Retinal degeneration and blindness, possibly preventable

Photo by Aaron (~Sayn)

Neurodegenerative diseases such as retinitis pigmentosa (RP) currently ravage through the eyes of millions of people worldwide unhindered and untreated. Genetic disorders like these often leave patients blind with no good news from the time of diagnosis. That is likely to change soon as researchers of the Universities of Toronto, Lausanne, Lund, and The Centre of Biomedical Genetics (Amsterdam) found Bmi1 and cyclin-dependent kinases (CDKs) a potential targets to prevent blindness caused by neurodegeneration.

Retinal pigmentosa results from the mutation of around 200 loci or genes leading to the loss of rod and cone photoreceptors. Previous studies showed that neurons prepared to die (due to a neurodegenerative disease) reexpress cell cycle-related proteins like CDKs. Specifically CDK4 and CDK6 activation was seen as involved with neuronal death in these conditions.

Bmi1 to E2F1 cycle

Bmi1 is a polycomb group protein (proteins that silence genes) which inhibits CDK inhibitors. These normally lessen the activity of CDK’s, which inhibit retinoblastoma (Rb) proteins. The Rb proteins down-regulate E2F1, which causes the cell to divide past it’s prime. This little cell cycle here has been shown to be the cause of neurodegeneration in Parkinson’s disease; therefore, researchers are investigating the effects of it in ophthalmological cases.

Rb1 mice (those with induced RP) were first analyzed for their expression of cell cycle markers. Between postnatal day nine (P9) and P12, the amount of CDK4/6 significantly increased in the apoptotic cells of the Rd1 mice. However, almost no CDK4/6 was detected in the wild type mice’s retinal cells.

Because of the higher expression seen, CDK interference was run. An ex vivo (pulled part of the retina out of the mouse to study) assay was performed with retinal explants of Rd1 mice. Using roscovitine (CDK inhibitor) vs. no treatment groups, photoreceptor degeneration was measured. The roscovitine group showed 42% less apoptotic photoreceptors. This meant CDK4/6 were contributing to the loss of photoreceptors.

Consistent with this, inhibited Rb1 was found in Rb1 mice and not wild type mice. This meant E2F proteins were allowed to freely push the cell into apoptotic division. Playing with alleles and expression patterns of E2F1,2,3 in combination, researchers were able to determine ESF1 was more important than E2F2/3 in neurodegeneration. Deleting the gene resulted in slowed, but not stopped photoreceptor degeneration.

Finally, Rd1/Bmi1-/- mice were analyzed vs. Rd1 mice to see the protective effect of removing Bmi1 all together. Respectively, 40% and 90% photoreceptor loss was seen in the mice. Rd1/Bmi1-/- mice lost 50% less photoreceptors than the normal retinitis pigmentosa mice.

Pulling all together, retinal degeneration was significantly slowed and prevented leading to a protection of photoreceptors by inhibition of Bmi1, CDK4/6, and E2F1. Being diagnosed with RP may not be as hopeless any longer. Once therapies are pushed into the clinic using the targets found in this study, RP patients may shrug at their diagnosis rather than shudder.

Dusan Zencak, Karine Schouwey, Danian Chen, Per Ekström, Ellen Tanger, Rod Bremner, Maarten van Lohuizen, Yvan Arsenijevic. Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins. Proceedings of the National Academy of Sciences of the United States of America, 2013.


Stopping Leukemia’s regeneration and preventing relapse

Photo Credits: Eric V. Grave / Photo Researchers, Inc., ISM/Phototake

Many cancers, and leukemia specifically, are difficult to manage because of the chance of relapse if even a tiny cancerous cell is left behind once treatment stops. Therefore, a hot topic in cancer research is the prevention of cancerous regrowth and metastasis. The ADAR1 enzyme has just been identified as a potential target to block relapse of chronic myeloid leukemia by a team bellwethered by researchers of the University of California, San Diego School of Medicine.

