It’s amazing to me that the tiny, one-celled yeast can be such a powerful research tool. Now geneticist Aaron Gitler, PhD, has shown that the diminutive organism can even help advance the understanding of Parkinson’s disease and aid in identifying new genes involved in the disorder and new pathways and potential drug targets. He published his findings today in Neuron and told me in an email:
Parkinson’s disease is associated with many genetic and environmental susceptibility factors. Two of the newest Parkinson’s disease genes, EIF4G1 and VPS35, encode proteins involved in protein translation (the act of making protein from RNA messages) and protein sorting (shuttling proteins to the correct locations inside the cell), respectively. We used unbiased yeast genetic screens to unexpectedly discover a strong genetic interaction between these two genes, suggesting that the proteins they encode work together.
The proteins, EIF4G1 and VPS35, have changed very little from yeast to humans. Gitler and his colleagues showed that VPS35 interacts functionally with another protein implicated in Parkinson’s disease, alpha-synuclein, in yeast, round worms and even laboratory mice. As Gitler described:
Together, our findings connect three seemingly distinct Parkinson’s disease genes and provide a path forward for understanding how these genes might contribute to the disease and for identifying therapeutic interventions. More generally, our approach underscores the power of simple model systems for interrogating even complex human diseases.
Stanford researchers published a paper today in Science Translational Medicine describing how stem cells are involved in the development of Duchenne muscular dystrophy, a disease that results in progressive, often severe muscle weakness. It affects about one in every 3,600 boys born in the U.S.
The research team determined that the stem cells surrounding muscle tissue gradually became less able to create new muscle cells and instead begin to express genes that lead to connective tissue formation. Excess connective tissue accumulation, which is called fibrosis, occurs in many diseases. Thomas Rando, MD, PhD, a Stanford neurologist and one of the authors of the paper said in a release about the new study:
These cells are losing their ability to produce muscle, and are beginning to look more like fibroblasts, which secrete connective tissue. It’s possible that if we could prevent this transition in the muscle stem cells, we could slow or ameliorate the fibrosis seen in muscular dystrophy in humans.
The researchers also found that a drug already approved to treat high blood pressure in humans called losartin can slow these changes in stem cells in laboratory mice, although much more work is needed to find out if it could be helpful in children with Duchenne.
The researchers are focusing on how to get the drug to target only muscle cells, but they’re also interested in how they can apply their findings to other diseases. Rando, who directs the Glenn Center for the Biology of Aging at Stanford, also commented:
Fibrosis seems to occur in a vicious cycle. As the muscle stem cells become less able to regenerate new muscle, the tissue is less able to repair itself after damage. This leads to fibrosis, which then further impairs muscle formation. Understanding the biological basis of fibrosis could have a profound effect on many other diseases.
Here’s an interesting factoid about our genomes: If you stretched out the DNA in a single cell, which is only a few millionths of an inch wide, it would span more than six feet. And another: DNA folding is a dynamic process that changes over time. Scientists have been trying to understand how DNA folds itself up so efficiently, and a recent post on the NIH Director’s Blog highlights new research illustrating how the human genome folds inside the cell’s nucleus, as well as how DNA folding affects gene regulation. The research team created this delightful video that demonstrates the principles involved using origami art.
Researchers have been working to determine how cells regulate gene expression for nearly as long as we’ve known about DNA. How, for example, do nerve cells know to turn off only nerve cell genes and turn off bone cell genes? DNA folding loops are part of the answer. This research team, which published their findings in a paper in Cell yesterday, found that the number of loops is much lower than expected. There are only 10,000 loops instead of the predicted millions, and they form on/off switches in DNA. As explained in the blog post:
[The] paper inCelladds fascinating details to that map, and it confirms that DNA loops appear to play a crucial role in gene regulation. The researchers found that many stretches of DNA with the potential to fold into loops have genes located at one end and, at the other end, novel genetic switches. When a loop forms, placing a hidden switch in contact with a once-distant gene, the gene is turned on or off. In fact, the mapping work uncovered thousands of these “secret” switches within the genome—information that may provide valuable new clues for understanding cancer and many other complex, common diseases.
If I were to go back to school for a PhD, I think I’d study telomeres. Telomeres, the protective caps at the end of each chromosome, shrink with aging and other stressors leaving an organism vulnerable to a various disorders and cancer.
