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

It’s almost too good to be true. A Thanksgiving story about sex, death, gender conflict and… roundworms. A Stanford study published today in Science Express suggests that, in some species of worms and flies, males secrete compounds specifically to shorten the lifespan of nearby females. As a result, their mere presence initiates an inexorable early death sequence that the researchers call “male-induced demise.”

(Let’s all pause here for a deeply satisfying comparison to certain relationships in our own lives…)

The researchers, including Stanford geneticist and longevity expert Anne Brunet, PhD, and postdoctoral scholar Travis Maures, PhD, studied the laboratory roundworm, C. elegans, which has hermaphrodites rather than true females. Their research indicates that male roundworms secrete as-yet-unidentified molecules that act on hermaphrodites sequestered on the other side of a laboratory dish, or those added to a laboratory dish from which a batch of males had recently been evicted. Those hermaphrodites have a lifespan more than 20 percent shorter than controls not exposed to males.

The finding appears to counteract previous theories suggesting that the act of mating (which in worms can be – shall we say – quite rowdy) is responsible for the hermaphrodites’ early demise. As I wrote in our press release:

For several years, it’s been known that the presence of some male worms and flies can shorten the lifespan of their female or hermaphroditic counterparts. But it’s not been clear why. Some researchers have speculated that the physical stress of mating may lead to their early death.

The Stanford research, however, suggests something more than sex is to blame — specifically, that the males are carrying out a calculated plan at the molecular level to off the baby-makers after they’ve done their jobs.

The motive? Brunet and Maures speculate the murderous spree could be triggered by a need to conserve resources for newly produced young, or to prevent other males from mating with the same female. From the release:

“In worms, once the male has mated and eggs are produced, the hermaphrodite mother can be discarded,” Brunet said. “The C. elegans mother is not needed to care for the baby worms. Why should it be allowed to stay around and eat? Also, if she dies, no other male can get to her and thus introduce his genes into the gene pool.”

The researchers found that the continuous presence of young males shortened the average lifespan of C. elegans hermaphrodites by more than 20 percent. This effect persisted even when the genders were prevented from co-mingling, or when the hermaphrodites were sterile — indicating that neither the physical stress of copulation nor the energy demands of producing offspring were entirely responsible for early death. Affected hermaphrodites also displayed symptoms of aging, including slower movement, an increased incidence of paralysis, general decrepitude and structural decline.

It’s almost unbearably tempting to extend these findings to mammals or even humans.The presence of males leads to general decrepitude and structural decline in nearby females? I’ll go with it. And they exert this lifespan shortening effect over both space and time? Check. (In my house this is accomplished by my husband’s refusal to put his dishes in the dishwasher before leaving the house, but your trigger may vary.)

However, such nefarious tactics are likely to seriously backfire when a mother (or a set of parents) is needed to care for helpless offspring. In that case, males would appear to have little incentive to kill off their partners. Even so, the results indicate that this tactic has been going on for millions of years:

Although the researchers first studied a domesticated strain of C. elegans, they were also able to observe male-induced demise in a wild strain of C. elegans, as well as in two other, distantly related species of worm — confirming that the phenomenon has been conserved over about 20 to 30 million years of evolution. The male-induced demise even occurred in species of roundworm that have true males and true females in an equal mix (similar to mammals), suggesting that this phenomenon is not just due to idiosyncrasies of C. elegans such as hermaphroditism or a low proportion of males.

“The observation that this male-induced demise is present in several species of worms and has also been shown in flies suggests that it could have some adaptive benefits,” Brunet said. “It will be interesting, of course, to determine whether males also affect the lifespan of females in other species, particularly mammals.”

Previously Longevity gene tied to nerve stem cell regulation, say Stanford researchers and NIH awards nine Stanford faculty funding for innovative research
Photo by Ryan Somma

Is it time to put away your fancy skin creams and moisturizers? A study published today in the Journal of Clinical Investigation by Stanford pediatric dermatologist Thomas Leung, MD, PhD, and developmental biologist Seung Kim, MD, PhD, suggests that a dilute solution of sodium hypochlorite (you’ll know it better as the bleach you use for cleaning and disinfecting), inhibits an inflammatory pathway involved in skin damage and aging.

The researchers conducted their studies in mice, but it’s been known for decades that dilute bleach baths (roughly 0.005 percent, or one-fourth to one-half cup bleach in a bathtub of water) are an effective and inexpensive way to combat moderate to severe forms of eczema in human patients.

