Metabolism underpins numerous cellular processes. Without it, cells would not grow, divide, synthesize or secrete. Another pathway, autophagy, degrades unwanted cellular materials, helping to maintain cell health. With these opposing roles, is there a connection between autophagy and metabolism? As it turns out, the answer is yes. Because molecules degraded by autophagy are recycled and fed into metabolism pathways as precursor compounds. There are interesting implications as a result of this connection, ones that affect cancer cells as described in a recent Cell Metabolism review article.
Autophagic flux, the process by which molecules and organelles are directed to the autophagosome, fuse with the lysosome and are degraded, involves a selective process that determines the cargo carried within the autophagosome. Autophagy-related genes (ATGs) direct the process and particular receptor proteins bind the cargo. What is interesting about the connection among cancer, autophagy and metabolism is the complexity of the role that autophagy plays in cancer. While autophagy was thought to act in a more tumor suppressive manner as shown when one copy of an ATG6 analogous gene in mice was deleted and the other left unaltered, and malignant tumors developed, but in mice mosaic for ATG5 deletions, the inhibition of autophagy resulted in benign tumors in the liver. This latter experiment suggested autophagy was needed for cancer progression, a hypothesis reinforced by the lack of ATG mutations in human cancers. Continue reading
Cancer has been studied for decades by scientists trying to find a vulnerability to exploit and testing compounds to develop as potential drugs. As the “Emperor of All Maladies”, cancer has proven itself to be a wily beast with many varieties of genetic mutations for eluding cellular control, tireless in its ability to divide and spread. In the end, a cancer cell is still a cell and subject to its environment even though cancer does not play by the same rules as the normal cells that exist around it. To be able to grow, a cell needs access to metabolites, molecules needed for building the materials and machinery needed by the cell to function and divide. These requirements also offer potential pathways to target for halting cancer growth and spread.
All cells use glucose to generate ATP, but normal and cancer cells differ in how glucose is converted to ATP. Most cells use glucose in oxidative phosphorylation, but cancer cells use aerobic glycolysis, converting glucose to lactate without oxygen. This Warburg effect (glucose converted to lactate) is a hallmark of cancer cells as they take up glucose at a much higher rate than normal cells. Blocking glucose uptake is one way to target cancer cells. While 2-deoxyglucose (2DG) has been shown to slow glucose uptake in vitro, the compound proved toxic in clinical trials and lower dosages do not seem to be an effective treatment against cancer. While not an ideal drug target, glucose uptake has been helpful in monitoring cancer response to therapies via fluorodeoxyglucose positron emission tomography (FDG-PET). Continue reading
In honor of Human Genome Month, I delved into our Cartoon Lab archives to retrieve this example of the excitement that occurred while sequencing the Human Genome Project.
For more entertaining science cartoons, visit our Cartoon Lab.
A few science news items caught my eye this week.Wood-Shattering Revelation: Termites have been recategorized based on genetic and other evidence. Turns out, they are just social cockroaches and thus, have become part of the cockroach order Blattodea rather than remaining in a separate order. This decision was not made lightly, but based on years of debate amongst American entomologists. The insects will still retain termite in their name, but they gain a reputation for surviving apocalyptic events. Read about the update to the insect name master list by the Entomological Society of America. Blood Pressure Measurements at the Tip of Your Finger: A blood pressure cuff is bulky, annoying but accurate for monitoring the effort needed for pushing blood around your body. While this device is a fairly simple one, in the developing world it is not that common. However, mobile phones are available to many more globally so why not find a way to put the two together? Turns out that smartphones are equipped with hardware that can be used to measure blood pressure. By adding a device that attaches to the back of a smartphone and with the press of a finger, you can monitor your blood pressure. While not currently as accurate as a blood pressure cuff, the people that tried the mobile blood pressure device were able to quickly adapt to using it, making it easy to take several readings for continuous monitoring. A pocket-sized blood pressure monitor without the nasty squeeze of your arm sounds like a great medical advancement for treating high blood pressure. See a video of the device. For a Forensic ID, All You Needed Was a Picture, Old Clothing and Some Numbers: The quest to find where Amelia Earhart may have landed in the Pacific Ocean has been investigated and speculated about since she and her navigator disappeared July 2, 1937. In fact, skeletal remains had been found on a remote island in the South Pacific in 1940 along with other artifacts–a woman’s shoe, an American sextant box, but the bones were identified as a man by a physician at the time. Unfortunately, these remains have subsequently been lost. Recently, an anthropologist decided to take the measurements made in 1940, and using a modern-day techniques including a program that estimates stature, sex and ancestry, and he found that the bone measurements were more consistent with Earhart than with 99% of the reference sample used. In addition, using a photograph of the American pilot that had scale generated bone lengths of her humerus and radius and measuring her clothing from a collection gave a number for her tibia. All these numbers strongly suggest the skeletal remains were Earhart’s. Read the press release.
Hate malaria? You can thank Tu Youyou for discovering artemisinin and dihydroartemisinin, compounds that are used to treat the tropical disease and save numerous lives. Her discovery was so significant, she received the 2015 Nobel Prize in Physiology or Medicine. Continue reading
There have been many changes in sequencing technology over the course of my scientific career. In one of the research labs I rotated in as a graduate student, I assisted a third-year grad student with a manual radioactive sequencing gel because, I was told, “every student should run at least one in their career”. My first job after graduate school was as a research assistant in a lab that sequenced bacterial genomes. While I was the one creating shotgun libraries for the DNA sequencing pipeline, the sequencing reaction was performed using dideoxynucleotides labeled with fluorescent dyes and amplified in thermal cyclers. The resulting fragments were separated by manual loading on tall slab polyacrylamide gels (Applied Biosystems ABI 377s) or, once the lab got them running, capillary electrophoresis of four 96-well plates at a time (ABI 3700s).
Sequencing throughput has only increased since I left the lab. This was accomplished by increasing well density in a plate and number of capillaries for use in capillary electrophoresis, but more importantly, with the advent of the short read, massively parallel next-generation sequencing method. The next-gen or NGS technique decreased the time needed to sequence because many sequences were determined at the same time, significantly accelerating sequencing capacity. Instruments have also decreased in size as well as the price per base pair, a measurement used when I was in the lab. The long-prophesized threshold of $1,000 per genome has arrived. And now, according to a recent tweet from a Nanopore conference, you can add a sequencing module to your mobile device:
Welcome to the future – DNA sequencing on your mobile phone – imagine where and how you can use it. Hats off to the @nanopore team for getting this to work at this form factor, voltage and watts. https://t.co/Tm6A5fj8M4
— Ewan Birney (@ewanbirney) November 30, 2017