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Applied Biotechnology, Biomed Bites, Genetics, History, Research, Videos

Basic research underlies effort to thwart “greatest threat to face humanity”

Welcome to this week’s Biomed Bites, a weekly feature that introduces readers to Stanford’s most innovative researchers. 

Stanley Cohen, MD, isn’t a household name. But it probably should be. The Stanford geneticist was instrumental in the discovery of DNA cloning – the technology that underlies innumerable advances in biotechnology and medicine, and led to the founding of biotech giant Genentech.

It wasn’t always thought possible to snip out a gene, stitch it into a new stretch of DNA – often in a different organism – and have it produce a desired protein.

In the video above, Cohen emphasizes that striving to achieve a concrete – and profitable – goal didn’t enable the discovery of gene cloning. First, researchers had to work to understand the basic biological processes. “In order to apply knowledge, it’s necessary to get that knowledge somehow.”

These days, Cohen isn’t resting on his laurels. Instead, he’s striving to thwart what he considers perhaps the “greatest threat to humanity,” drug-resistent microbes.

“My lab is still interested in understanding microbial drug resistance and the way in which microbes exploit host genes to carry out microbial functions such as entering cells, reproducing in cells and exiting from cells,” he said. Scientists need that basic knowledge to develop strategies to thwart the process, he added.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: The history of biotech in seven bite-sized chunks, The dawn of DNA cloning: Reflections on the 40th anniversary and Why basic research is the venture capital of the biomedical world

Aging, Genetics, Immunology, Infectious Disease, Research, Stanford News

In human defenses against disease, environment beats heredity, study of twins shows

In human defenses against disease, environment beats heredity, study of twins shows

Pfc. Lane Higson and Pfc. Casey Higson, identical twins serving in Iraq with the Enhanced Combat Aviation Brigade, 1st Infantry Division. The twins, natives of Myrtle Beach, S.C., joined the Army together and have not separated since.I’m one of those people who’ve paid to have their genomes analyzed for the purpose of getting a handle on susceptibility to this or that disease as time goes by. So it was with great interest that I came across a new study of twins conducted by immunologist Mark Davis, PhD, and fellow Stanford investigators. The study, published in CELL, shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body’s primary defense against disease. This is especially true as we age.

Improving gene-sequencing technologies have focused attention on the role of genes in diseases. But the finding that the environment is an even greater factor in shaping our immune response should give pause to anyone who thinks a whole-genome test is going to predict the course of their health status over a lifetime.

“The idea in some circles has been that if you sequence someone’s genome, you can tell what diseases they’re going to have 50 years later,” Davis told me when I interviewed him for a news release I wrote on the study. But, he noted, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation.

Davis, who heads Stanford’s Institute for Immunity, Transplantation and Infection, is worth taking seriously. He’s made a number of major contributions to the field of immunology over the last 30 years or so.  (Not long ago, I wrote an article about one of those exploits for Stanford Medicine.)

To find out whether the tremendous differences observed between different people’s immune systems reflec tunderlying genetic differences or something else, Davis and his colleagues compared members of twin pairs to one another. Identical twins inherit the same genome, while fraternal twin pairs are no more alike genetically than regular siblings, on average sharing 50 percent of their genes. (Little-known fun factoid: The percentage can vary from 0 to 100, in principle, depending on the roll of the chromosomal dice. But it typically hovers pretty close to 50 percent, just as rolling real dice gives you a preponderance of 6s, 7s, and 8s. Think of a Bell curve.)

Because both types of twins share the same in utero environment and, usually, pretty close to the same childhood environment as well, they make great subjects for contrasting hereditary versus environmental influence. (If members of identical-twin pairs are found to be no more alike than members of fraternal-twin pairs with respect to the presence of some trait, that trait is considered to lack any genetic influence.)

In all, the researchers recruited 78 identical-twin pairs and 27 pairs of fraternal twins and drew blood from both members of each twin pair. That blood was hustled over to Stanford’s Human Monitoring Center, which houses the latest immune-sleuthing technology under a single roof. There, the Stanford team applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system cell types, substances and activities.

Said Davis: “We found that in most cases – including your reaction to a standard influenza vaccine and other types of immune responsiveness – there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver.”

It makes sense. A healthy human immune system has to continually adapt to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more.

“The immune system has to think on its feet,” Davis said.

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Immunology escapes from the mouse trap

Genetics, Research, Science, Stanford News

Show-off! Protein upstages DNA by ordering amino-acid add-ons

Show-off! Protein upstages DNA by ordering amino-acid add-ons

Show-offEvery living cell is a metropolis in which the vast bulk of work is performed by phenomenally productive laborers called proteins. Proteins work so hard – and the work that must be done in a cell changes so rapidly – that turnover in the labor force is immense. To maintain the brisk pace of life inside a cell, new proteins must constantly be assembled.

The machines responsible for that assembly are called ribosomes – as many as 10 million of them within a single mammalian cell, each capable of stapling together up to 200 amino acids (the building blocks of proteins) per second. The resulting amino-acid strings immediately fold themselves into characteristic structures reflecting their precise composition.

