A skeptical look at popular diets: The lowdown on low carb

In the seventh post in the series A Skeptical Look at Popular Diets, physician Randall Stafford examines down the pros and cons of a low-carb diet.

By Randall Stafford

As the name implies, this diet reduces dietary carbohydrates, including many common foods that contain sugars and/or starches. To make up for this reduction, the intake of protein and fat can increase. Frequently, however, low-carb dieters do not fully replace the calories from reducing carbs and they lose weight as a result.

This diet has several favorable features, but a high intake of animal-based saturated fats can offset the benefits. One version, the Atkins Diet, was promoted to facilitate weight loss. A problem with interpreting “low carbohydrate” is that there is no consensus on how low is “low.”

Health rationale slogan: Restricting carbs helps you lose weight and solves many metabolic problems.

Analysis: Depending on how low carb you go, a lower carb diet potentially restricts multiple common foods including grains, legumes, fruits, breads, desserts, pastas, and starchy vegetables. Particularly off-limits: processed foods made with flour and added sugars. Food sources higher in protein and fat take their place, such as meats, eggs and nuts.

The diet’s potential benefits are many, including helping reverse insulin resistance, an early stage in the development of type 2 diabetes. It does this by restoring normal carbohydrate processing. By restricting carb intake, the body no longer has to cope with a large, sudden influx of sugar into the bloodstream. In addition, people following this diet may experience less hunger when they restrict calories, which facilitates weight loss (at least in the short term).

Stanford nutrition scientist Christopher Gardner, PhD, studied longer term weight loss and demonstrated similar favorable benefits from a lower carb vs. a lower fat diet when both approaches focused on healthy choices.

The food sources that are low carb range widely in healthfulness. For example, meat has no carbohydrates, but if meat intake is increased to replace carbohydrates, this can boost unfavorable saturated fats. Interestingly, in Gardner’s weight loss study, the group that followed a healthy low-carb diet had no adverse metabolic effects. This group decreased overall calories almost solely by restricting carbohydrate-rich foods, without substantially increasing protein or saturated fat intake.

If the carbohydrate restriction goes beyond added sugars and refined grains, to the point of restricting vegetables, whole grains and beans/legumes, this can result in vitamin and mineral deficiencies. And, if carb intake is low enough, ketosis can occur with its accompanying nausea, headache, physical and mental effects, and bad breath. Additionally, carbohydrate-rich foods are the primary sources of fiber, and low-fiber diets increase the risk of colon cancer and may have adverse effects on the gut microbiome.

Easy to follow?: Depending on how severe the carbohydrate restriction, this diet can be difficult to follow because it can dramatically restrict the intake of most of the major food groups, including fruits, beans/legumes, grains, starchy vegetables, and dairy.

Dominant source of protein: Animal proteins such as meat and eggs, which don’t contain carbs (unlike protein-rich legumes and grains).

Most common fats: Oils and saturated fats from meat.

What about carbs?: Limited carbs, but some variations of this diet can include potentially good carbs found in fibrous vegetables and beans/legumes.

When it goes wrong: Emphasizing meat consumption can lead to problems. High intake of the saturated fats found in meat may increase the risk of future heart disease and cancer. This harm would be greatest from emphasizing fatty red meats (steak, bacon, etc.) or processed meats, as opposed to leaner meats, such as poultry.

To make it healthier: The potential health benefits of lower carb diet can be maximized by focusing primarily on eliminating added sugars and refined grains, and emphasizing sources of fat from plant sources (e.g., olive oil, nuts, avocados), from fatty fish (e.g., salmon), or from lean meats.

Variations: The Atkins diet emphasizes restricting carbs, but allows as much fats and protein as desired. If carbohydrates are severely restricted, a low-carb diet becomes a ketogenic diet.

If you’re going to cheat: Including beans/legumes may make sense because their more complex starches and fiber differ from the simple starches in processed grains and starchy vegetables. Eating these foods provides a much greater range of possible foods, making the diet easier to follow.

Conclusion: A lower carb diet can offer weight loss and metabolic improvements. In its extreme forms where all starchy vegetables, bean/legume, fruit, and grain intake is restricted, it is difficult to follow and has the drawback of high saturated fat and low fiber intake.

Nonetheless, this diet could be a good starting place for initiating weight loss when the focus is on minimizing added sugars and refined grains, and maintaining or even increasing fibrous vegetables.

