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Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Applied Biotechnology, Bioengineering, Cancer, Genetics, Research, Stanford News

Minuscule DNA ring tricks tumors into revealing their presence

Minuscule DNA ring tricks tumors into revealing their presence

cool minicirclesAn animal study just published in Proceedings of the National Academy of Sciences shows how, in the not-distant future, doctors may be able to not only detect tumors early in humans, but also monitor the effectiveness of cancer drugs in real time, guide clinical trials of new drugs, and even screen entire populations of symptom-free people for nascent tumors that could have otherwise slipped under the radar.

The potential is huge. And the principal investigator, Sam Gambhir, MD, PhD, is credible: He chairs Stanford’s radiology department, directs the Canary Center at Stanford for Cancer Early Detection and has authored or co-authored nearly 600 peer-reviewed research publications.

From my news release about the study:

Imagine: You pop a pill into your mouth and swallow it. It dissolves, releasing tiny particles that are absorbed and cause only cancerous cells to secrete a specific protein into your bloodstream. Two days from now, a finger-prick blood sample will expose whether you’ve got cancer and even give a rough idea of its extent. That’s a highly futuristic concept. But its realization may be only years, not decades, away.

The key to early cancer detection lies in finding valid biomarkers: substances whose presence in a person’s blood or urine flags a probable tumor. (High blood levels of the molecule known as PSA, for example, can signify prostate cancer.) But although various tumor types indeed secrete characteristic substances into the blood, these same substances typically are made in healthy tissues, too, albeit usually in smaller amounts. So a positive test result for, say, PSA doesn’t necessarily mean the person has cancer. Contrariwise, a small tumor just may not secrete enough of the trademark substance to be detectable.

Gambhir’s team appears to have found a way to force any of numerous tumor types to produce a biomarker whose presence in the blood unambiguously signifies cancer, because no adult tissues – cancerous or otherwise – would normally be making it. This particular substance is a protein naturally present in human embryos as they’re forming and developing, but absent in adults.

The scientists designed a genetic construct, called a DNA minicircle, that contains a single gene coding for the telltale substance. DNA minicircles are tiny, artificial, single-stranded DNA rings about 4,000 nucleotides in circumference – roughly one-millionth as long as the strand that you’d get if you stretched the DNA in all 23 chromosomes of the human genome end to end.

Gambhir and his colleagues rigged their minicircles so that this sole gene would be “turned on” only inside cancer cells. (For more details on how to do this, please see my release.) They injected the minicircles into mice who had small tumors and mice who didn’t. Within 48 hours, a simple blood test indicated the presence of the biomarker in the blood of mice with tumors, but not in the blood of the tumor-free mice.The bigger the tumor volume, the more of the biomarker in the blood.

The technique will likely apply to a broad range of cancers, and can possibly be modified to help pinpoint budding tumors’ location in the body.

Previously: Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later, Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal and Nanomedicine moves one step closer to reality
Photo by Jim Strommer

Aging, Cancer, Emergency Medicine, Medical Education, Pregnancy, Stanford News

Stanford Medicine magazine reports on time’s intersection with health

Stanford Medicine magazine reports on time's intersection with health

Why is it that giant tortoises typically live for 100 years but humans in the United States are lucky to make it past 80? And why does the life of an African killifish zip past in a matter of months?

I’ve often mused about the variability of life spans and I figure pretty much everyone else has too. But while editing the new issue of Stanford Medicine magazine’s special report on time and health, “Life time: The long and short of it,” I learned that serious scientists believe the limits are not set in stone.

“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics Anne Brunet, PhD, in “The Time of Your Life,” an article on the science of life spans. My first thought was, wow! Then I wondered if some day humans could live like the “immortal jellyfish,” which reverts back to its polyp state, matures and reverts again, ad infinitum. Now that would be interesting.

Also covered in the issue:

  • “Hacking the Biological Clock”: An article on attempts to co-opt the body’s timekeepers to treat cancer, ease jetlag and reverse learning disabilities.
  • “Time Lines”: A Q&A with bestselling author and physician Abraham Verghese, MD, on the timeless rituals of medicine. (The digital edition includes audio of an interview with Verghese.)
  • “Tick Tock”: A blow-by-blow account of the air-ambulance rescue of an injured toddler.
  • “Before I Go”: An essay about the nature of time from a young neurosurgeon who is now living with an advanced form of lung cancer. (The neurosurgeon, Paul Kalanithi, MD, is featured in the video above, and our digital edition also includes audio of an interview with him.)

The issue also includes a story about the danger-fraught birth of an unusual set of triplets and an excerpt from the new biography of Nobel Prize-winning Stanford biochemist Paul Berg, PhD, describing the sticky situation he found himself in graduate school.

