple supplements could protect people at risk or in the early stages of Parkinson’s disease and stroke, reports Daniel S. Levine in the San Francisco Business Times .
One study in weaver mice (which have a damaged motor cortex) showed that a natural inflammatory response meant to clean out dead neurons actually causes more neurons to die. Given an antibiotic (minocyclin) to suppress anti-inflammatory activity, mice that did not yet show symptoms sustained, after three weeks, a 30 percent loss of neurons in a key part of the brain, compared with a 50 percent loss in mice untreated mice.
The findings suggest a possible treatment for Parkinson’s disease prior to the onset of symptoms if the disease could be detected at an early stage before its outward manifestations become visible and too much damage occurs.
The second study found that mice genetically engineered to overproduce neuroglobin – a protein closely related to hemoglobin but expressed mostly in the brain – suffered 30 percent less tissue damage following strokes and 25 percent less damage following heart attacks compared with normal mice. This suggests that a drug similar to the iron supplementation used to increase hemoglobin in patients with anemia could to encourage the overproduction of neuroglobin in humans and provide protection against stroke and heart attack.
The key missing piece is the ability to identify people at the earliest stages of these diseases or those at risk of developing them. By the time someone with Parkinson’s is diagnosed, the brain has already been damaged.
Gene Tests for Lung Cancer Patients
Scientists in Taiwan have developed a simple, five-gene test aimed at showing which lung cancer patients most need chemotherapy, as similar tests now do for people with breast cancer and lymphoma, reports AP medical writer Marilynn Marchione. The test has been validated in small studies in Asian populations, but can’t be approved until validated in larger trials, so widespread use is at least a few years away.
The test is simple enough to administered by ordinary physicians rather than by people with special genetics training.
Aided by a relatively new molecular tool that can spot medium-scale variations of DNA code – at the scale of thousands of DNA letters, as opposed to standard techniques that look either at individual base pairs or at the chromosome – a British-led international research team has identified “vast stretches” of duplicated or even missing DNA code in 270 people studied, reports the BBC News.
The tool is known as copy number variation (CNV). While most of the newly discovered variations are unrelated to health, some play a role in a number of disorders. Apparently, the assumption that the DNA of any two humans is 99.9 percent identical no longer holds. The researchers found 1,447 CNVs in nearly 2,900 genes – amounting to at least 12 percent of the genome and presenting a “huge, hitherto unrecognised, level of variation between one individual and the next,” says the BBC report.
This difference will make a difference in the search for genes involved in disease. A US researcher involved in the study said “A recent review lists 17 conditions of the nervous system alone — including Parkinson’s disease and Alzheimer’s disease — that can result from such copy number changes.” The research will also inform the study of human evolution.
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