This is the seventh post in a series called A Skeptical Look at Popular Diets. The series will review the eight currently most prominent diets in America. The next blog post will discuss low-fat diets.

Randall Stafford, MD, PhD, is a professor of medicine at Stanford. He practices primary care internal medicine and studies strategies for preventing chronic disease. Stanford professor and nutrition scientist Christopher Gardner, PhD, examines the impact of diet on health and disease. Min Joo Kim provided research assistance.

Photo by Jakub Kapusnak

Once uninsured, a medical student — and her peers and mentors — are giving back

In this Stanford Medicine Unplugged post, medical student Yoo Jung Kim reflects on how being uninsured has inspired her to provide care for others.

By Yoo Jung Kim

I’m constantly awed by the fact that I get to be part of one of the best hospitals in the world, especially because as a kid, I grew up without health insurance.

These were the days before the Affordable Care Act; there was no penalty for going without health coverage. As a non-citizen, I was ineligible for Medicaid, and private health care was prohibitively expensive for my family. Fortunately, I was a healthy kid with a robust immune system, and I never had to go to the doctor’s office except for mandatory school physicals and vaccinations. When I rotated through my pediatrics rotation, I was struck by how many well-child visits that I had unknowingly missed.

But not having insurance meant that when my family had to pay, we paid big time. When I was in high school, my otherwise healthy dad developed an acute infection — just a stroke of terrible luck. He was whisked away in an ambulance, evaluated in the emergency room, and admitted to the hospital.

Fortunately, he made a full recovery, but the financial costs of the ambulance ride, the expertise of numerous medical providers, and the medications, were astronomical. It took months to negotiate the bill with the numerous parties — hospitals, physician groups, diagnostic services — that had contributed to his care. On the advice of a patient financial counselor, I wrote letters to various offices to beg for discounts. Fortunately, many recipients acquiesced, but even so, it took years to pay off the bills.

From this experience, I got the sense that health care was a privilege for those with the means to pay for it, like a good union or white-collar job. In a way, it sparked my interest in medicine because I wanted to be a doctor to those who needed my services the most.

So far, I’ve been able to pursue this goal at Stanford. I’m starting my third year as a specialty clinic coordinator at Arbor, one of two free medical clinics run by Stanford students under the guidance of residents and attendings who graciously volunteer time out of their busy schedule.

Even after the implementation of the ACA, the clinic’s waiting room is packed with people wanting to be seen. Some of our patients are undocumented residents who are ineligible for Medicaid or Medicare. Others are elderly parents of savvy graduate students and postdoctoral fellows visiting from developing countries for a rare opportunity to see their children and get care from U.S. physicians. Then there are people who are just down on their luck or between jobs and haven’t been connected to the social services available to them.

At the specialty clinic that I co-manage, I receive referrals from the general free clinic, call patients to make appointments, organize student and physician volunteers, and arrange supplies for various in-clinic procedures. I’ve seen students and physicians help underserved patients by treating illnesses, preventing downstream consequences of chronic conditions, and coordinating a care plan to make sure that patients can get the follow-up that they need.

It is a team effort: The amazing attendings have volunteered for years to help patients and teach trainees, and the residents ensure one of their own is present to help every clinic date and that our supply closet is appropriately stocked. The medical students learn more about the specialty from the attendings and the residents, and, most importantly, patients get the care they need.

Some patients have been harboring their illnesses for years, using folk remedies or over-the-counter medications to treat their symptoms instead of going to see a physician. An ounce of prevention may be worth a pound of cure, but I understand their rationale because the same thing kept me awake at night as a kid: what if the doctors find something wrong with me or my parents, how will we be able to pay for the treatment? Maybe it’s better not knowing, but what if the condition gets worse and becomes more difficult and expensive to treat? How will we pay for the treatment?

Now that I have insurance and have more flexibility with my schedule during my research gap year, I’m finally catching up on my health, including well-woman’s exams, recommended vaccinations, minor surgeries, and dental check-ups. I’m acutely aware of how lucky I am that I can get care and follow-up from incredible Stanford providers, some of whom I’ve worked with before (this is admittedly a bit awkward, but that’s a story for another time), but many others still struggle to access even the most basic medical services.

Growing up without health insurance helped me to understand the plight of many individuals who still face similar challenges, and as a medical student, I am awed and inspired by the physicians at Stanford who make time out of their busy schedules to help the underserved.

