It’s been years (fortunately) since I’ve needed a prescription for anything more than a simple antibiotic. But when I did, I remember I was always thankful on those occasions when my doctor offered a free sample of a medication to try before (or sometimes instead of) pulling out the prescription pad. I appreciated the chance to see if a medication would work for me, and I was happy for any opportunity to save myself (or, at times, my insurance company) a few dollars. The fact that the samples were invariably for drugs that were still on patent (known as brand name drugs or branded generics) to a particular company certainly escaped me.

Now, a study by Stanford dermatologist Al Lane, MD, highlights the dark side of such free samples, which are provided to doctors by the pharmaceutical companies who make the drugs. The research, along with an accompanying editorial, is published today in JAMA Dermatology. As Lane comments in my release on the work:

Physicians may not be aware of the cost difference between brand-name and generic drugs and patients may not realize that, by accepting samples, they could be unintentionally channeled into subsequently receiving a prescription for a more expensive medication.

Specifically, Lane and medical student Michael Hurley found that dermatologists with access to free drug samples wrote prescriptions for medications with a retail price of about twice that of prescriptions written by dermatologists without access to samples. All of the patients had the same first-time diagnosis of adult acne. The difference is nothing to sniff at – $465 for docs who accepted samples and about $200 for docs who did not. What’s more, the overall prescribing patterns of the two groups of physicians showed almost no overlap. Physicians without access to samples prescribed mainly generic drugs (83 percent of the time), whereas those with access to samples prescribed generics much less frequently (21 percent of the time). Only one drug of the top ten most commonly prescribed by physicians without access to samples even made it into the top ten list of physicians who did accept samples.

The distribution of free drug samples in this country is big business. It’s been estimated that pharmaceutical companies give away samples of medications with a retail value of about $16 billion every year. But many physicians feel the availability of samples doesn’t sway their prescribing choices, and instead feel the samples allow them more flexibility to treat their patients. Lane himself thought so, until Stanford Medicine prohibited physicians to accept samples or other industry gifts in 2006. As he explains in the release:

At one time, we at Stanford really felt that samples were a very important part of our practice. It seemed a good way to help poorer patients, who maybe couldn’t afford to pay for medications out-of-pocket, and we had the perception that this was very beneficial for patients. But the important question physicians should be asking themselves now is whether any potential, and as yet unproven, benefit in patient compliance, satisfaction or adherence is really worth the increased cost to patients and the health-care system.

Clearly Lane has had a change of heart, in part based on the data in the study. Now he’s hoping to get the word out to other physicians. He and Hurley conclude in the paper, “The negative consequences of free drug samples affect clinical practice on a national level, and policies should be in place to properly mitigate their inappropriate influence on prescribing patterns.”

Previously: Consumers’ behavior responsible for $163 billion in wasteful pharmacy-related costs and Stanford’s medical school expands its policy to limit industry access
Photo by StockMonkeys.com

Stanford scientists have shown that it’s possible to simultaneously screen for dozens of cancer-associated mutations from a single blood sample using a multiple-gene panel. The research is published today in the Journal of Clinical Oncology (subscription required).

As I describe in my release:

Gene panels allow researchers to learn the sequences of several genes simultaneously from a single blood sample. It stands to reason that screening for mutations in just a few select genes is quicker, easier and cheaper than whole-genome sequencing. The technique usually focuses on fewer than 100 of the approximately 21,000 human genes. But until now, few studies have investigated whether homing in on a pre-determined panel of suspects can actually help people.