Previously Stanford Medicine magazine traverses the immune system, Stanford Medicine magazine opens up the world of surgery and Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions.

Cancer, Imaging, In the News, Research, Technology

Stanford instructor called out for his innovative – and beautiful – imaging work

Stanford instructor called out for his innovative - and beautiful - imaging work

breast cancer cells

I’ll skip the name word play – it’s just too obvious – but I won’t skip Michael Angelo’s work. Angelo, MD, a pathology instructor at Stanford, developed a new imaging technique that labels antibodies with metallic elements, then uses an ion beam to scan the tissue, revealing up to 100 proteins at once in a single cancer cell.

This technique, called multiplexed ion beam imaging, or MIBI, captured the attention of the National Institutes of Health, which featured Angelo in its NIH Director’s Blog this week. The images are lovely to look at, but also quite useful to learn more about tissue types.

Here’s Angelo describing the image above:

Angelo used MIBI to analyze a human breast tumor sample for nine proteins simultaneously—each protein stained with an antibody tagged with a metal reporter. Six of the nine proteins are illustrated here. The subpopulation of cells that are positive for three proteins often used to guide breast cancer treatment (estrogen receptor a, progesterone receptor, Ki-67) have yellow nuclei, while aqua marks the nuclei of another group of cells that’s positive for only two of the proteins (estrogen receptor a, progesterone receptor). In the membrane and cytoplasmic regions of the cell, red indicates actin, blue indicates vimentin, which is a protein associated with highly aggressive tumors, and the green is E-cadherin, which is expressed at lower levels in rapidly growing tumors than in less aggressive ones.

Taken together, such “multi-dimensional” information on the types and amounts of proteins in a patient’s tumor sample may give oncologists a clearer idea of how quickly that tumor is growing and which types of treatments may work best for that particular patient.  It also shows dramatically how much heterogeneity is present in a group of breast cancer cells that would have appeared identical by less sophisticated methods.

Angelo was given a NIH Director’s Early Independence Award last fall, and he’s ramping up his investigations of breast cancer.

Cancer, Patient Care

Bone marrow transplantation: The ultimate exercise in matchmaking

Bone marrow transplantation: The ultimate exercise in matchmaking

candy heart - smallStanford Blood Center is home to one of the top human leukocyte antigen (HLA) histocompatibility laboratories in the country. While the center is best known for supplying blood products to hospitals, SBC’s HLA lab supports the success of hundreds of bone marrow transplants administered at Stanford Health Care by providing and developing tests to determine donor and recipient organ compatibility.

What Is Bone Marrow?

Bone marrow is in the center of the bone and contains hematopoietic stem cells (HSC). These cells are immature cells that can grow into red blood cells, white blood cells or platelets, which serve the following purposes in the body:

  • Red blood cells carry oxygen throughout the body
  • White blood cells help fight infections
  • Platelets help control bleeding

When bone marrow is damaged or destroyed, it can no longer make normal blood cells and a stem cell transplant (bone marrow transplant) is required.

Bone Marrow Transplantation

A bone marrow transplant is the process of replacing unhealthy HSC with healthy ones in order to restart hematopoiesis, the process of generating red blood cells, white blood cells, and platelets.

Patients requiring a bone marrow transplant are often being treated for one of the following:

Patients requiring a bone marrow transplant are often being treated for one of the following:

  • Blood cancers like leukemia
  • Diseases which result in bone marrow failure like aplastic anemia
  • Other immune system diseases

In some cases, the patient will receive an autologous transplant where the stem cells come from the patient’s own blood or bone marrow, which would need to have been drawn and stored prior to the patient becoming ill.

When a patient receives stem cells from another person, it’s called an allogeneic transplant. When conducting an allogeneic transplant, it’s of the utmost importance that the donor and patient’s immune systems are closely matched; otherwise the patient will either reject the healthy donor HSC or the donor cells can attack the patient. The latter scenario is called graft-versus-host disease, and can be fatal in some cases.

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Cancer, Research, Stanford News

The medical benefits of a little chemistry know-how

The medical benefits of a little chemistry know-how

molecules and beakers

I’ve been writing about medical science for close to 20 years now, and in that time I shudder to think how often I’ve written stories about basic science discoveries that could result in potential future drugs.

I wasn’t exaggerating in those stories. The scientists I had the pleasure of working with really were hopeful about the potential of treating patients. But developing a drug is a long and arduous process and not all discoveries lend themselves to drugs.

As I wrote in a story today:

The chemical in the pill we swallow has to survive the burbling acidic soup of our stomachs and the digestive enzymes capable of reducing steak and potatoes into tiny particles. Once in our bloodstream, a potential drug has to endure the liver’s attempts to detoxify it, and then reach the cell in question and – the hardest part – actually work.