Stanford Medicine Unplugged is a forum for students to chronicle their experiences in medical school. The student-penned entries appear on Scope once a week during the academic year; the entire blog series can be found in the Stanford Medicine Unplugged category.

Yoo Jung Kim is a fourth-year Stanford medical student and the co-author of What Every Science Student Should Know, a guide for aspiring college STEM students. She also writes for Doximity and U.S. News and World Report.

Image by Tumisu

At event, experts talk heart health and share the latest on Apple Heart Study

If you happened to have dropped by the Apple Store in downtown San Francisco Monday evening, you might have caught sight of something out of …

By Michelle Brandt

If you happened to have dropped by the Apple Store in downtown San Francisco Monday evening, you might have caught sight of something out of the ordinary. Under the direction of an enthusiastic woman with a tight bun in her hair and a huge smile, dozens of people on the second floor of the bright, airy store suddenly stood up and began squatting and marching — and two people even hit the floor to demonstrate a push up and plank.

The crowd was there for a free special program called Heart Health with Apple, and long-time celebrity trainer Jeanette Jenkins had encouraged attendees to try a few moves. She was part of a panel of health, tech and fitness experts brought together to discuss heart health, share practical tips and describe how the Apple Watch is being used to shed light on heart disease.

Before the audience was prompted out of their seats by Jenkins, panel moderator Julz Arney, with Apple Fitness Technologies, posed some important questions to the experts at hand. Bob Harrington, MD, a Stanford cardiologist and president-elect of the American Heart Association, took the mic first to remind the audience that heart disease is the number one killer in the world and explain there’s a growing awareness of the seriousness of the problem, especially among women. He also noted that an increasing number of patients have come to him over the years with their own health data — something he says empowers patients and “allows physicians to partner with them.”

Much of that data comes from wearables, and Harrington and fellow panelist Sumbul Desai, MD, a practicing physician at Stanford and VP of Health at Apple, spent a chunk of time at the event discussing the data being captured through the Apple Heart Study. That study, which was launched by Stanford in collaboration with the company last year, is exploring whether an app on the Apple Watch that analyzes pulse rate data can identify a potentially deadly heart disease called atrial fibrillation.

The Apple Heart Study is the largest study ever done on the disease — which is characterized by an irregular heartbeat and can increase the risk of stroke and heart failure — with more than 400,000 participants enrolled. “I’ve been doing clinical trials for 30 years, and having 5,000 participants is considered a big study,” said Harrington in explaining the scope of this research. The ability for researchers to reach this many people, he said, shows “the power of new technology.”

The researchers hope to glean much information from the study, including, Harrington said, details on how often atrial fibrillation occurred among this population and how exactly study participants and their physicians used the technology. For example, did participants who received an irregular pulse notification on their watch go on to seek medical attention?

The study is in its final phase of data collection, and initial results will be released at the American College of Cardiology conference in New Orleans next month. Desai, for one, is excited. “I went to medical school to make an impact,” she said. “And to be able to do this at scale” is rewarding.

Before ending their session, Arney and the panelists made the point of encouraging attendees to tend to their hearts and overall health well before there’s a problem. Harrington shared the AHA’s recommendation of walking for 30 minutes a day for five days a week, and Jenkins offered “practical and tactical tips” for the audience: Add exercise to your to-do list on a weekly basis; choose a work-out program that can easily be done, even in your living room; and, if you’re a parent, involve your kids. Desai’s advice was even simpler: “Just move.”

Photo by Michelle Brandt

“Scientific serendipity” identifies link between type of RNA and autism

Long non-coding RNAs, are important but poorly understood regulatory elements. Now Stanford scientists have uncovered they play a role in autism.

Krista Conger

I’ve written here before about long non-coding RNAs, or lncRNAs. These molecules are created from DNA but, unlike messenger RNA, they don’t contain the coding instructions for any proteins. Instead, they perform critical regulatory functions within the cell — many of which are as yet undetermined.

Now researchers, including dermatologist and genome scientist Howard Chang, MD, PhD, graduate student Cheen Euong Ang, and stem cell scientist Marius Wernig, MD, are finding that at least one of these lncRNAs appears to control neurodevelopment. In particular, this lncRNA is linked to autism spectrum disorders and intellectual disabilities. They published their findings earlier this month in eLife.

