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Genetics, Research, Stanford News

Surprise discovery links cancer protein with developmental disorder

Surprise discovery links cancer protein with developmental disorder

Attardi

Scores of scientific discoveries — including dynamite, penicillin, and heaps of others — were accidents. Fiddling around in the lab and wa-zam, there’s a cure for syphilis.

The same sort of thing happened recently in the Stanford lab of Laura Attardi, PhD, professor of radiation oncology and genetics. Her team studies the protein p53, a key tumor suppressor. Normally, when switched on, p53 tells other proteins to kill ailing cells — a critical role to keep cancer in check.

To investigate its behavior in an organism, the researchers created a mouse with a mutated form of p53. This mutated protein had no off switch, but it also couldn’t communicate with its “minion” proteins that kill cells, so when a mouse had two copies of the mutated protein, it survived. A mouse with two normal copies of p53 also survived.

But surprisingly, when researchers created a mouse with one copy of the mutated p53, and one normal copy, it died before birth. What was going on?

To figure it out, Jeanine Van Nostrand, PhD, a former Stanford graduate student, now a researcher at The Salk Institute for Biological Studies, tried to figure out exactly why the mice were dying. They also had a unique set of problems — inner and outer ear deformities, heart abnormalities and a rare gap in the eye among others. After consulting with developmental experts, the researchers linked the mice deaths to CHARGE syndrome, a rare developmental disorder that causes eye, ear, nasal and genital problems, among other symptoms. “It was a very big surprise and very intriguing,” Van Nostrand comments in a release. “P53 had never before been shown to have a role in CHARGE.”

The researchers learned the mice with one normal p53, and one mutant p53, had hybrid p53 proteins, Frankenstein-like molecules that lacked an off switch, but retained the ability to trigger cell death.

These proteins led to the CHARGE symptoms. And thanks to the study, which appeared online yesterday in Nature, researchers can use the new clues about CHARGE to begin developing potential therapies, said Donna Martin, MD, PhD, associate professor of pediatrics and genetics at the University of Michigan Medical School, a CHARGE expert and co-author of the paper.

Becky Bach is a former park ranger who now spends her time writing, exploring, or practicing yoga. She’s currently a science writing intern in the medical school’s Office of Communication & Public Affairs.

Photo of Attardi by Steve Fisch

Genetics, Research, Stanford News

A molecular “flag” marks key genes

A molecular "flag" marks key genes

metronome - smallPoint to an important gene in a cell, any cell, from most any creature, and it’s likely to have a particular elongated molecular flag stuck onto the proteins wrapped around its DNA.

This isn’t just a pretty flag, plopped in for decoration. It’s thought to regulate how often this gene is transcribed, according to Anne Brunet, PhD, associate professor of genetics here. She’s the senior author of a study appearing in the July 31 issue of Cell.

Little is known about the importance of transcriptional consistency — how regularly a gene is transcribed, Brunet said. “I think the notion of transcriptional consistency is new, and it’s very important,” she commented in a release. “This is completely uncharted territory.”

It surely matters if a polymerase — that molecular workhorse that kicks off the protein-making process — spurts out dozens of copies, then chills for a bit, picking up only when it is good and ready.

This flag, abbreviated as H3K4me3, physically standardizes the transcription process, ensuring the polymerase pops off copies as if governed by a metronome — tic, tic, tic, tic, tic, tic…

The genes that are important enough to merit this transcriptional timekeeper — about 1,000 per cell, although it’s a different 1000 in each type of cell — can provide clues to the cell’s function, Brunet said. Her team plugged all the data into an online database, which other researchers can use to find the key genes in the cells of their choice.

The opportunities are endless and Brunet, for one, is psyched. Her lab focuses on the biology of aging, but this molecular flag holds all kinds of research promise.

And, as Brunet is keen to point out, it wouldn’t be possible without the megadata-crunching that’s possible at top research universities like Stanford. Other researchers had spotted this stretched-out H3K4me3, but no one had taken the time, or the computing power, to determine its extent and function, Brunet said.

“This is the new era of using available data to make really new hypotheses and new discoveries,” Brunet said.

Becky Bach is a former park ranger who now spends her time writing, exploring, or practicing yoga. She’s currently a science writing intern in the medical school’s Office of Communication & Public Affairs.