Chronic myeloid leukemia (CML) is a cancer of the white blood cells in which the blood forming tissue of the bone marrow (myeloid tissue) proliferates out of control and causes anemia, easy bruising, decreased ability to fend off infection, fever, and joint pain. To combat this, constant intake of tyrosine kinase inhibitors (TKIs) via chemotherapy is necessary. This works to starve the bulk of the tumor of its energy (ATP) and allow the cells to die. This method is usually long term because the TKIs do not always catch every cancerous cell. Relapse is imminent if treatment stops.

For this reason scientists looked to ADAR1.

This enzyme is expressed during very early development of the fetus to promote blood cell proliferation and protect hematopoietic stem cells from viral attack. Leukemic tumors sequester this enzyme for the protection of their own cells activating ADAR1 when it is not needed. This protects the cancerous white blood cells from chemotherapy and allows for enhanced proliferation of the cells.

Researchers performed a 50% knockdown of ADAR1 in vivo using a murine model to test the effects on CML progenitor cells. The self-renewal rate of the leukemia stem cells was reduced by about 30% by this ADAR1 knockdown test. This confirmed the enzyme’s role in the self renewal of the CML cells.

This puts ADAR1 on the table as a potential drug target for cancer treatment. ADAR1 knockdown in patients receiving tyrosine kinase inhibitors may be what is needed to  kill myeloid leukemia tumors, stop its regeneration, and eradicate the disease from the body for good without the need for perpetual treatment.

Combination treatments get another thumbs up from me if we see this therapy in the clinic soon.

Qingfei Jiang, Leslie A. Crews, Christian L. Barrett, Hye-Jung Chun, Angela C. Court,
Jane M. Isquith, Maria A. Zipeto, Daniel J. Goff, Mark Minden, Anil Sadarangani,
Jessica M. Rusert, Kim-Hien T. Dao, Sheldon R. Morris, Lawrence S. B. Goldstein, Marco A. Marra, Kelly A. Frazer, Catriona H. M. Jamieson. ADAR1 promotes malignant progenitor reprogramming
in chronic myeloid leukemia. PNAS, 2012.

Mutations for cancer begin before cancer

Cancer cells mid-division. Photo courtesy of The Telegraph

Cancer cells mid-division.
Photo courtesy of The Telegraph

Cancer can prove one of the nastiest diseases to crop up in one’s body due to it remaining hidden until it has already metastasized and spread around the system. A Baltimore/Boston collaboration of researchers set out to prove over half of the somatic mutations that make up a tumor are present before “tumor growth” of self-renewing tissues even starts.

Tumors form as the result of genetic mutations in which more cell replication and division happens than cell death. This causes the overgrowth of cells resulting in cancerous masses. Cancers aren’t caused by a single mutation, however. Many things must go wrong in cells before they get out of control. The basis of this study was to see how many passenger mutations (those that do not affect cell growth) actually occur before the tumor is initiated (by driver mutations) and whether or not this was affected by patient age.

To test, data was analyzed from The Cancer Genome Atlas and the International Cancer Genome Consortium of 676 patients with chronic lymphocytic lekemia (CLL), uterine corpus endometrioid carcinoma, colorectal cancer, or pancreatic cancer. The researchers first found that the total number of somatic mutations found in these cancers increased with patient age (at diagnosis) (P<0.01). The mutation to age correlation was independent of cancer stage.

The results further indicated that over 50% of passenger mutations developed before a single driver mutation in median aged patients. Using the regression data shown in the article, the number of somatic mutations at the earliest stage of cancer detection (after 25 years for colorectal, after 7 years for leukemia, and after 10 years for uterine) was estimated as 5.86, 33.3, and 50.2 in the different cancers. This suggested 68%, 57%, and 51% respectively of the somatic mutations happened before the tumors initiated.

Finally, the mutations rates were estimated, but did not deviate much from that of normal cells and bacteria.

The results from this study showing that the number of somatic mutations in a patient are age dependent and that a large number of these mutations appear before cancer growth begins are relevant for current genome-cancer studies. From this data, it may be possible to predict a cancer’s appearance before it even starts.

Catching cancer early is one of the most important keys to stopping it. This project is a step closer to faster cancer detection and elimination.

Cristian Tomasetti, Bert Vogelstein, Giovanni Parmigiani. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. PNAS, 2013.