As Chang explained in an email:

We discovered this lncRNA due to its ability to help turn other kind of cells into neurons through a process called transdifferentiation. In a bit of delightful scientific serendipity, genetic association studies of patients and families with autism and intellectual disability turned up the same lncRNA. We think there are likely to be additional ‘brainy lncRNAs’ that help to build or regulate the brain circuits affected in autism and other neurodevelopmental disorders.

In 2011, researchers in Wernig’s lab described how to create human neurons directly from skin cells without going through a transition state known as induced pluripotency. Eager to learn how this transition happened, the researchers have been studying the genes that seem to trigger this change. Surprisingly, Ang found that about 40 percent of those genes were lncRNAs. After a variety of screening methods, the researchers homed in on 35 of these lncRNAs most likely to affect brain function in some way.

Ang and his colleagues found that one of these 35 lncRNAs, fetchingly called lnc-NR2F1, is repeatedly mutated in people with autism spectrum disorders or intellectual disabilities.

As Chang explained:

We were impressed to find evidence of recurrent lncRNA mutations in people with autism. The point was really brought home by finding an affected family with a single break the chromosome that chopped the lnc-NR2F1 gene in half. This suggests that inactivation of just one copy of this neurogenic lncRNA has a potential impact.

Although more research needs to be done to clarify the role of lnc-NR2F1, the study points at the importance of lncRNAs in brain development and function.

“The knowledge of lncRNA involvement means that genetic studies of autism need to include and look closely at the effects of lncRNAs and not just at standard protein-coding genes,” said Chang.

Image by Nevit Dilmen, NIH 3D Print Exchange, National Institutes of Health


Stanford researchers solve a long-standing mystery as to how mutations in a neighboring stretch of DNA can increase the expression of a cancer-associated gene called Myc. The finding highlights a potential new class of targets to block cancer cell growth.

Author Krista CongerPublished on May 3, 2018May 3, 2018

About the future: A look at the Pediatric Innovation Showcase

Experts came to Stanford for the Pediatric Innovation Showcase to learn about many approaches to helping children’s health, from social media to surgery.

By Erin Digitale

Scientists, innovators, venture capitalists and medical industry experts gathered at Stanford last week for the second annual Stanford Children’s Health Pediatric Innovation Showcase, a daylong event highlighting new devices and developments in pediatric medicine.

The conference covered wide ground, including engaging patients with social media, better hospital design, commercialization of scientific innovations, the promises of gene therapy, and several medical uses of virtual reality. Capping the day, pediatric health innovators vied for funding in a pitch competition hosted by the UCSF-Stanford Pediatric Device Consortium. Of 80 entries, 13 finalists described the medical devices they are developing for babies and kids.

Lloyd Minor, MD, dean of the School of Medicine, welcomed participants by highlighting Stanford’s culture of collaboration. For example, nearly a third of Stanford engineering faculty are currently conducting research with medical applications, he said. “It’s because that’s where the really interesting problems are today,” Minor said.

At the same time, innovation in pediatric medical devices lags behind those for adults, he noted. “The consortium’s mission to ensure that the latest technologies are available to all — in this case our youngest patients — mirrors that of Stanford Medicine’s precision health vision.”

Paul King, president and CEO of Stanford Children’s Health, offered uplifting opening remarks. “Pediatric medicine at its core is about optimism — it’s about the future.”

Social media and other online tools have great power to provide parents with evidence-based information about pediatrics, keynote speaker Wendy Sue Swanson, MD, told the audience. Swanson, chief medical officer of Before Brands and chief of digital innovation at Seattle Children’s Hospital, writes a pediatrics-focused blog, Seattle Mama Doc, and uses many other channels to reach out to parents.

“Communication may be your most important technology,” Swanson told the audience. “Are you making information online to contribute to something better?”

Swanson shared several stories from her work. Her most popular blog post, Toddler Sleep: 4 reasons toddlers wake up at night, covers a topic from the bread and butter of well-child pediatrician visits. Why was it so widely read?

Swanson said she found an answer in data on her readers’ engagement with the post. When it was midnight in Seattle, views were peaking there; when it was midnight in Singapore or India, that was where readership was highest. Parents want just-in-time information, and pediatricians need to help ensure that what parents find online is medically accurate, Swanson said.

Similarly, doctors need to make sure that families can get scientifically accurate information about subjects like vaccines, no matter when or where they look for it. Recently, Swanson has worked with Seattle Children’s to build a tool called Flu Doctor that answers basic questions about flu vaccines via Alexa. Swanson wants more doctors to join such efforts to counteract anti-vaccine propaganda and anecdotes that proliferate online.

