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Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Genetics, Medicine and Society, Pain, Research, Science, Stanford News

From plant to pill: Bioengineers aim to produce opium-based medicines without using poppies

From plant to pill: Bioengineers aim to produce opium-based medicines without using poppies

Basic RGBStanford bioengineer Christina Smolke, PhD, and her team have been on a decade-long mission to replicate how nature produces opium in poppies by genetically engineering the DNA of yeast and then further refining the process to manufacture modern day opioid drugs such as morphine, codeine and the well-known painkiller Vicodin.

Smolke outlined the methods in a report  (subscription required) published in this week’s edition of Nature Chemical Biology, which details the latest stages in the process of manufacturing opium-based medicines, from start to finish, in fermentation vats, similar to the process for brewing beer.

An article published today in the Stanford Report offers more details:

It takes about 17 separate chemical steps to make the opioid compounds used in pills. Some of these steps occur naturally in poppies and the remaining via synthetic chemical processes in factories. Smolke’s team wanted all the steps to happen inside yeast cells within a single vat, including using yeast to carry out chemical processes that poppies never evolved to perform – such as refining opiates like thebaine into more valuable semi-synthetic opioids like oxycodone.

So Smolke programmed her bioengineered yeast to perform these final industrial steps as well. To do this she endowed the yeast with genes from a bacterium that feeds on dead poppy stalks. Since she wanted to produce several different opioids, her team hacked the yeast genome in slightly different ways to produce each of the slightly different opioid formulations, such as oxycodone or hydrocodone.

“We are now very close to replicating the entire opioid production process in a way that eliminates the need to grow poppies, allowing us to reliably manufacture essential medicines while mitigating the potential for diversion to illegal use,” Smolke added.

While it could take several more years to refine these last steps in the lab, bioengineering opioids would eventually lead to less dependence on legal poppy farming, which has numerous restrictions and international dependencies from other countries. It would also provide a reliable supply and secure process for manufacturing important pain killing drugs.

Previously: Blocking addiction risks of morphine without reducing its pain-killing effects, Do opium and opioids increase mortality risk? and Patients’ genetics may play a role in determining side effects of commonly prescribed painkillers 
Photo by Kate Thodey and Stephanie Galanie

Genetics, Humor, Medicine and Society, Science, Stanford News

Using epigenetics to explain how Captain America and the Incredible Hulk gained their superpowers

Using epigenetics to explain how Captain America and the Incredible Hulk gained their superpowers

When I was kid I used to watch the Incredible Hulk on TV and wait for Bruce Banner to fly into a rage, his muscles inflating like balloons, pants torn to shreds while his entire body turns green as he transforms into the Hulk. As I grew up, and learned more about the advances in genetics, it never occurred to me that cutting-edge genome-editing techniques could explain the scientific principles behind the Hulk’s metamorphosis or his fellow Marvel Comics star-spangled hero Captain America. In a recent Stanford Report story,  Sebastian Alvarado, a postdoctoral research fellow in biology, creatively applies the concepts of epigenetics to illuminate the process by which average Joes become superheroes.

As Alvarado notes in the piece and above video,  over the past  70 years scientists have developed tools for selectively activating and deactivating individual genes through chemical reactions, a process termed epigenetics. Similar to flipping on a light, switch gene expression can be “turned on” or “turned off. “We have a lot of genome-editing tools – like zinc finger nucleases, or CRISPR/Cas9 systems – that could theoretically allow you to epigenetically seek out and turn on genes that make your muscles physically large, make you strategically minded, incredibly fast, or increase your stamina,” he said.

In the case of Captain America, the process of deliberately switching on and off genes could offer a real-world explanation as to how scrawny Steve Rodgers gained extraordinary, strength, stamina and intelligence after being injected with “Super Solider Serum” and then blasted with  “Vita-Rays.” When it comes to Bruce Banner, a little more creative license is required. Alvarado’s theory is:

First, when gamma radiation hits DNA, it breaks the molecule’s double-stranded, ladder-like helix, a process known as chromothripsis. Your body can repair a few breaks without significant loss of function.

