Alzheimer’s protein pathology
While a wise Dane once proposed that predictions are dangerous, especially concerningÂ the future, it’s usuallyÂ helpful to plan ahead. Here are five biomedical research topicsÂ we think will occupy our attention in 2015.
1. Alzheimer’s Weâ€™re hearing discordant music coming from Alzheimerâ€™s researchers. Large pharmaceutical companies are shutting down clinical trials in frustration, but researchers keep coming forward with biomarkers that mightÂ predict future disease. This confusing situation calls for some new thinking. Allan Levey, Jim Lah and colleagues have been preparing the way for a â€œbeyond the usual suspectsâ€ look at Alzheimerâ€™s disease. We are looking forward to Leveyâ€™s appearance at the 2015 AAAS meeting and to drug discovery wizard Keqiang Yeâ€™s continuing work on new therapeutic targets.
2. Ebola While the scare over Ebola in the United States may be over (we hope so!), the outbreak continues to devastate countriesÂ in West Africa. Clinical trials testingÂ vaccines and experimental drugs are underway or will be soon. Read more
One of Lab Landâ€™s regular features is a post exploring a biomedical term that seems to be appearing frequently in connection with Emory research. This month Iâ€™d like to focus on frailty, which has been an important concept in treating elderly patients for some time. (This pieceÂ in The Atlantic nudged me into it.) Assessing frailty is emerging as a way for surgeons to predict post-operative complications.
Several teams of researchers have been trying to develop a standardized way of measuring frailty to aid in weighing the risks and benefits of surgery. Frailty may seem like a subjective quality (echoing Supreme Court Justice Potter Stewartâ€™s remarks on obscenity: â€œI know it when I see itâ€) but if frailty can be defined objectively, doctors and patients can use it to help in decision-making.
Frailty can be thought of as a decrease in physiological reserve or a decrease in the ability to recover from an infection or injury. Much of the credit for developing the concept of frailty should go to Linda Fried, now dean of Columbiaâ€™s school of public health. While at Johns Hopkins, her team developed the Hopkins Frailty Score: a composite based on recent weight loss, self-reported exhaustion, low daily activity levels, low grip strength and slow gait. Read more
Loud applause for the members of SWAE. The student group Science Writers at Emory, previouslyÂ dormant, has relaunched the publication â€œIn Scriptoâ€. We look forward to seeing more from SWAE.
The newÂ Halloween-themed issue of In Scripto is published in â€œISSUUâ€, but Iâ€™ve broken it down into a table of contents by author, graduate program and article: Read more
PeopleÂ interested in drug discoveryÂ may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. TheyÂ basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelinesÂ have been the topic of much debate among medicinal chemists and pharmacologists.
The namesakeÂ forÂ this set of rules, Chris Lipinski, will be speakingÂ at Winship Cancer Institute Wednesday afternoonÂ (4:30 pm, Nov 5, C5012) onÂ “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there,Â he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.
DNA bricks keep getting larger. In 2012, a team of researchers at Harvard described their ability to make self-assembling structures –made completely out of DNA — that were about the size of viruses (80 nanometers across).
Yonggang Ke, PhD
Now theyâ€™re scaling up, making bricks that are 1000 times larger and getting close to a size that could be barely visible to the naked eye.
The advances were reported in Nature Chemistry.
Who: a team of researchers at the Wyss Institute at Harvard led by Peng Yin, and including Yonggang Ke, PhD, now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.
At Emory, Ke and his team are continuing to design 3D DNA machines, withÂ potential functionsÂ such as fluorescent nanoantennae, drug delivery vehicles and synthetic membrane channels.
How: The DNA brick method uses short, synthetic strands of DNA that work like interlocking LegoÂ® bricks to build complex structures. Structures are first designed using a computer model of a molecular cube, which becomes a master canvas. Each brick is added or removed independently from the 3D master canvas to arrive at the desired shape. TheÂ DNA strands that would match up to achieve the desired structure are mixed together and self assemble — with the help of magnesium salts — to achieve the designed crystal structures.
“Therein lies the key distinguishing feature of our design strategyâ€“its modularity,” Ke says. “The ability to simply add or remove pieces from the master canvas makes it easy to create virtually any design.”
What for: AsÂ part of this study the team demonstrated the ability to position gold nanoparticles less than two nanometers apart from each other along the crystal structure â€” a critical feature for future quantum computational devices and a significant technical advance for their scalable production.
Biomedical engineer Yonggang Ke‘s “DNA origami” artwork appears on the cover of Nature Methods, as part of a celebration of the journal’s 10th anniversary. Ke designed self-assembling DNA strands that would form a cylinder and a ring structure, let them assemble, and obtained images with transmission electron microscopy. The height of the final image is 120 nanometers, smaller than the wavelengths of visible light and about the size of an influenza or HIV virion.