“If you don’t do it, someone’s going to confuse your expertise with someone else’s experience,” she said.

At the end of a day, teams vied for about $300,000 during a pitch competition. The three platinum awards were given to:

  • Bionic Tot, for its Button Huggie, a device for children with gastronomy tubes, which helps prevent infections, leaking and skin breakdown at the tube’s external site.
  • Gravitas Medical, for its sensor-enabled nasogastric feeding tubes. The sensors guide placement of the tubes and warn caregivers if tubes end up in the esophagus or lung instead of the stomach.
  • Palmm, for its bio-electronic glove that provides low levels of electrical stimulation to stop excessive sweating in patients’ hands.

Photos courtesy of Stanford Children’s Health

Mystery novel, prophetic dream, decades of work spur breakthrough in hypertrophic cardiomyopathy

One night Jim Spudich knocked off a few chapters of a murder mystery before falling asleep, to awaken with a vision that would solve a medical mystery.

By Bruce Goldman

In December 2014, Lasker Award-winning Stanford biochemist and structural biologist Jim Spudich, PhD, had a dream that changed the course of his research and led to a new understanding of — and perhaps a breakthrough treatment for — hypertrophic cardiomyopathy, a mostly inherited heart defect that affects 1 in every 500 people throughout the world.

Hypertrophic cardiomyopathy’s defining clinical symptom is a hypercontractile heart. “It’s as if you’re out for a short run,” Spudich says. “The problem is, you’re doing that 24 hours a day, every day of your life.” The upshot can be sudden death at an early age.

As I wrote in a recent feature article about this fascinating (and, remarkably, true) story:

The heart beats because it’s made of muscle cells that rhythmically shrink in sync and then relax, pumping blood throughout the vascular system. This nonstop throbbing owes its rhythm to a pair of proteins that make all muscular contraction possible.

Hypertrophic cardiomyopathy can arise due to hundreds of different genetic mutations, most of them occurring in just a handful of proteins comprising the heart’s muscle-contraction machinery. One protein in particular, myosin, has been on Spudich’s mind since 1969 — his unraveling of this contractile molecule’s workings is what won him the coveted Lasker in 2012. Another key protein in this machine is called actin.

Here’s a riddle that stymied Spudich for years: Usually mutations cause a protein not to work as well as the unmutated version does. But the mutations responsible for hypertrophic cardiomyopathy do the opposite! They somehow cause the protein to work ‘better.’ The result is a heartbeat that’s too powerful.

The lion’s share of those mutations affect myosin. A myosin molecule’s general structure resembles a two-headed monster: two large globular “heads” protruding from a stalk-like tail. (See illustration below.) It’s long been known that myosin sometimes adopts a posture in which its heads fold over and snuggle up against its tail, reminiscent of a sleeping flamingo with its head tucked under a wing.

But nobody cared. To see why they should have, it helps to know how healthy muscles contract. From my article:

A cardiac muscle cell contains perhaps a hundred repeating structural subunits called sarcomeres, [each] composed of myosin-rich ‘thick filaments’ alternating with parallel ‘thin filaments’ made of actin…

In response to electrical impulses traversing the heart, the myosin heads protruding from the thick filament chomp down on the nearest actin filament, then tug against it like sailors tugging in tandem on a rope, pulling the sarcomere walls closer together and making the muscle fiber contract, before relaxing again. That’s a heartbeat.

And if those myosin sailors are tugging too hard on those actin ropes? That’s hypercontractility, the hallmark of HCM.

But why would this happen? Spudich and his labmates had been focusing on this question for years. And they’d been stumped.

One night as Spudich lay awake in bed late, wondering what clue he’d been overlooking, his wife told him to take a break. She slipped him some bedtime reading, a murder mystery. Spudich knocked off a few chapters before falling asleep, only to awaken in the dark with the germ of a vision that would solve the mystery he’d been brooding over for more than a year.

I think I’ll stop here and leave you in suspense. Want to know more? Read the article. But I will leave you with this: Amazing discoveries and inventions, from the sewing machine to the periodic table and the theory of relativity, have sprung from the dream of sleeping scientists.

Photo by Edward Caldwell; Protein image courtesy of Jim Spudich

New algorithm could accelerate diagnosis of genetic diseases using clinical records

By Helen Santoro

In a continued effort to speed up the diagnostic process of severe genetic diseases, Stanford’s Gill Bejerano, PhD, and his colleagues have developed a new algorithm that can quickly locate important disease-related information within a patient’s medical record.