If many breaks occur – say, if you were caught in a giant gamma explosion – the repairs can become sloppy, and new instructions can be keyed into the genetic code. Alvarado suggested that it’s possible that when Banner’s DNA reassembled after the initial blast, it now included a handful of epigenetic switches. Instead of the switches being activated by light, however, the hormones produced when Banner is angry might flip the genetic switches to reconfigure his DNA to transform him into the big, green Hulk.

As for the Hulk’s skin turning green, anyone who has suffered a nasty bruise has firsthand knowledge of the process that might be behind this transformation. When you bruise, red blood cells at the point of injury die and the oxygen-carrying molecule on their surface, hemoglobin, begins to break up. One of hemoglobin’s metabolites, Alvarado said, is a molecule called biliverdin, which can make the blood appear green and is responsible for the avocado hue at the edge of a bruise.

Giant gamma explosion and epigenetics aside, there’s one question that has scientifically stumped Alvarado: How do the Hulk’s pants stay on after every transformation?

From August 11-25, Scope will be on a limited publishing schedule. During that time, you may also notice a delay in comment moderation. We’ll return to our regular schedule on August 25.

Cancer, Genetics, Research, Science, Stanford News

Unraveling the secrets of a common cancer-causing gene

Unraveling the secrets of a common cancer-causing gene

The Myc protein can cause a lot of trouble when it’s mutated or expressed incorrectly. Under those condition it’s called an oncogene, and it’s associated with the development of more than half of all human cancers. But because its cellular influence is vast (it controls the expression of thousands of genes and regulatory molecules), it’s been tough for scientists to learn which of its many effects are cancer-causing.

Now oncologist Dean Felsher, MD, PhD, and his colleagues have found that just a handful of genes are responsible for the Myc oncogene’s devastating outcomes. Their work was published today in Cancer Cell. As I wrote in our release:

The genes identified by the researchers produce proteins that govern whether a cell self-renews by dividing, enters a resting state called senescence or takes itself permanently out of commission through programmed cell suicide. Exquisite control of these processes is necessary to control or eliminate potentially dangerous tumor cells.

In particular, the researchers found that Myc works through a family of regulatory RNA molecules that govern how (and when) tightly packaged genes in the DNA/protein complex called chromatin are made available for transcription into proteins that do much of the work of the cell. Understanding this process might help researchers find ways to throw a molecular wrench into the Myc mechanism.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Felsher told me. “These experiments begin to reveal how Myc affects the self-renewal decisions of cells. They may also help us target those aspects of Myc overexpression that contribute to the cancer phenotype.”

The reliance of many cancer cells on oncogenes like Myc is called oncogene addiction. In many cases, blocking the expression of an oncogene, or tinkering with its activity, causes cancer cells to stop growing and tumors in animals to regress. Recently Felsher and his colleagues published an article in the Proceedings of the National Academy of Sciences describing how inactivating two oncogenes at once can work better to fight cancer in animal models by making it more difficult for the cancer cells to develop resistance to therapy.

Previously: Tool to identify the origin of certain types of cancer could be a “boon to doctors prescribing therapies” and  Smoking gun or hit-and-run? How oncogenes make good cells go bad

From August 11-25, Scope will be on a limited publishing schedule. During that time, you may also notice a delay in comment moderation. We’ll return to our regular schedule on August 25.

Evolution, Genetics, Obesity, Research, Science, Stanford News

Tiny fruit flies as powerful diabetes model

Tiny fruit flies as powerful diabetes model

Seung Kim

Fruit flies in your kitchen are unquestionably annoying. But the next time you’re trying to bat one out of the air around your too-ripe apples and bananas (or maybe that’s just me?), spare a few seconds to realize how important the tiny insects have been to science. They’ve been a darling of developmental biology for decades, as researchers identified genes (subsequently shown to be shared in mammals and humans) critically important in the metamorphosis from egg to animal. Frankly, it’s hard to over-estimate their contribution to science.