The researchers, medical oncologists and geneticists James Ford, MD and Allison Kurian, MD, used a customized 42-gene panel to investigate the presence of cancer-associated mutations in 198 women with a family or personal history of breast or other cancers. The women had been referred to Stanford’s Clinical Cancer Genetics Program between 2002 and 2012 to undergo screening for mutations in their BRCA1 or BRCA2 genes. They found that the panel was  a useful way to quickly screen and identify other cancer-associated mutations in women who did not have a BRCA1/2 mutation. From our release:

Of the 198 women, 57 carried BRCA1/2 mutations. Ford and Kurian found that 14 of the 141 women without a BRCA1/2 mutation had clinically actionable mutations in one of the 42 genes assessed by the panel. (An actionable mutation is a genetic variation correlated strongly enough to an increase in risk that clinicians would recommend a change in routine care — such as increased screening — for carriers.)

Eleven of the 14 women were reachable by telephone, and 10 accepted a follow-up appointment with a genetic counselor and an oncologist to discuss the new findings. The family members of one woman, who had died since giving her blood sample, also accepted counseling. Six participants were advised to schedule annual breast MRIs, and six were advised to have regular screens for gastrointestinal cancers; many patients received more than one new recommendation.

One woman, with a history of both breast and endometrial cancer, learned she had a mutation that causes Lynch syndrome, a condition that increases the risk of many types of cancers. As a result, she had her ovaries removed and underwent a colonoscopy, which identified an early precancerous polyp for removal.

The study shows that gene panels can be a useful tool that can change clinical recommendations for individual patients. It also indicates that patients are willing and eager to receive such information. As Ford explains in the release:

Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information.

Previously: Whole genome sequencing: the known knowns and the unknown unknowns,  Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside and Blood will tell: In Stanford study tiny bits of circulating tumor DNA betray hidden cancers.

Blood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there’s another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don’t) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

…

“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

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Vitamin D is a darling of the supplementation world. Deficiencies in the vitamin have been blamed for all manner of ailments, including diseases of the skeletal system, autoimmunity, infections and cancer.

Now researchers from the University of Edinburgh, Imperial College London and the University of Ioannina School of Medicine in Greece have analyzed 107 systematic literature reviews and 161 meta-analyses regarding vitamin D supplementation or levels in blood plasma and the occurrence of 137 various medical outcomes. They’ve published their findings in today’s issue of the British Medical Journal, where they wrote:

In conclusion, although vitamin D has been extensively studied in relation to a range of outcomes and some indications exist that low plasma vitamin D concentrations might be linked to several diseases, firm universal conclusions about its benefits cannot be drawn.

In particular, the researchers found that the evidence does not support a role for vitamin D in increasing bone mineral density or reducing the risk of falls and fractures in older people. As senior author and Stanford study design expert John Ioannidis, MD, DSc, explained to me in an e-mail:

Vitamin D has been evaluated in thousands of studies in terms of its relationship to at least 137 health outcomes. We hope that systematic consideration of the available evidence will help avoid hot debate about health decisions involving vitamin D  that have mostly depended on speculations rather than evidence to-date.

Rather than writing off vitamin D altogether, the researchers note that additional, well-designed studies and trials are necessary before any firm conclusions can be drawn about its efficacy. The paper is accompanied by a second from researchers at the University of Cambridge analyzing relationships between vitamin D levels and the risk of mortality from several causes, as well as an editorial declaring that, despite much study, vitamin D is “no magic bullet.”

Previously: The Lancet documents waste in research, proposes solutions, “US effect” leads to publication of biased research, says Stanford’s John Ioannidis and Shaky evidence moves animal studies to humans, according to Stanford-led study
Photo by Colin Carmichael

As a writer, I think a lot about editing. Will this sentence work here? Maybe I should change this word. Argh – a typo! But I’m not alone. Biologists also appreciate the power of editing, particularly when it comes to modifying genes in cells or organisms.

Recently a powerful new technology has emerged (called CRISPR) that allows researchers to make small, precise and permanent changes in the DNA of animal and human cells. It builds on the concept of genome editing that is key to generating cells, cell lines or even whole animals such as laboratory mice, containing specific genetic changes for study. With CRISPR, however, researchers can generate in days or weeks experimental models that usually take months or years. As a result, they can quickly assess the effect of a particular gene by deleting it entirely, or experiment with repeated, tiny changes to its DNA sequence.