In a paper recently published in Nature Genetics in Medicine, Bejerano and Cole Deisseroth, a Bio-X undergraduate fellow, along with researchers including Johannes Birgmeier, a graduate student in computer science, developed an algorithm that scans through records of patients and extracts the patient’s key phenotypes, or observable traits.

The team focused particularly on patients with life-threatening genetic diseases such as sickle cell anemia, cystic fibrosis and Huntington’s disease. Manually scanning through patient notes without a computer, a dedicated clinician can process around 200 patient records in a 40-hour work week, the researchers said. This algorithm can do the same job in 10 minutes, further saving busy doctors an additional three to five hours per every downstream disease diagnosis.

“A diagnosis is extremely valuable for the patient, for the family and for the attending clinician,” said Bejerano. But finding the diagnosis within the patient’s genome is very time consuming and, “for that we need computational tools.”

The algorithm is called ClinPhen — a combination of “clinical” and “phenotypes.” After examining a patient’s medical records, the algorithm parses the sentences into short phrases. For example, if the clinical note reads, “The child has short stature and long eyelashes. She has a cleft palate and a small jaw,” the phrases, “The child has short stature”, “and long eyelashes”, “She has a cleft palate”, and “a small jaw” would be selected.

These phrases are converted into codes from an existing phenotype database called the Human Phenotype Ontology, or HPO. The codes are then sorted, with the most- and earliest-mentioned phenotypes at the top of the list. ClinPhen can also identify words, such as “father” and “does not have” and not associate any phenotypes mentioned in that sentence with the patient.

ClinPhen’s accuracy, phenotype filter and speed was validated using six sets of real patient clinical notes from four different medical centers. When compared to other phenotype extraction algorithms, ClinPhen was more precise and 20 times faster, the research showed.

“ClinPhen actually guesses slightly better than a clinician,” Bejerano said. “We can capture clinician intuition and pick the right set of phenotypes to best facilitate the diagnosis.”

The HPO codes produced by ClinPhen will then be fed to Phrank, another algorithm designed by Bejerano and his colleagues that ranks patients’ genes that have rare variants for their ability to explain the phenotypes, or traits, identified by ClinPhen.

Bejerano describes the efforts as a “computational ecosystem”, and said he hopes to see this ecosystem implemented in clinical settings soon.

“The medical establishment is very conservative. And for good reason… You want to protect the patient,” Bejerano said. “[But] I think that slowly, very slowly, there is a shift towards using more of these automated systems. With 60 million patients to be sequenced in the next several years, we simply have no choice.”

Image by Darryl Leja, NHGRI

Originally published at scopeblog.stanford.edu on December 5, 2018.

A stage IV cancer patient discusses what it means to live well with serious illness

By Holly MacCormick

The first time I saw Amy Berman, RN, speak she was standing on a glacier telling her Twitter friends (via video selfie) how “absolutely beautiful” Iceland was. She was snowmobiling and wished everyone could join her there. Genuine joy radiated from her face and a broad smile touched her cheeks made rosy by the cold.

“Can you believe I’m living well with stage IV breast cancer?” she asked.

Honestly, I couldn’t — I’d lost a parent and two best friends to cancer, and snowmobiling on a glacier at stage IV just didn’t line up with my experience of the disease. Then I heard Berman share her story at the recent Jonathan King Lecture series, and I began to understand.

Palliative care expert Stephanie Harman, MD, welcomed guests to the event sponsored by Stanford’s Center for Biomedical Ethics. She explained that King, a computer scientist “with a deep concern for the dignity of all individuals” gave the first lecture 28 years ago before dying of cancer at age 41 so others could know the choices that patients and families face near death.

“I’m going to put you into the perspective of someone who has a serious illness to discuss what matters most,” Berman said. “It may or may not be what you think.”

“People often view palliative care as ‘turning off’ care for a patient, when in reality it may be the thing that helps keep them going,” she said before sharing:

About eight years ago, I had a red spot appear on my right breast. It was a very funny-looking spot. It looked like the skin of an orange.

The spot was a cardinal sign of inflammatory breast cancer, a serious and rare form of the disease. Berman got a mammogram, a biopsy and a diagnosis the next day.

She described sitting outside the radiology room next to an “elegant woman in pearls,” both of them wearing white waffle weave robes. We looked like “we were set up to get mani-pedis” instead of waiting for radiographs, Berman said.