Flying bug beats viral bug

Iridescent blowfly meets praying mantis. Photo Credits: kpcmccombs of Chaos – it’s not just theory…

Researches of universities spanning Europe recently conducted a study indicating a normal process in fruit flies (drosophila melanogaster) keeps viruses at bay. Internal machinery of these invertebrates turns on to induce RNA interference (RNAi), a process that inhibits the expression of targeted genes, when high enough levels of double stranded RNA (dsRNA), genetic material common to many viruses, are detected.

In this study, drosophila were infected with Invertebrate iridescent virus 6 (IIV-6) to make possible analysis of their virus fighting capabilities. IIV-6 turns certain regions of the fruit fly, eyes and abdomen for example, iridescent colors making for easy visual detection of successful viral infection. Therefore, as virus spreads within, more coloration would be seen. Infected wild type flies survived past the 31 day marking point of the study. Dcr-2 or Argonaute-2 Knockout flies with the functionality of one of two essential components for RNAi broken were infected with IIV-6 to test efficacy of viral infection without RNAi response. These flies showed increased signs of infection and many died after the 18 day mark. This indicated RNAi mechanisms were necessary for successful viral defense.

Antisense transcripts were of detectable levels during infection. Furthermore, high levels of vsiRNAs were found in infected flies as effectively silencing or reducing the effects of the IIV-6 genome. This byproduct analysis showed RNAi as an effective antiviral defense.

This insect antiviral may prove useful in protecting against viruses such as Dengue or the common cold in humans and other animals. Viral havoc may no longer be wreaked over the human body once this insect mechanism is utilized further.

Alfred W. Bronkhorst, Koen W. R. van Cleef, Nicolas Vodovar, İkbal Agah İnce, Hervé Blanc, Just M. Vlak, Maria-Carla Saleh, Ronald P. van Rij. 2012. The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery. Proceedings of the National Academy of Sciences.

Extremophile bacteria hint at possibility of life on other planets

Courtesy of the Desert Research Institute of Nevada.

2010 camp set up on the Antarctic Lake Vida allowing scientists to core the ice and retrieve subglacial brine and ice samples. Courtesy of the Desert Research Institute of Nevada

Lake Vida of Antarctica is home to some of the saltiest waters on the entire planet, but researchers recently found bacteria living under the cap of these ice covered waters. The subglacial environment of this lake is anoxic with an average temperature of -13 °C and 200 on the salinity scale. These waters are 2,000 times saltier than safe drinking water and nearly six times saltier than the Red Sea, one of the saltiest bodies of water on the planet. The lake is encapsulated by 800-970m of permafrost making for a very isolated environment. Despite the conditions, Lake Vida was found to house a phylogenetically diverse and metabolically active bacteria.

Though the exact species has not been determined as of yet, the observed microbes’ means of survival was analyzed. The waters contain high levels of reduced metals, ammonia, molecular hydrogen, organic carbon, oxidized nitrogen species, and sulfate. These elements alone would not be able to sustain an ecosystem for long if at all; however, it is estimated that Vida’s bacteria have persisted here for over 2,800 years. Researchers hypothesize this is because of the brine-rock reactions occurring, which release electron acceptors to allow the bacteria to get the energy needed to survive. The chemoheterotroph nature of these bacteria coupled with their slowed down metabolism caused by the icy environment has allowed them to survive through millenia.

The study of these bacteria and their relatives helps provide a better view of how life can exist in a myriad of environmental systems. Mars, Europa, and Enceladus are three extraterrestrial environments with terrain parallels to what was seen in Lake Vida giving hope of life beyond what Earth has seen. It is possible that under the icy encapsulations of these celestial bodies, life undiscovered may exist.

Alison E. Murray, Fabien Kenig, Christian H. Fritsen, Christopher P. McKay, Kaelin M. Cawley, Ross Edwards, Emanuele Kuhn, Diane M. McKnight, Nathaniel E. Ostrom, Vivian Peng, Adrian Ponce, John C. Priscu, Vladimir Samarkin, Ashley T. Townsend, Protima Wagh, Seth A. Young, Pung To Yung, Peter T. Doran. 2012. Microbial life at -13 °C in the brine of an ice-sealed Antarctic lake. Proceedings of the National Academy of Sciences.