According to a recent New York Times article, scientists roundly agree that CRISPR is revolutionary. At least three companies have been launched in the mere 18 months since the first results were reported by researchers at the University of California, Berkeley and Umea University in Sweden, and more than 100 research papers based on the technique have been published. But, although it’s highly specific, it’s (sadly) not perfect. According to the New York Times piece:

Quick is not always accurate, however. While Crispr is generally precise, it can have off-target effects, cutting DNA at places where the sequence is similar but not identical to that of the guide RNA.

Obviously it’s important to know when (and how frequently) this happens. Unfortunately, that’s been difficult to assess.

Enter researchers in the laboratory of pediatric cancer biologist Matthew Porteus, MD, PhD. Porteus’s lab is interested in (among other things) learning how to a particular type of genome editing called homologous recombination to treat diseases like sickle cell anemia, thalassemia, hemophilia and HIV. They’ve devised a way to monitor the efficiency of genome editing by CRISPR (as well as other more-traditional genome editing technologies) that could be widely helpful to researchers worldwide. Their technique was published today in Cell Reports. As postdoctoral researcher Ayal Hendel, PhD, told me:

We have developed a novel method for quantifying individual genome editing outcomes at any site of interest using single-molecule real-time (also known as SMRT) DNA sequencing. This approach works regardless of the editing technique used, and in any type of cell from any species.

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It’s an interesting question that got a lot of traction in the media last week. Does the contribution of a tiny amount of DNA from a third person during in vitro fertilization really mean that the resulting child would have three genetic parents? Researchers in Oregon have proposed the technique as a way to avoid genetic diseases arising from faulty mitochondrial DNA by replacing an egg’s mitochondria with one from a second, healthy woman either before or after fertilization with a man’s sperm. They’ve shown that it works in monkeys, and the FDA met last week to consider whether the technique is safe enough to be used in humans.

Yesterday, Stanford law professor and bioethicist Hank Greely, JD, posted a great analysis of the topic on the university’s Law and Biosciences blog, complete with an elegant explanation of the problem for women with mitochondrial DNA mutations:

The mitochondria (high school biology’s “energy powerhouses of the cell”) have their own very short stretch of DNA, separate from the 6.8 billion base pairs found on 46 chromosomes in the cell’s nucleus (the nuclear DNA).  The 16,569 base pairs of the mitochondrial DNA (hereafter “mtDNA”) hold 37 (some say 38) genes, providing instructions for making 13 (or 14) proteins and another 24 RNA molecules.  The full importance of these genes is unknown, but it is clear that some (happily rare) variations in the mtDNA cause quite severe illnesses. Unfortunately, each child gets all of its mitochondria (and hence its mtDNA) in the egg from its mother; if the mother’s mtDNA is dangerously flawed, so will be the mtDNA of all her children. With almost all other genetic diseases, no matter how inevitably the “bad” genetic variation leads to a disease (how “penetrant” the genetic variation is), a woman will have only a 50% or 25% chance of passing on the condition.  With these, her genes can give rise to no healthy children.

Greely gets at the heart of the matter when he compares the statistically minute contribution from the donated mitochondria to a hypothetical child he calls Heather:

I have DNA from four people in each of my cells:  my mother’s mother, my mother’s father, my father’s mother, and my father’s father. Actually, my DNA really came from all eight of my great-grandparents, and all 1024 of my great great great great great great great great grandparents, and all roughly one million of my great (18) grandparents. Yes, all that DNA passed through my (genetic) parents before coming to me, but why does that matter?

Heather gets her DNA from more than two people a bit differently from the way the rest of us do, but so what? How does getting what is, in effect, “gene therapy,” where the gene is delivered in a natural package called the mitochondrion, turn our hypothetical (and healthy) child into a powerful argument against the procedure?