Now they’re set to take up a starring role in diabetes research. Stanford developmental biologist and Howard Hughes Medical Institute investigator Seung Kim, MD, PhD, and research associate Sangbin Park, PhD, have devised a way to measure insulin levels in fruit flies at the picomolar level – the level at which insulin concentrations are measured in humans. They’ve done so by successfully tagging the fruit fly insulin-like-peptide 2, or Ilp2, with a chemical tag. Their research was published today in PLOS Genetics.

From our release:

The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.

In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.

In 2002, Kim and developmental biologist Roel Nusse, PhD, surprised many researchers when they showed that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed. Further research has been stymied, however, by the difficulty of accurately measuring circulating insulin levels in the tiny animals. When speaking to me about the research, Kim called the new technique a “breakthrough” in the field.

Unlike many previous attempts by many groups, Park found two places in Ilp2 where the tag can be placed without affecting its biological activity. This allowed Kim and Park to track Ilp2 through its life cycle, as it’s produced by neurons in the brain (this is different from humans, who make insulin in beta cells in the pancreas), secreted into the blood stream and binds to insulin receptors in cells throughout the body. Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. More from our release:

Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don’t reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.

Continue Reading »

In the News, Public Health, Research, Science, Stanford News, Technology

NPR highlights Google’s Baseline Study and what it might teach us about human health

NPR highlights Google's Baseline Study and what it might teach us about human health

Late last month, my colleague reported on Stanford partnering with Google [x] and Duke on a research study to better understand the human body. On the most recent edition of NPR’s Science Friday, project collaborator Sanjiv Sam Gambhir, MD, PhD, professor of radiology at Stanford, discussed the project and joined Jason Moore, MD, professor of genetics at Dartmouth College, in a segment called “Will big data answer big questions on health?”

According to Gambhir, what makes the new project unique is the focus on understanding the baseline of healthy human beings. Will it ultimately yield meaningful data about what makes us healthy? Listen here for the researchers’ thoughts.

Previously: Stanford partnering with Google and Duke to better understand the human body

Research, Science, Stanford News

They said “Yes”: The attitude that defines Stanford Bio-X

They said "Yes": The attitude that defines Stanford Bio-X

bio-X peopleI write a lot about interdisciplinary research (it’s my job), but it was just recently that I heard the best description of what it is that makes interdisciplinary collaborations possible. It came from Carla Shatz, PhD, who directs Stanford Bio-X — an interdisciplinary institute founded in 1998 that brings together faculty from the schools of medicine, humanities & sciences and engineering. She told me:

You have to be able to walk into someone’s lab and say, “You know, I have this problem in my lab. Would you like to have a cup of coffee and talk about it?” And then that person needs to say, “Yes.”

We were talking about a recent report by the National Research Council of the National Academies. They had put together a workshop and then published a report giving advice and best practices for supporting interdisciplinary research. The report used Bio-X as a success story for the type of innovation that can come out of programs that cross disciplines.

Nowhere in the report is there a subhead reading, “Faculty have to say yes,” but a lot of the other advice is straight out of the Bio-X playbook. The institute needs to be located at the cross section of several schools or departments (check). The institute needs a building that brings people together (check). The institute needs to support students (check). The institute needs to be a financial value add rather than taxing participating departments (check).

This isn’t specifically called out in the report, but Shatz added that a good interdisciplinary institute also needs good food. She pointed out that people come from all over campus to eat at Nexus, located in the middle of the Clark Center that houses Bio-X and serves as a focus for its activities. It turns out scientists are just like the rest of us: offer good food and they will come. And then they will chat, and the next thing you know they’ll be collaborating.