Photo by Niki Odolphie

Cancer, Genetics, Research, Stanford News

Stanford partnering with Google [x] and Duke to better understand the human body

Stanford partnering with Google [x] and Duke to better understand the human body

Most biomedical research is focused on disease and specific treatments for illness, rather than on understanding what it means to be healthy. Now researchers at Stanford, in collaboration with Duke University and Google [x], are planning a comprehensive initiative to understand the molecular markers that are key to health and the changes in those biomarkers that may lead to disease. The project was featured in a Wall Street Journal article today.

The study is at the very early stages, with researchers planning to enroll 175 healthy participants in a pilot trial later this year. The participants will undergo a physical exam and provide samples of blood, saliva and other body fluids that can be examined using new molecular testing tools, such as genome sequencing.  The pilot study will help the researchers design and conduct a much larger trial in the future.

“We continue as a global community to think about health primarily only after becoming ill,” Sanjiv Sam Gambhir, MD, PhD, professor and chair of radiology, told me. “To understand health and illness effectively, we have to have a better understanding of what ‘normal’ or ‘healthy’ really means at the biochemical level.”

“The study being planned will allow us to better understand the variation of many biomarkers in the normal population and what parameters are predictive of illness and may eventually change as a given individual transitions from a healthy to a diseased state. This will be a critical study that will likely help the field of health care for decades to come,” said Gambhir, who also directs the Canary Center at Stanford for Cancer Early Detection.

The researchers hope the work will provide insights on a variety of medical conditions, such as cancer and heart disease, and point to new methods for early detection of illness. Their studies will focus on the genetic basis of disease, as well as the complex interplay between genes and environment.

These kinds of studies haven’t been done before because of the cost and complexity of molecular measurement tools, the scientists say. However, the cost of some technologies, such as DNA sequencing, has been steadily declining, while some new tools and new ways of analyzing large quantities of data have just recently become available. So a first step in the study is to determine how best to use these technologies and determine what questions need to explored on a larger scale.

The work is sponsored by Google [x] and will be led by Andrew Conrad, PhD, a cell biologist and project manager at the company.

Genetics, In the News, Pediatrics, Research

New Yorker story highlights NGLY1 research

New Yorker story highlights NGLY1 research

PackardGirl260x190The new issue of the New Yorker, out today, includes a fascinating medical story with a notable Stanford connection. As we’ve described before, a team of scientists from institutions around the world reported earlier this year on their discovery of a new genetic disease, NGLY1 deficiency. Stanford’s Gregory Enns, MB, ChB, was co-lead author of the paper describing the new finding, and one of his patients, Grace Wilsey, was among the small group of children in whom the disease first was identified. Grace’s inability to make tears when she cries was a key clue in unlocking the mystery of the disease.

But, as the New Yorker piece (subscription required) explains in detail, there’s much more to the story than that. In particular, it tells how the families of patients – especially Grace’s parents, Matt and Kristen Wilsey, and Matt and Cristina Might, who are the parents of index patient Bertrand Might – successfully encouraged researchers at different institutions to collaborate with each other in a way that advanced the discovery with exceptional speed. This was counter to the usual practice in science, the story explains. Typically, scientists avoid sharing data with competitors, even if doing so would advance the research:

If a team hunting for a new disease were to find a second case with the help of researchers from a competing lab, it could claim to have “solved” a new disease. But it would also have to share credit with competitors who may have done nothing more than grant access to existing data. When I asked [Duke University geneticist and NGLY1 deficiency co-discoverer Vandana] Shashi if she could imagine a scenario that would result in one research team’s publishing a paper with data from a different research group working on a similar project, she said, “Not that I can think of.”

David Goldstein [another Duke geneticist who collaborated with Shashi] added, “It’s not an overstatement to say that there are inherent conflicts of interest at work.” Daniel MacArthur, a genetics researcher at Massachusetts General Hospital, is even more blunt. “It’s an enormous deal,” he told me. “And it’s a big criticism of all of us, but it’s a criticism we all need to hear. The current academic publication system does patients an enormous disservice.”

Fortunately for patients like Grace and Bertrand, and for the doctors who want to help them, the culture is shifting. One marker of the shift is the NIH’s announcement earlier this month that it will be expanding its Undiagnosed Diseases Program to a network of seven sites across the country (including Stanford) and building in a requirement that all seven centers share data with each other.