During the event, she gave the packed auditorium a whirlwind overview of telomere biology. Blackburn explained to attendees that telomere length is affected by both genes and the environment, and that some folks just start out with longer ones. Telomeres are maintained by an enzyme called telomerase. Slashing the amount of telomerase can cause early, immune dysfunction, cancer and diabetes. Some genetic telomere troubles manifest as disorders such as aplastic anemia or pulmonary fibrosis.
In general, telomere length correlates with what Blackburn called a “health span,” or duration of time someone stays healthy.
Recently she and colleagues measured telomere length in 100,000 people of all ages, a project they needed to develop a special robot to complete. They found that length of telomeres decreases into age 75. Then, it curves up to 95, accounting for the longevity of individuals with long telomeres. And yes, older women tend to have longer telomeres than older men.
Here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to scientists in a variety of biomedical disciplines.
Viruses, by their very definition, are dependent. They can’t dive into a body and wreak havoc by themselves — they need a little help, and that help often comes from our own genes. But which genes do viruses use to reproduce and thrive? Which genes are the enablers?
Stanford microbiologist Jan Carette, PhD, is patiently trying to figure that out — using the process of elimination. Here’s Carette in the video above:
In our lab, we have developed a new technique where we take away each of the individual genes and then measure very precisely which of the genes are important for the virus… If we know which are the targets of the human genes, we can start creating a whole new class of antiviral reagents that target the human genes and not so much the virus genes as is commonly done…
This technique might lead to treatments for viruses such as influenza A, Ebola or yellow fever. Said Carette: “The research that we’re doing can have a direct effect on human health… We can impact the lives of many people that are affected by viral disease.”
Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.
Looking for the perfect holiday gift for the science geek in your life? Have an extra $3 million sitting around? If so, you can bid on James Watson’s Nobel Medal, which will be auctioned off by Christie’s on December 4 and is expected to fetch between $2.5 and $3.5 million. Watson, now 86, won the Nobel Prize in Physiology or Medicine in 1962 for deciphering the structure of DNA, along with Francis Crick and Maurice Wilkins. An article in Reuters noted the significance of the medal’s auction and the 1953 finding for which it was awarded:
“It is recognition of probably the most significant scientific breakthrough of the 20th century and the impact of it is only being played out now in the 21st century,” said Francis Wahlgren, international head of books and manuscripts at Christie’s. “Whole industries have developed around it.”
Countless subsequent scientific discoveries in the last half century have their foundation in Watson and Crick’s work. Last year, Francis Crick’s Nobel medal garnered $2.27 million. Watson’s handwritten notes for his acceptance speech will also be auctioned the same day. He plans to donate part of the proceeds from the sales to charities and to scientific research.
Here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of biomedical disciplines.
The most common form of muscular dystrophy, Duchenne muscular dystrophy, is genetic, resulting from a defective gene on the X chromosome, so it affects primarily boys. That makes it a prime target for genetic therapy – currently the goal of Stanford geneticist Michele Calos, PhD.
Calos started out as a basic scientist, examining the nature of DNA and the controls of genes; they developed techniques used to insert new genes into existing cells and ensure they are turned on.
Now, Calos has found applications for her earlier research. Capitalizing on the work that won the 2012 Nobel Prize in Medicine, Calos and her team have set their sights on developing healthy muscle cells that can restore function for muscular dystrophy patients. Here’s Carlos in the video above:
We’re repairing the mutation in the patients’ cells… then putting back the correct copy of the gene, differentiating them into muscle precursors and injecting them into muscles where they can form healthy muscle fibers.
Calos said she and her team are currently perfecting the technique in mice, before it can be used in human patients. “Our dream really is to develop a therapy in the lab that would be translatable to clinical use in the future,” she said.
Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.
Scientists have long considered the laboratory mouse one of the best stand-ins for researching human disease because of the animals’ genetic similarity to humans. Now Stanford researchers, as part of a consortium of more than 30 institutions, have confirmed the mouse’s utility in clinical research by showing that the basic principles controlling genes are similar between the two species. However, they also found some important differences.
“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “We are interested in what makes a mouse a mouse and a human a human.”