Overcoming those obstacles and turning that discovery into a drug requires medicinal chemistry know-how as well as a detailed knowledge of the drug development and approval process, which aren’t skills in the toolbox of most biologists.

In today’s story, which describes a discovery in pancreatic cancer cells by gastroenterologist Anson Lowe, MD, that could result in a new drug for several different types of cancers, I also got to write about a new medicinal chemistry program started by Stanford ChEM-H.

ChEM-H is a relatively new interdisciplinary institute with a focus on bringing chemistry expertise to issues in human health. With their new medicinal chemistry program, the institute is hoping they can help people like Lowe fulfill the promise that I’ve written about in so many stories – that of turning a discovery into a drug that helps people.

Previously: Stanford ChEM-H bridges chemistry, engineering and medicine, Listening in on the Ras pathway identifies new target for cancer therapy, and New clues arise in pancreatic cancer from Stanford researchers
Photo from Shutterstock

Cancer, Chronic Disease, Clinical Trials, Science Policy

A look at crowdfunding clinical trials

A look at crowdfunding clinical trials

1024px-Assorted_United_States_coins I’ve been able to watch the crowdfunding phenomenon up close: My husband is a Kickstarter addict, and he, like millions of others, funds projects that speak to his passions and social priorities. In recent years, some non-profits have applied the crowdfunding model to clinical trials (something he hasn’t funded yet), and others may follow suit as federal-funding dollars dries up. Last week, Nature Medicine published an article that describes the first few years of those efforts and the questions they bring up.

As outlined in the piece, critics argue that the system unfairly penalizes those that may not have a large online social network to use to publicize their funding efforts, while proponents say it makes it possible for donors to connect more directly with the research and it increases transparency of research funding. As one source explains:

“One key thing is tangibility,” says Catherine Ferguson, Innovation Project Lead at Cancer Research UK, “It’s an inherent part of crowdfunding that isn’t inherent in regular funding.” Whether it’s a particular type of cancer or a particular therapy, crowdfunding allows for a “more direct relationship with both the researcher and the research,” she adds, emphasizing that this directed approach is good for maintaining relationships with donors.

Cancer Research UK, which we’ve written about before, was one of the early advocates of clinical trial crowdfunding. It recently concluded it first effort to crowdfund a clinical trial to study a vaccine for Epstein-Barr virus in cancer patients. The group fell far short of their goal, raising only six percent of the £40,000 ($61,000) goal on their Indiegogo campaign, so it returned the funds to donors. Again, from the article:

The organization chose a so-called fixed-funding model, in which they chose a goal amount but kept none of the funds that were raised if the goal wasn’t met. “It felt disingenuous to keep some of the money but not make the research happen,” said Ferguson. “We really wanted to emphasize that the money was for a specific project and if the project couldn’t be fully funded, then why keep the money?” Because the campaign wasn’t successful, the funds raised were returned to those who pledged the money, but Ferguson said that many of the donors reached out to make contributions to the organizations anyway.

Other organizations are using slightly different models, and the coming months, or maybe years, will reveal whether any are able to successfully fund clinical trials through this new avenue.

Previously: New crowdfunding sites apply Kickstarter model to health and medicineCan crowdfunding boost public support and financing for scientific research? and Crowdsourcing the identification of cancer cells
Photo by Elembis

Cancer, Stanford News

For this doctor couple, the Super Bowl was about way more than football

For this doctor couple, the Super Bowl was about way more than football

Paul and Lucy at Super Bowl - smallEarlier this month, football fans across the world watched as the New England Patriots shocked the Seattle Seahawks with a very dramatic last-minute win. While the game itself was a thrill, equally as exciting for two people in the seats at University of Phoenix Stadium was what had gotten them there. Neurosurgeon Paul Kalanithi, MD, and his wife, Lucy, had won a trip to the big game by raising money for lung-cancer research and winning the Lung Cancer Survivors Super Bowl Challenge, sponsored by the Chris Draft Family Foundation.

Kalanithi had attended Stanford as an undergrad in the 90s, the same time as did Draft, a former professional football player who later started his foundation and whose wife, Keasha, died of lung cancer in late 2011. Kalanithi received a diagnosis of lung cancer in 2013 and re-connected with Draft not long after.

“The foundation is putting a new face on the disease,” Lucy Kalanithi, MD, a clinical instructor in general medical disciplines at Stanford, told me during a recent conversation. Team Draft, an initiative of the foundation, puts the spotlight on, and brings together, young lung-cancer patients such as Paul Kalanithi, with the aim of getting out the message that anyone can get lung cancer. It’s also working to stop the smoking stigma from negatively impacting research funding for lung cancer.