I wrote a Q&A with Shatz based on our conversation. From now on, when I hear the phrase “She said yes” I’ll think of her, and her great description of the attitude that underlies collaboration.

Previously: Bio-X Kids Science Day inspires young scientists, Dinners spark neuroscience conversation, collaboration, Stanford’s Clark Center, home to Bio-X, turns 10 and Pioneers in science
Photo from Bio-X

Research, Science, Stanford News, Stem Cells

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cells, also called iPS cells, made from easily accessible skin or other adult cells, are ideal for disease modeling, drug discovery and, possibly, cell therapy. That’s because they can be generated in large numbers and grown indefinitely in the laboratory. They also reflect the genetic background of the person from whom they were generated. However, some fundamental questions still remain before they’re ready for the full glare of the clinical limelight. Does it matter what type of starting cells scientists use to create the pluripotent stem cells? And what’s the best control to use when studying the effect of a particular, patient-specific mutation?

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have addressed and answered these questions. Their work was published yesterday in two back-to-back papers in the Journal of the American College of Cardiology. (Each paper is also accompanied by an editorial.) As Wu explained in an e-mail to me:

If your goal is to generate healthy iPS cell derivatives for regenerative therapy, it’s important to know whether the starting material makes a difference. For example, if I’m treating Alzheimer’s disease, is there a benefit to using iPS cell-derived brain cells made from brain cells? Likewise, if I’m treating a skin disorder, is there a benefit to using iPS cell-derived skin cells made from skin cells? As cardiologists, we are asked this quite often and each time, I had to say “I don’t know.” So we decided to do a study comparing the differentiation and functional ability of iPS cell-derived cardiomyocytes generated from two different sources: skin and heart. We also wanted to devise more efficient ways for researchers to quickly and easily create their own “designer” iPS cell lines to study particular mutations.

To answer the first question, the researchers created iPS cells from two types of starter cells: human fetal skin cells and cardiac progenitor cells. Not surprisingly, only the cardiac progenitor cells expressed genes known to be expressed in heart tissue. Wu and his colleagues then exposed the newly created pluripotent stem cells to growing conditions that favor the development of heart muscle cells called cardiomyocytes. They found that, although iPS cells derived from cardiac progenitor cells were more efficient at becoming cardiomyocytes, both types of starting material produced heart muscle cells that functioned similarly after a period of growth in the laboratory. As Wu explained:

These two populations of cells are essentially no different from one another over time. It appears that they lost the memory of their starting material (this memory is stored in the form of chemical tags on the cells’ DNA in a phenomena known as epigenetic marking). This suggests that I could take my own skin cells, make iPS cells and then create specialized brain, heart, liver or kidney cells for cell therapy. This is much easier than biopsying each tissue, and could be a good way to create universal iPS cell lines for research or cell therapy.

In the second paper, Wu and his colleagues devised a way to introduce specific mutations into iPS cells before transforming them into particular tissues. The approach relies on the use of what’s known as “dominant negative” mutations that exert their disruptive effect even when the unmutated gene is still present. This is important because it’s much easier and quicker than previous similar efforts, which required a complicated, time-consuming procedure to snip out and then replace individual genes. The technique also allows researchers to generate two cell lines that are identical except for the mutation under study. That way researchers can be confident that differences between the cell lines are due only to that mutation, which is particularly important when the lines are used to test the effect of therapeutic drugs. Again, from Wu:

Investigators can make their own designer iPS cell lines to study particular mutations with genetically identical controls to use in their experiments. We won’t have to make new iPS cells from each patient, which is laborious and time consuming. Instead we can create standardized lines to study many different mutations alone and in combination. This has the potential to revolutionize the field of disease modeling and drug discovery.

The two papers describe ongoing research in the Wu lab designed to optimize iPS cells for a variety of applications. The group, including graduate student Arun Sharma, recently published research using human iPS cell-derived cardiomyocytes to investigate the effect of various antiviral drugs againse coxsackievirus, a leading cause of an infection of the middle layer of the heart wall in children and the elderly. The research is the first time that iPS cell-derived heart muscle has been used to investigate the mechanisms behind an acquired viral disease.