Suddenly all of the fellows were called into the radiology room, Berman recalled:

The very elegant woman in pearls looked like she was gonna throw up. You could just tell that she thought it was her, but in my heart of hearts I knew that it was me. …

I said, ‘I’m Amy Berman, are those my images?’

The woman asked everybody to leave the room and invited me in. She said, ‘Would you like to meet the enemy?’

And that’s how I found out that I had cancer.

Others may not wish to learn they had cancer in this way, Berman acknowledged, but she was grateful. “I’m sure that it was against every single protocol for this woman to tell me,” Berman said. “I’ll never forget her kindness.”

The first oncologist Berman met with asked what was important to her. At the time, she had no noticeable symptoms other than the red spot and a little pain on the breast.

“I want the Niagara Falls trajectory,” Berman said, “I want to feel good, good, good and then drop off the cliff.” This oncologist said she could make a treatment plan that would keep Berman feeling well as long as she could.

The second oncologist Berman saw reconfirmed her diagnosis, but didn’t ask what kind of care she wanted. Instead, he told Berman, “this is what we are going to do.” She’d get the most intense chemotherapy her body could handle, a mastectomy and another round of intense chemotherapy.

“I’m stage IV,” Berman said to the audience. “The cat’s out of the bag.” The cancer was already in her lower spine and bloodstream. Berman chose the first oncologist.

“If I went with the other clinician I would have dropped off a cliff at the beginning and gone out to the same end point,” Berman said.

Berman chose not to pursue aggressive therapy, but she does receive therapy and confers with her oncologist and palliative care team to identify treatments that help her stay active and control her pain.

She receives infusions to keep her bones strong and received single fraction radiation, a therapy her palliative care providers recommended, to reduce the sharp pain caused by cancer advancing up her spine. Palliative care, she said, is “the best friend of the seriously ill.”

“What do people want most when living with serious illness?” Berman asked at one point, displaying a photo of her standing alongside a surfboard. With a twinkle in her eye she said, “as a surfer, I can say that I want to live well.”

Photo of Amy Berman (left) and Ms. King (right) by Kelly Cox-Gonzalez

Originally published at scopeblog.stanford.edu on October 22, 2018.

“Mitotic catastrophe” describes how aged muscle stem cells die, and provides clues to keeping them healthy

By Krista Conger

As a parent, I chuckled a bit when I first heard the term ‘mitotic catastrophe.’ The phrase describes a situation in which cells attempting to divide bungle the complicated maneuver and die an ignominious death. Even cells, it seems, sometimes find that the attempt to create happy, functional offspring is fraught with peril.

But, joking aside, the death of dividing cells — aka mitotic catastrophe — can have serious consequences, particularly when those cells, namely stem cells, are responsible for regenerating new muscle in response to injury or aging.

Now neurologist Thomas Rando, MD, PhD, together with senior research scientist Ling Liu, PhD, and pathologist Gregory Charville, MD, PhD, have pinpointed mitotic catastrophe as a cause of death of old muscle stem cells. These cells are less able than their younger counterparts to repair muscle damage. They’ve also shown that this “death by dividing” is the result of a malfunction of the cross-talk that occurs between the stem cells, nestled along the lengths of muscle fibers, and their neighboring cellular support team known as the stem cell niche.

They recently published their work in Cell Stem Cell.

As Rando explained in an email to me:

Mitotic catastrophe has primarily been described in the scientific literature as a way that cancer cells die, especially after treatment with chemotherapeutic agents. So it was a surprise to us to see the old muscle stem cells dying in this way. In fact, prior to this research, I had not even heard the term mitotic catastrophe.

In contrast, younger muscle stem cells usually divide without issue when called upon to do so, the researchers found.

Further investigation revealed that the catastrophic death of the aged muscle stem cells is related to a reduction in the amount of a protein called p53 in the cells. p53 is a well-known tumor suppressor that normally works to pause the division of cells with DNA damage to allow them the necessary repair time. When p53 is mutated, damaged cells continue dividing and sometimes become cancerous.

The researchers went on to discover that the decline in p53 is due to a reduction in the activity of a biochemical signaling cascade called the Notch pathway, which is activated in the stem cells by signals produced by neighboring cells. This close relationship between the stem cells and their niche has been shown by Rando and others to be vital in maintaining the function of stem cells.