The research effort, Mouse ENCODE, complements a project called the Encyclopedia of DNA Elements, or ENCODE, both funded by the National Human Genome Research Institute. ENCODE studied specific components in the human genome that guide genes to code for proteins that carry out a cell’s function, a process known as gene expression. Surrounding the protein-coding genes are noncoding regulatory elements, molecules that regulate gene expression by attaching proteins, called transcription factors, to specific regions of DNA.
The Mouse ENCODE consortium annotated the regulatory elements of the mouse genome to make comparisons between the two species. Because many clinical studies and drug discovery use mice as model organisms, understanding the similarities and differences in gene regulation can help researchers understand whether their mouse study applies to humans.
Scientists from Stanford and elsewhere have been hunting for a genetic explanation for extreme longevity for the past four years and are realizing that it is a more difficult proposition than they initially hoped.
Their research compared the genomes of 17 “supercentenarians” – those who have lived 110 years and beyond – with those of 4,300 “regular” people recorded earlier in a National Institutes of Health study. The study was geared toward finding a single gene or group of genes responsible for a particular trait – in this case longevity – similar to genes which have been found to cause disease or confer immunity. But they have had no luck. Stuart Kim, PhD, a Stanford geneticist and molecular biologist and founder of the Kim Lab for the study of aging, commented in a San Francisco Chroniclepiece:
We were looking for a really simple explanation in a single gene, and we know now that it’s a lot more complicated, and it will take a lot more experiments and a lot more data from the genes of more supercentenarians to find out just what might account for their ages.
However, data about the oldest people in the world still suggests that the reason they can live so long has to do with their genes, and not with lifestyle choices. The supercentenarians have average rates of cancer, heart disease, and stroke, although they have escaped many age-related diseases, and their smoking, alcohol, exercise and diet appear no different than among ordinary people. Furthermore, as noted in the article, the parents, siblings and children of the centenarians have also lived well beyond average.
A human has only about 25,000 genes. So, it’s tough to imagine just how our immune systems can manage to recognize potentially billions of differently shaped microbial or tumor-cell body parts. But that’s precisely what our immune systems have to do, and with exquisite precision, in order to stomp invading pathogens and wanna-be cancer cells and leave the rest of our bodies the heck alone.
How do they do it?
Stanford immunologist Mark Davis, PhD, tore the cover off of immunology in the early 1980s by solving that riddle. As I wrote in “The Swashbuckler,” an article in the latest issue of Stanford Medicine, T cells are one of two closely related, closely coordinated workhorse-warrior cell types that deserve much of the credit for the vertebrate immune system’s knack of carefully picking bad guys of various stripes out of the lineup and attacking them:
[Q]uite similar in many respects, B cells and T cells are more like fraternal than identical twins. B cells are specialized to find strange cells and strange substances circulating in the blood and lymph. T cells are geared toward inspecting our own cells for signs of harboring a virus or becoming cancerous. So it’s not surprising that the two cell types differ fundamentally in the ways they recognize their respective targets. B cells’ antibodies recognize the three-dimensional surfaces of molecules. T cells recognize one-dimensional sequences of protein snippets, called peptides, on cell surfaces. All proteins in use in a cell eventually get broken down into peptides, which are transported to the cell surface and displayed in molecular jewel cases that evolution has optimized for efficient inspection by patrolling T cells. Somehow, our inventory of B cells generates antibodies capable of recognizing and binding to a seemingly infinite number of differently shaped biological objects. Likewise, our bodies’ T-cell populations can recognize and respond to a vast range of different peptide sequences.
In the late 1970s, scientists (including then-graduate student Davis, who is now director of Stanford’s Institute for Immunity, Transplantation and Infection) unraveled the genetic quirks behind B cells’ ability to recognize a mind-blowingly diverse set of different pathogens’ and tumor-cells’ characteristic molecular shapes. As a follow-on, Davis and a handful of colleagues – working with what would today be considered the most primitive of molecular-biology tools – isolated the gene underlying the T-cell receptor: an idiosyncratic and very important surface protein that is overwhelmingly responsible for T cells’ recognition of myriad pathogen- and cancer-cell-specific peptide sequences. And they figured out how it works.
The result? (Again from my article:)
With the T-cell receptor gene in hand, scientists can now routinely sort, scrutinize, categorize and utilize T cells to learn about the immune system and work toward improving human health. Without it, they’d be in the position of a person trying to recognize words by the shapes of their constituent letters instead of by phonetics.