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells, “Clinical trail in a dish” may make common medicines safer, say Stanford scientists and Lab-made heart cells mimic common cardiac disease in Stanford study

Humor, Parenting, Science

A humorous look at how a background in science can help with parenting

A humorous look at how a background in science can help with parenting

Scientist-moms out there might enjoy this playful (tongue-in-cheek) Huffington Post essay on how having a science degree made the writer a better parent. I had to chuckle at Sarah Gilbert’s list of how she’s found uses for the sciences in her day-to-day life:

Physics: Knowing that my house will return to complete disorder immediately after I clean it, because entropy.

Biology: Knowing everything my baby ate by the contents of her diaper, because scat identification.

Neuro-psychology: Knowing that my toddler freaking out over sandwich crusts is just a phase, because frontal lobe development.

Statistics: Knowing that the chance of having a baby brother is 50/50 no matter what my mother-in-law thinks, because mutually exclusive events.

Astronomy: Knowing that the woman judging me by my yogurt-spattered shirt isn’t the only thing in the universe, because cosmology.

In the News, Science, Stanford News

Internships expose local high-schoolers to STEM careers and academic life

Internships expose local high-schoolers to STEM careers and academic life

beakersIt’s summertime: Do you know where your teenagers are? A piece in the Palo Alto Weekly discusses some of the choice science internships available to local high-school students at Stanford and other universities in the region. Shadowing scientists in the lab and even contributing to research, the young interns learn real-world applications for subjects they learn in school. They also gain work experience and exposure to academic careers in STEM fields. And a high-profile internship couldn’t hurt to include on college applications.

From the piece:

Coordinators often have to sift through hundreds of applications from students applying from all over the country and internationally. One of the most sought after is the Stanford Institutes of Medicine Summer Research Program, which alone received about 1,400 applications this year to fill about 70 to 75 openings. Decisions are based on academic grounds to help narrow down the number of prospective candidates — a tough task in a pool of extremely well-educated candidates.

But coordinators also recognize the need to provide opportunities for students who don’t have the chance to join accelerated science programs and express that oftentimes the most important quality of an applicant is a passion for science.

The article notes that internships gained through family and friend connections can be unevenly distributed, and  how programs like Stanford’s Raising Interest in Science and Engineering (RISE) Summer Internship Program have made the experiences more accessible. More from the piece:

“Typically those are kids with very educated parents who speak fluent English and who are comfortable poking around Stanford a little bit … or have a network and know somebody who works in a lab here. The RISE students typically just don’t have family members that can help them in that way,” [Kate Storm] says. “I think it’s important to serve all students, not just the privileged gifted students who are going to thrive and do well no matter what because they’ve got the backing of their school and parents and siblings.”

These types of opportunities are important to start curbing the racial disparities that exist in STEM occupations. Roughly 70 percent of the people in STEM occupations were Caucasian, 14 percent Asian, 6.5 percent Hispanic and 6.4 percent African American, according to an American Community Survey Report from the U.S. Census Bureau in 2011. Since 2008, Storm says about 80 percent of RISE graduates have gone on to major in math, engineering or science in college.

Researchers are also passionate about increasing the number of girls in labs since women are also largely underrepresented in STEM fields. The same 2011 U.S. Census Bureau report stated that roughly 25.8 percent of those in STEM occupations are women, compared to 45.7 percent of all jobs.

Previously: Residential learning program offers undergrads a new approach to scientific inquiry, The “transformative experience” of working in a Stanford stem-cell lab, Image of the Week: CIRM intern Brian Woo’s summer projectImage of the Week: CIRM intern Christina Bui’s summer project and Stanford’s RISE program gives high-schoolers a scientific boost
Photo by Amy

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