Paul at Super Bowl - small“Even though Paul and I are both physicians, prior to his diagnosis, neither of us was fully aware of the global toll of lung cancer and the major gap in federal and private funding due to the anti-smoking stigma,” Lucy Kalanithi said. “More people die from lung cancer than from breast, colon and prostate cancers combined: It’s the top cancer killer.”

I asked if her husband had ever experienced the sense of judgment or blame that can come with a lung-cancer diagnosis. “Paul’s never had the experience – common among lung-cancer patients – of being asked, ‘Did you smoke?’ Kalanithi said, noting that her husband was never a smoker. “But everyone with lung cancer is affected by the anti-smoking stigma, because it means that much, much less money goes to lung cancer research compared with other cancers. And survival rates for all cancers are directly related to research funding. When people think of breast cancer, they think of a sympathetic character like a young mom. But when people think of lung cancer, they don’t think of a vibrant young dad like Paul.”

Through the foundation, the Kalanithis connected with other young families affected by lung cancer (“There’s a lot of camaraderie and optimism,” Kalanithi told me), and when they learned of the Super Bowl Challenge, a friendly fundraising competition among lung-cancer survivors, they jumped at the chance to compete. There was an “overwhelming response from Paul’s friends, family and colleagues – including many from Stanford,” Kalanithi said, which led to a call from Draft on New Year’s Day. They had won the challenge, Draft told the couple, and they would be attending not only the Super Bowl but also Taste of the NFL, a fundraiser attended by former NFL players and renowned chefs from around the country, and an exclusive pre-game stadium tour. As icing on the cake: Their (too-cute-for-words) seven-month-old daughter, Cady, would be making the trip with them.

Kalanithis at Super Bowl - smallWhen I asked Kalanithi for a sampling of the moments etched in her mind from the weekend, she offered two: lying on the Super Bowl field and getting a photo taken with her husband and baby daughter forty-eight hours before the game (“It was surreal”) and watching Paul, a huge football fan, “jump up and down” in their incredible seats on the Seahawks’ 50-yard line. (For the record, they were rooting for the Seahawks. And next year, “we hope to see [Stanford alum] Andrew Luck out there.”)

Despite the excitement of this once-in-a-lifetime experience, the Kalanithis’ relationship with Team Draft seemingly extends far beyond the football field. Kalanithi has noted that the foundation has “helped boost our family’s spirits during this challenging time,” and she sounds eager to partner with Draft on other initiatives. “Helping raise awareness and research funds impacts families everywhere, and it gives me hope,” she said.

Previously: Tackling the stigma of lung cancer – and showing the real faces of the disease, A neurosurgeon’s journey from doctor to cancer patient“Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness and A Stanford physician’s take on cancer prognoses – including his own
Photos courtesy of Lucy Kalanithi

Cancer, Research, Stanford News

The Big Bang model of human colon cancer

The Big Bang model of human colon cancer

big bangLike the Big Bang model of the formation of the universe, the Big Bang model of human colon cancer deduces tumor conditions in the past based on current data. Instead of cosmic radiation, the cancer model uses genomic data from a mature tumor to infer how it grew, starting from when it was composed of a small number of mutated cells.

Christina Curtis, PhD, a recent addition to Stanford’s School of Medicine, and her collaborators at the University of Southern California developed the model, which was published online this week in Nature Genetics.

Testing the Big Bang model confirmed that most detectable differences in tumors come from early disordered growth patterns of cells.

As I wrote in a story about the Big Bang model:

Using an array of genomic techniques, Curtis and her team profiled colorectal tumors at multiple spatial scales, ranging from single cells to tumor glands consisting of fewer than 10,000 cells, as well as “bulk” tumor fragments that were taken from opposite sides of a full-grown tumor. These methods provided a panoramic and high-resolution view of how cells within a tumor were different and how tumors from the same patient differed from one another. From the genomic data, the researchers reconstructed a tumor growth history. A tumor growth history can be thought of like a slide-show at a graduation party, which starts off with baby pictures and ends with images of the young adult. The Big Bang model describes how a tumor evolves from a few thousand cells to a full-grown tumor composed of billions of cells.

Carcinomas had disordered growth histories — identifiable even when the tumors were just a few thousand cells — and benign adenomas had ordered growth histories. Curtis told me that these findings suggest that some tumors are “born to be bad” and the malignant potential of a tumor is determined early. She added that disordered growth patterns identified in emerging tumors could potentially serve as a biomarker, enabling early detection of cancerous growths.

Kimberlee D’Ardenne is a writing intern in the medical school’s Office of Communication and Public Affairs.

Previously: Stanford researchers explore new ways of identifying colon cancer, Bacterial balance in gut tied to colon cancer risk, Study shows evidence-based card eliminates racial disparity in colon-cancer survival rates and Researchers explore colonoscopy’s effect on the incidence of colorectal cancer
Image by Atilla Szűcs

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