According to our release:

Leung and his colleagues knew that many skin disorders, including eczema and radiation dermatitis, have an inflammatory component. When the skin is damaged, immune cells rush to the site of the injury to protect against infection. Because inflammation itself can be harmful if it spirals out of control, the researchers wondered if the bleach (sodium hypochlorite) solution somehow played a role in blocking this response.

The researchers found that the bleach solution blocks the activation of a molecule called NF-kappaB, or NF-kB, that is involved in inflammation and aging. They collaborated with radiation oncologist Susan Knox, MD, to investigate potential clinical applications. From our release:

Radiation dermatitis is a common side effect of radiation therapy for cancer. While radiation therapy is directed at cancer cells inside the body, the normal skin in the radiation therapy field is also affected. Radiation therapy often causes a sunburn-like skin reaction. In some cases, these reactions can be quite painful and can require interrupting the radiation therapy course to allow the skin to heal before resuming treatment. However, prolonged treatment interruptions are undesirable.

“An effective way to prevent and treat radiation dermatitis would be of tremendous benefit to many patients receiving radiation therapy,” said Susan Knox, MD, PhD, associate professor of radiation oncology and study co-author.

The researchers tested the effect of daily, 30-minute bleach baths on laboratory mice with radiation dermatitis, and on healthy, but older mice. They found that animals bathed in the bleach experienced less severe skin damage and better healing and hair regrowth after radiation,  and the fragile skin of older animals grew thicker than control animals bathed in water. But don’t ditch the contents of your medicine cabinet just yet– mice aren’t exactly tiny people, and more research needs to be done.

The researchers are now considering clinical trials in humans, and they are also looking at other diseases that could be treated by dilute-bleach baths. “It’s possible that, in addition to being beneficial to radiation dermatitis, it could also aid in healing wounds like diabetic ulcers,” Leung said. “This is exciting because there are so few side effects to dilute bleach. We may have identified other ways to use hypochlorite to really help patients. It could be easy, safe and inexpensive.”

Previously: Master regulator for skin development identified by Stanford researchers
Photo by Shawn Campbell

Upcoming holidays likely mean time spent eating and talking with rarely seen relatives – something that could be considered a boon or a trial. One thing I enjoy, however, is the opportunity to learn more about my family history and ancestry through discussions with older family members.

Now, research conducted by Stanford geneticists Carlos Bustamante, PhD, and Andres Moreno-Estrada, MD, PhD, has shown that we carry a surprising amount of similar information in our genes. The strands of DNA include information not just about who our parents, grandparents and great grandparents were, but also about how they mingled with other population groups throughout history. And they did so by studying one of the biggest melting pots of recent past: the Caribbean. The research, conducted in collaboration with  Eden Martin, PhD, from the University of Miami, was published today in PLoS Genetics.

As described in our release:

The researchers compared patterns of genetic variation found in populations in and around the Caribbean, which has had a particularly tumultuous past since Christopher Columbus stumbled into the Bahamas in 1492. Not only did they identify an influx of European genes into the native population that occurred within a generation of Columbus’ arrival, but they also discovered two geographically distinct pulses of African immigration that correspond to the beginning and height of the transatlantic slave trade.

The study demonstrates how deciphering genetic echoes from the distant past can illuminate human history. But it also helps explain why some populations, like Latinos, who may be classified by medical researchers as a single group, display marked differences among populations in susceptibility to diseases or responses to therapeutic drugs.

If you’re into history, the findings are fascinating. For example, the research shows that the Caribbean islands were first populated about 2,500 years ago by people from inland South America, and it indicates that the European component of the Caribbean gene pool was likely contributed by relatively few individuals who settled in the islands (subsequent waves of European immigrants came primarily to the mainland of the Americas). But geneticists and clinicians are also paying close attention to studies such as these. As Moreno-Estrada told me:

All this affects what we call a genetic-mapping strategy to identify disease variants specific to population subgroups. For example, those individuals with more European influence may be at increased risk for certain diseases because that genetic contribution was made by only a few individuals. Or, perhaps Caribbeans with more African ancestry may share an increased risk of diseases with others from West Africa. We’re not yet at the point where we are able to say which populations are most likely to have specific diseases, but now we can begin to figure out the important components.

Previously: On the hunt for ancient DNA, Stanford researchers improve the odds, Stanford study investigates our most recent common ancestors and Recent shared ancestry between Southern Europe and North Africa identified by Stanford researchers
Photo by Navin75

Recently there have been intriguing suggestions that breast cancer patients whose tumors appear insensitive to a class of drug known as anti-HER2 (the drug trastuzumab, marketed as Herceptin, is a well-known example) may somehow still benefit from treatment with the medication. Although there’s an ongoing clinical trial to determine if trastuzumab, given in combination with other treatments, really is beneficial to more patients than previously thought, the reason why it could be helpful is unknown.