There are about 20 different varieties of amino acids, so the number of possible combinations a ribosome can make, in theory, is mind-boggling. But a ribosome doesn’t just piece together whatever protein suits its passing fancy. It carefully heeds instructions stored on lengthy strands of DNA inside the cell’s nucleus, in a massive library known as the genome: a gigantic set of genes (the recipes for proteins), written in a ribosome-readable chemical code. But genes never leave the nucleus, and ribosomes never enter it.

Bridging that physical gap is a substance called messenger RNA, chemically similar to DNA but physically far more flexible and athletic. Like couriers carrying copies of a royal edict, messenger RNA molecules constantly exit the nucleus, where they were produced as portable copies of one gene or another. They head for the watery suburbs of the cell where protein construction takes place. And there, they find a ribosome, climb in, are fed through the ribosome’s molecular machinery, and get spit out like spent ticker tape once the ribosome has finished reading the recipe and assembling the specified protein product.

Under ordinary circumstances, ribosomes faithfully follow genetic instructions. But with all that whirling and whirring, sometimes things go wrong: The mRNA molecule or the ribosome is defective or, for some other reason, the protein-in-the-making is faulty.

Misspelled or misfolded proteins can wreak havoc. Happily, cells have “quality control” teams that can pick apart poorly produced proteins, tear up malfunctioning messenger RNA and retire rotten ribosomes.

In exploring that process, Stanford biochemist Onn Brandman, PhD, and colleagues at the University of California and University of Utah may have turned molecular-biological dogma on its head. In a new study in Science, Brandman and his associates report that they’ve identified a member of the quality-control squad, a protein called rqc2, that gloms onto stalled ribosomes – and then does something no protein has ever previously been shown to do: call out for the delivery of two particular amino acids, which get attached in random sequences to the aberrant protein under construction.

“Our results defy textbook science, showing for the first time that the building blocks of a protein, amino acids, can be assembled without the standard blueprints,” Brandman told me. “In the case we observed, neither DNA nor messenger RNA but a protein directs that a pair of amino acids be randomly added, in small stretches, to the ends of proteins that have stalled mid-synthesis. The function of these ‘tails’  isn’t known. But in yeast, elevated levels are correlated with proteotoxic stress, a condition that in humans may be involved in disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease.”

Previously: Key to naked mole rat longevity may be related to their body’s ability to make proteins accurately and Night of the living dead gene: Pseudogene wakes up, puts chill on inflammation
Photo by Iain Farrell

Biomed Bites, Genetics, Research, Videos

Gene regulation controls identity – and health

Gene regulation controls identity - and health

Welcome to the first Biomed Bites of 2015. We’ll be continuing this series this year — check each Thursday to meet more of Stanford’s most innovative biomedical researchers.

Push play and prepare to blow away many of your preconceptions about genetics. ‘Cause gene aren’t the thing these days. At least not for Michael Snyder, PhD. He leads Stanford’s genetics department and directs the Stanford Center for Genomics and Personalized Medicine. Here’s Snyder:

One of the things we’ve found is that our DNA has a lot more regulatory elements than people previously appreciated. In fact, there are more regulatory elements for genes than the genes themselves.

And that’s not all. What makes you you, is, in fact, your regulatory elements, not so much your genes, which really aren’t that different from those of a chimpanzee or that next-door neighbor you dislike.

Your health may also be governed by these regulatory elements, Snyder says:

This is going to be very, very powerful in a world where many people are getting their human genome sequences and trying to understand what diseases they might be at risk for or what diseases they have and what the underlying causes are.

This knowledge might lead to swifter diagnoses, or even prevent the disease from emerging at all.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Of mice and men: Stanford researchers compare mammals’ genomes to aid human clinical research, Personal molecular profiling detects diseases earlier and  You say “protein interactions,” I say “mosh pit”: New insights on the dynamics of gene expression

Genetics, In the News, NIH, Public Health, Research

The genomics revolution and the rise of the “molecular stethoscope”

The genomics revolution and the rise of the “molecular stethoscope”

ATCGBack in 2012, Stanford bioengineer Stephan Quake, PhD, and colleagues sequenced the genome of a fetus using only a maternal blood sample for the first time. Technology Review later recognized the work as one of the “10 Breakthrough Technologies 2013.”

In a recently published opinion piece (subscription required) in the Wall Street Journal, Quake and Eric Topol, MD, a professor of genomics at the Scripps Research Institute, discuss the method and how it exemplifies the potential of the genomics revolution to provide scientists and clinicians with a new type of stethoscope that allows one to see “inside the body at the molecular level.” They write:

The prenatal molecular stethoscope is the first truly widespread clinical application to result from the human-genome project. The National Institutes of Health has an opportunity to build on this new knowledge of “alien” DNA in healthy individuals, and determine whether it may change their clinical course—the molecular-stethoscope approach. Meanwhile, whole genome sequencing of the germ-line, or native, DNA from populations is under way, with seven ongoing world-wide projects, each sequencing the native DNA from 100,000 or more individuals. It’s projected that nearly two million people will be sequenced by 2017.