It shouldn’t.  Heather will not be getting superpowers, she will not be in any meaningfully way “designed” (except to avoid a nasty genetic disease), and she will not be given a newly made DNA sequence never before found in the human gene pool. She will get mitochondria with mtDNA that will allow her to have normal health, not a grave disease. That mtDNA will have been taken from a woman, who, though not a source of Heather’s nuclear DNA, is certainly a participant in the human gene pool.

“Heather has three parents” is NOT an argument. It is an irrelevant but attention-getting slogan that is uncritically put forward as, and sometimes mistaken for, a real argument. Yes, the proposed process is a way of bringing forth living and healthy babies that is somewhat new and different, but so were obstetric forceps, (safe) C-sections, and in vitro fertilization. Novelty is not, in itself, a respectable argument against it.

Previously: Medical practice, patents and “custom children”: A look at the future of reproductive medicine, Five million babies and counting: Stanford expert offers conversation on reproductive medicine and Stanford researchers work to increase the odds of in vitro fertilization success
Photo by Christian Pichler

Recently, a medical situation with one of my children had me gnawing my fingernails and laying awake at night waiting for scary-sounding test results. Thankfully, my growing anxiety was relieved after several days by a reassuring phone call from our doctor. Unfortunately, the health concerns of the stars of my most recent magazine story - the Bingham family of eastern Oregon – are not so easily dismissed.

Three of the five Bingham children have a heart condition called dilated cardiomyopathy; two of the three (14-year-old Sierra and 10-year-old Lindsey) have already had heart transplants at Lucile Packard Children’s Hospital Stanford. Their parents, Jason and Stacy, were gracious enough to share their family’s story with me for my article in our most recent issue of Stanford Medicine magazine.

Heart transplants are life-saving, but they come with a lifetime of medication and monitoring. Many physicians feel that cardiac medicine is on the cusp of a revolution – one in which the power of stem cells will be harnessed to help hearts heal themselves, or perhaps even to grow new, perfectly matched organs for transplant. The California Institute for Regenerative Medicine has awarded more than $120 million to pursue potential therapies. No matter how fast any advances occur, however, they can’t come soon enough for the Bingham parents, who are now anxiously monitoring 5-year-old Gage’s battle with the same disease that led to his sisters’ transplants.

At the same time, physicians at the Stanford Center for Inherited Cardiovascular Disease are searching to find the (presumably) genetic cause for the Bingham family’s heart problems through gene sequencing while researchers in the laboratory of Stanford cardiologist and director of the Stanford Cardiovascular Institute Joseph Wu, MD, PhD, work to create induced pluripotent stem cells from the family to better understand the molecular basis of their illnesses.

I’ve been thinking a lot about Jason and Stacy this past week while I faced my own fears for my daughter. I cannot comprehend how strong they have to be for their children. And, although I work daily with many amazing doctors and researchers, I have to say that Jason and Stacy (and other parents like them) are my true heroes.

Previously: Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions, At new Stanford center, revealing dangerous secrets of the heart and Packard Children’s heart transplant family featured tonight on Dateline and
Illustration, which originally appeared in Stanford Medicine, courtesy of Jason Holley

There are definite perks to sticking with the same job for several years. For me, it means the chance to see the progression of research findings I first wrote about in their infancy actually enter human testing. Last week Raptor Pharmaceuticals, based in Novato, Calif., reported positive results in a clinical trial of a possible treatment for Huntington’s disease called RP103. RP103 is a delayed-release cysteamine – a compound first identified in 2002 as a potential therapy in the Stanford laboratory of Lawrence Steinman, MD. As I wrote in my release at that time (courtesy of the way-back machine):

By enhancing the brain’s natural protective response to the disease, researchers were able to alleviate the uncontrollable tremors and prolong the lives of mice with a neurological disorder that mimics Huntington’s. Their finding suggests that a similar treatment strategy may be effective in humans.