Another is that researchers are realizing that families like the Wilseys and Mights will continue to make an impact. In fact, the Wilsey family has recently launched the Grace Wilsey Foundation to raise awareness about NGLY1 deficiency and promote investigation of possible treatments for the disease.

As Shashi puts it at the conclusion of the New Yorker story:

“Gone are the days when we could just say, ‘We’re a cloistered community of researchers, and we alone know how to do this.’”

Previously: NIH network designed to diagnose, develop possible treatments for rare, unidentified diseases and Crying without tears unlocks the mystery of a new genetic disease
Photo of Grace Wilsey courtesy of Lucile Packard Children’s Hospital Stanford

Ethics, Genetics, Medicine and Society, Parenting, Pediatrics, Stanford News

Genome testing for children: What parents should consider

Genome testing for children: What parents should consider

Genome testing: Would you do it?

Okay, next question: Would you have your child’s whole genome tested?

In the recent issue of Stanford Medicine News, Louanne Hudgins, MD, chief of medical genetics and director of perinatal genetics at Lucile Packard Children’s Hospital Stanford, weighs in on the issue: “I strongly advise parents against whole-genome testing for their children unless performed in the context of a medical evaluation following formal counseling regarding its utility, limitations and possible unrelated findings,” she said.

In the piece, Hudgins comments on privacy and ethics considerations, and explains why what we partially know (for instance, if your child is found to have a gene predisposing him or her to a disease) can sometimes provide more cause for worry or false hope than helpful or conclusive information.

The whole piece (a short one) is worth a read.

Previously: Stanford patient on having her genome sequenced: “This is the right thing to do for our family”, Personal molecular profiling detects diseases earlier, Stanford geneticist discusses genomics and medicine in TEDMED talk and Medical practice, patents, and “custom children”: A look at the future of reproductive medicine

Cardiovascular Medicine, Genetics, Research, Stanford News

Stanford patient on having her genome sequenced: “This is the right thing to do for our family”

Stanford patient on having her genome sequenced: "This is the right thing to do for our family"

genomicsImagine you were diagnosed, seemingly out of the blue, with hypertrophic cardiomyopathy, a condition that is caused by mutations in genes involved in the heart’s muscle cells and is the most common cause of sudden death in young people. If given the chance, would you have your entire genome analyzed to understand more about your genetics and the condition? That’s the decision Julie Prillinger faced and, in the end, she embraced the opportunity to untangle the mystery of her DNA. “This is the right thing to do for our family – and our friends and family have been very supportive,” she said in a Stanford Medicine News story.

As described in the piece, Prillinger’s genome was among the first to be sequenced through a pilot program of the new Clinical Genomics Service at Stanford Hospital & Clinics. The pilot phase of the service is limited to specific patient groups, including: children with mystery diseases, patients with unexplained hereditary cancer risk, patients with inherited cardiovascular or neurological disease and those with severe, unexplained drug reactions. More details about the service from the article:

Stanford’s service will apply a highly integrated approach that includes professional genetic counseling, the most advanced genome sequencing technology available, and expert interpretation by molecular genetic pathologists and other physicians with expertise in this emerging and complex field.

The new service will be tied closely to other diagnostic genetic testing programs currently offered at the two hospitals. Those programs, which include molecular genetic pathology, cytogenetics and clinical biochemical genetics, have an outstanding record of compliance with the extensive regulatory requirements for diagnostic genetic testing.

In addition to providing Prillinger and her family with crucial information about their personal health, the results could reveal undiscovered information related to the condition encoded in the human genome, which may enable the expansion of current tests.

Previously: Using genetic testing to enhance students’ knowledge of personalized medicine, Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine and Direct-to-consumer genetic testing: A commentary

Cancer, FDA, Genetics, Research, Science, Stanford News

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

Cardiovascular Medicine, Genetics, Patient Care, Pediatrics, Research, Stanford News

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

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It’s an ‘edge-of-your-seat’ story: The newborn’s heart had stopped multiple times in the hours since her birth. Her doctors at Lucile Packard Children’s Hospital Stanford had tried everything to help her, but her situation was dire.

The baby had an unusually severe form of an inherited cardiac condition called long QT syndrome. The syndrome, which is most often diagnosed in older children or adults, can be caused by a mutation in any of several genes; until the doctors knew exactly which genetic mutation was causing the condition they wouldn’t know what drug would be most likely to help. The stakes were high: by her second day of life she’d received an implantable defibrillator and several intravenous drug infusions.