You may have been hearing about the advent of Big Data: truckloads of information coming from cell phones, satellites, microscopes, and perhapsÂ someday, wearable health monitoring devices.
At Emory, specialists in biomedical informatics have been in the forefront of efforts to design software that will allow scientists to learn from these mountains of data. Fusheng Wang was recently named as co-PI on a five-year $5 million National Science Foundation grant to create MIDAS (Middleware for Data-Intensive Analytics and Science), part of the NSF’sÂ Data Infrastructure Building Blocks program. For this grant, the team consists of seven institutions: Indiana University (lead — Geoffrey Fox), Arizona State, Emory, Kansas, Rutgers, Utah and Virginia Tech.
Wang also recently received a NSF Career award in this same area.
The MIDAS project addresses major data challenges in seven different communities: biomolecular simulations, network and computational social science, epidemiology,Â computer vision, spatial geographical information systems, remote sensing for polar science, and pathology informatics.Â Wang is responsible for pathology informatics and geospatial, gathering requirements from those communitiesÂ and implementing the spatial query and parts of the image analysis library. The libraries are supposed to beÂ interoperable across a range of computing systems including clouds, clusters and supercomputers. The project includes a plan to develop a open online course (MOOC), according to the NSF.
Cardiac cell therapy sounds like a promising idea: use the patientsâ€™ own cells to enhance healing or even regenerate the damaged heart muscle. Doctors have taken up the promise, testing it in clinical trials involving thousands of patients. But a basic problem facing the field is this: naked cells donâ€™t appear to stay in the heart orÂ stay alive for long enough to provide a sustained benefit.
Three labs at Emory have published papers in the last year addressing this problem. All describe some kind of supportive biomaterials, consisting of capsules or a gel, which help cells stay put and stay alive, in experiments where recovery from a heart attack is modeled in rodents.
The most recent comes from cardiologist Young-sup Yoon and colleagues, in ACS Nano. The first author is Kiwon Ban, a senior postdoc in Yoonâ€™s laboratory. Ban and his team use self-assembling peptides, developed in collaboration with biomaterials engineer Ho-wook Jun at UABÂ (see figure). The peptides form a gel that both physicallyÂ keeps cardiac muscle cells in the heart and eases their integration into the heart tissue over a period of weeks. As Katie Bourzac explains in Chemical & Engineering News:
One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells.
We thought it may be useful to readers to be able to compare and contrast these papers in chart form.Â Read more
Itâ€™s a fundamental rule governing how the genetic code works. Ribosomes, the factories that assemble proteins in all types of living cells, read three letters (or nucleotides) of messenger RNA at a time.
In some instances, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read. Biologists call this normallyÂ rare event ribosomal frameshifting. For an ordinary gene, the event of a frameshift turns the rest of the ensuing protein into nonsense. However,Â many virusesÂ exploit frameshifting, because they can then have overlapping genes and fit more information into a limitedÂ space.
Regulated frameshifting takes place in human genes too, and understanding frameshiftingÂ is key to recent efforts to expand the genetic code. Researchers are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.
â€œGoing back to the 1960s, when the genetic code was first revealed, there were many studies on ribosomal frameshifting, yet no-one really knows how it works on a molecular and mechanistic level,â€ says Christine Dunham, PhD, assistant professor of biochemistry at Emory University School of Medicine. â€œWhat we do know is that the â€˜yardstickâ€™ model that appears in a lot of textbooks, saying that the anticodon loop dictates the number of nucleotides decoded, while elegant, is probably incorrect.â€
Dunham, who first studied the topic as a postdoc, and her colleagues published a paper this week in PNAS where they outline a model for how ribosomal frameshifting occurs, based on structural studies of the ribosome interacting with some of its helper machinery. Co-first authors of the paper are postdoctoral fellows Tatsuya Maehigashi, PhD and Jack Dunkle, PhD.
Resistance to an entire class of antibiotics â€“ aminoglycosides — has the potential to spread to many types of bacteria, according to new biochemistry research.
A mobile gene called NpmA was discovered inÂ E. coliÂ bacteria isolated from a Japanese patient several years ago. Global spread of NpmA and related antibiotic resistance enzymes could disable an entire class of tools doctors use to fight serious or life-threatening infections.
Using X-ray crystallography, researchers at Emory made an atomic-scale snapshot of how the enzyme encoded by NpmA interacts with part of the ribosome, protein factories essential for all cells to function. NpmA imparts a tiny chemical change that makes the ribosome, and the bacteria, resistant to the drugsâ€™ effects.
The results, published in PNAS, provide clues to the threat NpmA poses, but also reveal potential targets to develop drugs that could overcome resistance from this group of enzymes.
First author of the paper is postdoctoral fellow Jack Dunkle, PhD. Co-senior authors are assistant professor of biochemistry Christine Dunham, PhD and associate professor of biochemistry Graeme Conn, PhD. Read more