As Rando explained:

Increasing evidence points to the cross-talk between stem cells and their niches as being essential to maintain normal tissue homeostasis and repair. If one disrupts the stem cells or the niche cells, these processes are impaired.

Some stem cells persist in a quiescent state for years or even decades, and normal structure and function of the stem cell-niche unit appears to be essential for such long-term cell, tissue, and even organismal survival.

Because DNA damage accumulates with age, Liu, Charville and Rando wondered whether it was possible to avert mitotic catastrophe in the aged stem cells by treating them with a drug that increases p53 expression — perhaps by giving them breathing room to repair the damage before dividing. Indeed, they found that boosting p53 expression in the stem cells allowed them to divide more successfully improved their ability to repair muscle damage.

Rando and his colleagues are now keen to learn whether intervening in this natural aging process of the stem cells and their niche can lead to therapies that can help old muscles, and potentially other tissues and organs, heal more quickly and efficiently.

As Rando said:

We want to know why Notch signaling declines in the muscle stem cell compartment with age. This could suggest another potential therapeutic approach to preventing mitotic catastrophe in aged muscle injury. And we would like to know whether these findings represent a general phenomenon in aged stem cell populations.

Photo by ChangGp

Originally published at scopeblog.stanford.edu on October 4, 2018.

Nature, not nurture: New evidence in mice that recognition of a stranger’s sex is baked into the brain at birth

Male mice are hardwired to recognize the sex of other mice, a new study shows. Females’ circuitry guiding that decision differs from males.

By Bruce Goldman

Male mice are hardwired to recognize the sex of other mice, a new study in Cell shows. No previous experience required. Female mice also catch on quickly to a stranger’s sexual identity, but researchers haven’t figured out yet where the brain circuitry guiding those decisions resides.

The findings add fuel to one side of a longstanding debate, carried on largely between bioscientists and social scientists, about the relative influences of hardwired versus socially acquired influences on sex-specific mammalian behaviors. (That debate was the central subject of “Two Minds: The Cognitive Differences between Men and Women,” an article I wrote for our magazine, Stanford Medicine, in 2017.)

In the new study, molecular neuroscientist Nirao Shah, PhD, and his Stanford colleagues pinpointed, for the first time in mammals, a small but essential set of neurons in the male mouse brain that drive even a sexually inexperienced animal’s ability to speedily determine another’s sex. The researchers used sophisticated genetic techniques that allowed them to remotely switch these neurons on and off at will and to observe the behavior that ensued in controlled social situations. Not the type of experiment you can do in people.

But this discovery is likely to be relevant to us humans, Shah told me, because, being mammals ourselves, we share with mice much of the same brain circuitry they use for recognizing a stranger’s sex — and, importantly, because human studies of this circuitry indicate substantial structural and physiological differences between men and women.

The brain structure that houses the nerve-cell circuitry governing male mice’s ability to distinguish between the sexes is called the “bed nucleus of the stria terminalis.” In humans, that structure is twice as large and more densely populated with neurons in men than in women, and studies have revealed different patterns of gene-activation levels in men versus women — a reliable clue that its function differs by sex.

It’s long been known that a male mouse on its own turf, whether it’s sexually naïve or experienced, responds predictably to the intrusion of another mouse. That response depends on the stranger’s sex: If it’s a male, the mouse will pick a fight, while he’ll try to mate with a female.

“All social and sexual encounters are predicated on first correctly identifying the sex of the other agent,” Shah said. “It’s a fundamental decision animals make.”

So, maybe not such a good idea to leave it to chance. From my news release about the study:

In its lifetime, a wild male mouse may get just a few shots at sexual reproduction, ratcheting up the advantage of being able to correctly identify a newcomer’s sex in short order without having to learn how first. If that ability is innately programmed, even a sexually inexperienced mouse can rapidly discern males from females of its species.

It makes strong evolutionary sense for the mammalian brain not to be a so-called “blank slate,” equally accessible to every experiential piece of chalk that comes along to write on it, but rather for some behavioral patterns to be genetically hardwired — and for the most hardwired behaviors of them all, such as reproduction, to be the ones most mission-critical to species’ survival. In Darwinian terms, that’s the successful generation of . . . well, of the next generation.

Having co-evolved for hundreds of millions of years, the two sexes have acquired differing reproductive strategies, with resulting divergent yet complementary behaviors. After all, why would evolution come to a screeching halt above the neck?

Image by Elizabeth Kunker, courtesy of the Shah lab