As cardiologist Euan Ashley, MD, PhD, explained to me:

The team literally tried everything we could think of to help this child, including trying every drug that could possibly make a difference. It was a heroic effort by a very diverse group of professionals.

The clinicians and researchers, including pediatric cardiologist Scott Ceresnak, MD, who managed the baby’s clinical care, realized it was critically important to identify the baby’s disease-causing mutation to learn which drug would be best for her. To do so, they dropped everything else they were doing and sequenced her entire genome to pinpoint the culprit within just ten days – an unprecedented feat. Ashley, who directs Stanford’s new Clinical Genomics Service as well as its  Center for Inherited Cardiovascular Disease, and pediatric cardiology fellow James Priest, MD, recently published the case study in the journal Heart Rhythm.

This is the future of genetic testing and we hope, the future of medicine.

Using customized commercial software and tools developed at Stanford, the researchers were able to zero in on a mutation in a gene called KCNH2 known to be associated with long QT. They also found another, novel mutation in a gene involved in determining the structure of the heart during development.

As Priest explained in an e-mail to me:

Whether it is a CT scan, x-ray, or genetic test, we work hard to make a diagnosis as quickly as possible when there is a critically-ill baby under our care. Whole genome sequencing returned this diagnosis in days instead of weeks. We were able to turn the raw sequence data into a diagnosis in about 12 hours.

Continue Reading »

Cardiovascular Medicine, Genetics, In the News, Research, Science, Stanford News

A simple blood test may unearth the earliest signs of heart transplant rejection

A simple blood test may unearth the earliest signs of heart transplant rejection

2123984831_b7d09079a4_oIs there an organ more precious than a donated heart? Heart transplant recipients would likely say no. But, in order to keep their new heart healthy, they have to identify any signs of rejection as early as possible. Unfortunately (and ironically), the gold standard procedure to detect rejection – repeated heart biopsies – involves snipping away and analyzing tiny bits of tissue from the very organ they waited so long to receive. The procedure is also uncomfortable, and can cause complications.

Now, Stanford bioengineer Stephen Quake, PhD, and his colleagues have found that a simple blood test that detects donor DNA in the bloodstream of the recipient can detect signs of rejection far earlier than biopsy. Their results were published today in Science Translational Medicine.

From our release:

The study of 65 patients (21 children and 44 adults) extends and confirms the results of a small pilot study completed in 2011 by the Stanford researchers. Whereas the earlier study used stored blood samples and medical histories from seven people, the new study followed patients in real time before and after transplant. The researchers directly compared the results of simultaneously collected biopsies and blood samples, and tracked how the values changed during the rejection process.

The blood test takes advantage of the fact that dying heart cells release genetic material into the recipient’s blood. Any increase beyond a normal baseline level indicates a possible attack by the immune system on the donated organ. As described in our release:

In the pilot study of 2011, the researchers first used the presence of the Y chromosome to track the donor DNA when a woman received a heart from a male donor. Then they hit upon using differences in SNPs instead; this method doesn’t require a gender mismatch between donor and recipient. They found that, in transplant recipients not experiencing rejection, the donor DNA accounted for less than 1 percent of all cell-free DNA in the recipient’s blood. During rejection episodes, however, the percentage of donor DNA increased to about 3 or 4 percent.

In the new study, the researchers monitored 565 samples from the 65 patients to assess the assay under real-time clinical conditions. They found they were able to accurately detect the two main types of rejection (antibody-mediated rejection and acute cellular rejection) in 24 patients who suffered moderate to severe rejection episodes, one of whom required a second transplant. They were also able to detect signs of rejection up to five months before the biopsies indicated anything troubling.

The test will still need to be optimized for regular clinical use. However, cardiologist Kiran Khush, MD, a co-senior author of the study, explained what the advance could mean to heart transplant recipients:

This test has the potential to revolutionize the care of our patients… It may also allow us to conduct several diagnostic tests simultaneously. For example, we could also look for microbial sequences in the blood sample to rule out infection or other complications sometimes experienced by transplant recipients. It could allow us to determine whether shortness of breath experienced by a patient is due to an infection or the start of a rejection episode. It could be a one-stop shop for multiple potential problems.