Raptor (a company which Steinman advises and in which he holds stock options) enrolled 96 patients in an 18-month-long double blind trial pitting RP103 against a placebo, followed by an 18-month period in which all the participants would receive RP103. Eighty-nine patients completed the first 18-month period; those who received the drug appeared to show slower progression in their disease than those who received the placebo.

It will likely still be years before we know whether the potential treatment will clear the necessary hurdles and become clinically available. But as Steinman said to me in a e-mail last week, “It’s very exciting to see this moving forward in humans.”

Previously: Drug found effective in two mouse models of Huntington’s disease, Amyloid, schmamyloid: Stanford MS expert finds dreaded proteins may not be all bad and Potential therapeutic target for Huntington’s disease discovered by researchers in Taiwan, Stanford

I’ve been pretty good about my gym workouts lately. But I’ve realized that it’s a lot more difficult to build muscle mass now than it was during my 20s. That’s because, as we age, muscle stem cells become less able to repair injury and generate new muscle fibers.

Now a report in Nature Medicine outlines some interesting findings from the laboratory of Stanford microbiologist and immunologist Helen Blau, PhD, suggesting it may be possible to perk up a population of elderly stem cells through a combination of biophysical and biochemical cues.

As I describe in our release:

Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. “Our findings identify a defect inherent to old muscle stem cells,” she said. “Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.”

Blau, who directs Stanford’s Baxter Laboratory for Stem Cell Biology, and postdoctoral scholar Ben Cosgrove, PhD, found that growing muscle stem cells from elderly laboratory mice (a 24-month-old mouse is roughly equivalent to an 80-year-old human, based on average lifespans) in a specialized matrix called hydrogel, coupled with a drug treatment to block an inhibitory pathway, caused the cells to divide rapidly. When implanted into elderly mice with a muscle injury, the cultured cells sprang to work.

“We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice,” Cosgrove said. “Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all.”
The researchers plan to continue their research to learn whether this technique could be used in humans. “If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person’s own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones,” Blau said. “This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury. Our data pave the way for such a stem cell therapy.”

Previously: Making iPS cells safer for use in human through the study of a cellular odd fellow, New mouse model of muscular dystrophy provides clues to cardiac failure and Mouse model of muscular dystrophy points finger at stem cells
Photo by Positively Fit

Science is hard work. So hard, in fact, that it’s pretty disheartening to hear that much of that effort is wasted. A major series of research papers was published yesterday in The Lancet documenting five major causes of waste in research (if you’re interested, the culprits include inefficiencies in setting research priorities, inappropriate study design and analysis, problems in research regulation and management, a lack of accessibility of research results and incomplete or unusable reporting of data).

Stanford’s John Ioannidis, MD, DSci, who has studied the subject extensively, co-authored the accompanying commentary and the article “How to Increase Value When Research Priorities are Set.” He is also the first author of “Increasing Value and Reducing Waste in Research Design, Conduct and Analysis.” (Stanford health research and policy experts  Rob Tibshirani, PhD, and Mark Hlatky, MD, are senior and co-author, respectively, of the article.)

It’s not all doom and gloom, however. The series does suggest ways to overcome these seemingly pervasive obstacles. From the opening article:

How might things be different? One protection from these distorting drivers would be the creation of a set of balancing counter-influences. So, instead of being judged on the basis of the impact factors of the journals in which their work is published, academics might be judged on the methodological rigour and full dissemination of their research, the quality of their reports, and the reproducibility of their findings. If these factors were to contribute substantially to promotion, funding, and publication decisions, institutions might even go so far as to audit the performance of their staff and, when substandard, pay more attention to continuation of professional development and appraisal of the research workforce.

Previously “U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis, Shaky evidence moves animal studies to humans, according to Stanford-led study and Neuroscience studies often underpowered, say researchers at Stanford, Bristol