Already, the scientific literature is brimming with new applications of the molecular stethoscope. Two studies in the New England Journal of Medicine in December showed that more than 10% of healthy people over age 65 carried so-called somatic mutations in their blood cells, and that these individuals had more than a tenfold increased risk of subsequently developing a blood-based cancer.

Previously: Stanford-developed eye implant could work with smartphone to improve glaucoma treatmentsA simple blood test may unearth the earliest signs of heart transplant rejection and Step away from the DNA? Circulating *RNA* in blood gives dynamic information about pregnancy, health
Photo by Stefano

Autism, Genetics, Research, Stanford News

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Snyder smilingGeneticist Michael Snyder, PhD, has a thing for ‘omes.’ He’s studied genomes, transcriptomes, proteomes and microbiomes. Each term represents looking at something (DNA, RNA, proteins or microorganisms on a grand scale, throughout an entire organism). Most recently he’s been known for combining omics information to generate a dynamic picture of his own changing health over time (he termed the analysis a “integrative personal omics profile, or iPOP, but really, the siren call of “the Snyder-ome” is almost too great to resist).

Now he and postdoctoral scholar Jingjing Li, PhD, have turned their attention to the human “interactome,” a database that includes information about more than 69,000 protein interactions. They’ve used sophisticated algorithms to identify who in the brain is playing nicely with whom, and identified a particular group that seems to play an important role in the development of autism in a part of the brain called the corpus callosum. Importantly, the analysis points a finger at a new cell type in the brain — the oligodendrocytes. These serve as kind of a pit crew for the neurons, coating them in an insulating material to keep electrical signals between cells running smoothly. They’ve published their work today in Molecular Systems Biology.

As Snyder explained in our release:

This is our first glimpse of autism’s underlying biological framework, and it implicates a cell type and region of the brain that have not been extensively studied in this disease. Until now, we’ve suspected that autism could be the result of defects in the neurons themselves. Now it appears that the oligodendrocytes can contribute to the problem by inhibiting neuronal signaling through poor cellular differentiation and myelination.

Snyder, who also directs Stanford’s Center for Genomics and Personalized Medicine, and Li hope that the finding will allow researchers to broaden their net to the corpus callosum, which helps the two halves of the brain communicate with one another. As psychiatrist and study co-author, Joachim Hallmayer, MD, commented:

Autism is an extremely heterogeneous disease. Many genes have been implicated, but environment also plays a role. This study suggests a possible way to subdivide patients into smaller, more homogenous populations based on which genes are mutated. Some of these may be very easy to treat, based on their mechanism, while others may be much more difficult. For those in this category, it’s possible we could one day find a way to train or improve the connection between the brain’s hemispheres.

It will be fascinating to see where this research goes next. In the meantime, here’s hoping the New Year-ome treats you and yours well!

Previously: New imaging analysis reveals distinct features of the autistic brain, Omics’ profiling coming soon to a doctor’s office near you? and A conversation with autism activist and animal behavior expert Temple Grandin
Photo of Snyder by Steve Fisch

Cancer, Genetics, Stanford News, Videos, Women's Health

Stanford specialists discuss latest advancements in breast cancer screening and treatment

Stanford specialists discuss latest advancements in breast cancer screening and treatment

Invasive breast cancer will affect one in eight women in the United States during their lifetime. Many women, and men, may believe that if they don’t have a family history of breast cancer, then they’re not at risk of developing the disease. However, this is a common myth: About 90 percent of patients diagnosed with the disease have no family history of breast cancer.

But the good news is that breast cancer detected in the early stages can be very effectively treated. Additionally, breast-cancer death rates have been falling over the past 25 years as a result of increased awareness, improvements in treatments and earlier detection.

During a recent Stanford Health Library talk, captured in the above video, breast-cancer specialists discussed the latest advancements in genetic testing, diagnostic imaging, reconstructive surgery and treatments and adjunct therapies to surgery.

Previously: Don’t hide from breast cancer – facing it early is key, Despite genetic advances, detection still key in breast cancer and Ask Stanford Med: Radiologist responds to your questions about breast cancer screening

Genetics, Neuroscience, Research, Science, Stanford News

Yeast advance understanding of Parkinson’s disease, says Stanford study

Yeast advance understanding of Parkinson's disease, says Stanford study

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.

Previously: Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Chronic Disease, Genetics, Pediatrics, Stanford News

Stem cells implicated in Duchenne muscular dystrophy

Stem cells implicated in Duchenne muscular dystrophy

640px-Duchenne-muscular-dystrophyStanford 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.

Previously: Working on a gene therapy for muscular dystrophy, New mouse model of muscular dystrophy provides clues to cardiac  failure, and Mouse model of muscular dystrophy points finger at stem cells
Photo of muscle cells affected by Duchenne disease by Edwin P. Ewing

Genetics, NIH, Research, Videos

DNA origami: How our genomes fold

DNA origami: How our genomes fold

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 in Cell adds 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.

Previously: DNA architecture fascinates Stanford researcher – and dictates biological outcomes

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