Full disclosure: Stanford has applied for a patent relating to the test described in this study. Quake is a consultant for and holds equity in CareDX Inc., a molecular diagnostics company that has licensed a patent from Stanford related to a method used in the study and is developing it for clinical use.

Previously: ‘Genome transplant’ concept helps Stanford scientists predict organ rejection, Stanford study in transplant patients could lead to better treatment and New techniques to diagnose disease in a fetus
Photo by Desi

Evolution, Genetics, Global Health, Public Health, Research, Stanford News

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

6626429111_df791cbb8d_zMexico is a vast country with a storied past. Indigenous Native American groups across the country maintain their own languages and culture, while its cosmopolitan residents of large cities are as globally connected as anywhere on Earth. But Mexicans and Mexican Americans are usually lumped together as “Latinos” for the purposes of genetic or medical studies.

Now an international collaboration headed by Stanford geneticist Carlos Bustamante, PhD, and the University of California, San Francisco pulmonologist and public-health expert Esteban Burchard, MD, MPH, has assessed the breadth and depth of genomic diversity in Mexico for the first time. Their work was published today in Science. As I explain in our release:

The researchers compared variation in more than 1 million single nucleotide polymorphisms, or SNPs, among 511 people representing 20 indigenous populations from all over Mexico. They compared these findings with SNP variation among 500 people of mixed Mexican, European and African descent (a category called mestizos) from 10 Mexican states, a region of Guadalajara and Los Angeles, as well as with SNP variation among individuals from 16 European populations and the Yoruba people of West Africa.

The researchers found that Mexico’s indigenous populations diverge genetically along a diagonal northwest-to-southeast axis, with differences becoming more pronounced as the ethnic groups become more geographically distant from one another. In particular, the Seri people along the northern mainland coast of the Gulf of California and a Mayan people known as the Lacandon found near the country’s southern border with Guatemala are as genetically different from one another as Europeans are from Chinese.

Surprisingly, this pattern of diversity is mirrored in the genomes of Mexican individuals with mixed heritage (usually a combination of European, Native American and African):

Consistent with the history of the Spanish occupation and colonization of Mexico, the researchers found that the European portion of the mixed-individuals’ genomes broadly corresponded to that of modern-day inhabitants of the Iberian Peninsula. The Native American portion of their genomes, however, was more likely to correspond to that of local indigenous people. A person in the Mexican state of Sonora, for example, was likely to have ancestors from indigenous groups in the northern part of the country, whereas someone from Yucatan was more likely to have a southern native component in their genome, namely Mayan.

“We were really fascinated by these results because we had expected that 500 years of population movements, immigration and mixing would have swamped the signal of pre-Columbian population structure,” said Bustamante

Finally, the researchers found that the origin of the Native America portion of an individual’s genome affected a clinical measure of lung function abbreviated FEV1:

The researchers drew on data that calculated the predicted normal FEV1 for each subject based on age, gender, height and ethnicity (in this case, the reference was a standard used for all people of Mexican descent). To understand implications of these results within Mexico, they modeled the predicted lung function across Mexico, accounting for differences in local Native American ancestry for a large cohort of mestizos from eight states. The model predicts a marked difference across the country, with the average predicted FEV1 for a person from the northern state of Sonora and another from the state of Yucatan differing by about 7.3 percent. (That is, the population from Sonora has predicted values that were slightly higher than the average for the country, and those from the Yucatan were slightly lower.)

“There’s a definite predicted difference that’s due only to an individual’s Native American ancestry,” said Gignoux. “Variations in genetic composition clearly give a different physiological response.”

The researchers emphasize that a lower FEV1 does not necessarily mean a particular ethnic group has impaired lung function. Disease analysis takes place in the context of standardized values of matched populations, and the study points out how it is necessary to match people correctly to their ethnic backgrounds before making clinical decisions.

Stanford’s Andres Moreno Estrada, MD, PhD, and Christopher Gignoux, PhD, share first authorship of the study with Juan Carlos Fernandez Lopez, a researcher at Mexico’s National Institute of Genomic Medicine.

Previously: Roots of disease may vary with ancestry, according to Stanford geneticist, Recent shared ancestry between southern Europe and North Africa identified by Stanford researchers, and Caribbean genetic diversity explored by Stanford/University of Miami researchers
Photo by DL

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