Now research from the laboratory of Stanford radiation oncologist Max Diehn, MD, PhD, has started to answer some of these questions. The research was published recently in Cancer Research.

Typically, only tumors in which the cells express abnormally high levels of a receptor molecule on their surface called HER-2 — about 25 percent of all breast cancer cases — seem to shrink in the presence of the drugs, which bind to and inactivate the receptor. As a result, only these patients are given anti-HER2 agents. As Diehn explained in an e-mail:

Trials of anti-HER-2 agents like Herceptin in metastatic patients with HER-2 negative tumors haven’t shown tumor shrinkage or improved outcomes, which is why these drugs are only approved for use in HER-2 positive tumors. However, more recent clinical analyses have indicated that patients with microscopic disease remaining after treatment for earlier stage disease may see improved survival from anti-HER-2 agents regardless of their HER-2 status.

Diehn and Cleo Yi-Fang Lee, PhD, wondered why this could be. How could trastuzumab and other anti-HER-2 agents effectively fight tumors that didn’t overexpress HER-2? They hypothesized that perhaps the drugs were targeting only a few very important cells in the tumor: the cancer stem cells. Also called tumor initiating cells, or TICs, cancer stem cells are able both to renew themselves and to generate all the cells of the original tumor. Killing them is vital to ensure that a tumor does not recur after seemingly successful treatment with chemotherapy, radiation or surgery. Unfortunately, however, these cancer stem cells are uncommonly resistant to normal cancer therapies. According to Diehn:

Our hypothesis was that the clinical observations described above could be explained if the anti-HER2 drugs work against microscopic deposits of cancer stem cells in at least a subset of HER2-negative tumors. Patients with visible metastatic disease do not show responses since only a small proportion of cells in tumor deposits are cancer stem cells. However, if most of the tumor has been killed or removed through standard approaches, anti-HER-2 drugs may effectively target remaining cancer stem cells and possibly prevent recurrence.

To understand how this could occur, Diehn, Lee and their colleagues studied mouse and human breast cancer cells. They learned that, in a subset of HER-2-low tumors, the stem cells produce high levels of a molecule called neuregulin 1. Neuregulin 1 works by activating HER-2 in these cancer stem cells to promote their growth and self-renewal. Blocking HER-2 or another molecule in the pathway, EGFR, together or separately inhibited the growth of breast cancer cells grown in the laboratory and after transplantation into mice. It also made the stem cells more sensitive to the types of radiation used in cancer therapies.

The researchers hypothesize that a similar mechanism may exist in other types of cancers. Diehn said:

Anti-HER2 therapies are already being used for esophageal and gastric cancers and they have been explored for use in other cancers like those of the head and neck. It will be interesting to see if there is a similar dependence by cancer stem cells on HER2 signaling in the absence of HER2 amplification in some of these tumors.

Previously: Weakness in lung cancer stem cells identified by Stanford scientists and Red Sunshine: One doctor’s journey surviving stage 3 breast cancer
Photo by Tips Times

It’s a huge responsibility (and a privilege) to write about someone’s life after they have died; I inevitably come away wishing I had known the subject personally. That’s how I felt when writing about Leonard Herzenberg, PhD, who died last week. He was a scientific giant and a passionate advocate for those less fortunate than himself, and he and his wife of 60 years, Leonore Herzenberg, collaborated scientifically at Stanford for five decades.

From the obituary:

“Len was a valuable and treasured member of our Stanford Medicine community for more than 50 years,” said Lloyd Minor, MD, dean of the medical school. “He was a kind, thoughtful and just person eager to share scientific discoveries and opportunities with his friends and colleagues, and to improve access to education and career-advancement opportunities to women and disadvantaged youth. FACS technology made possible the birth of modern immunology, stem cell research and proteomics, and significantly advanced the clinical care of people with diseases such as cancer and HIV infection. Len’s scientific accomplishments are prodigious. But it is his commitment to helping others that will be his enduring legacy.”

Over and over again I heard words like “warm,” “welcoming” and “remarkable” while writing this article. And, although I had worked with Len Herzenberg in the past (most notably in 2006 when he was awarded the Kyoto Prize), I didn’t realize the extent of his sense of fairness and responsibility to others. From the article:

Herzenberg was well known for his pursuit of social justice, his desire to help those less fortunate then himself and his warm and welcoming demeanor. He donated the money accompanying his Kyoto Prize to nonprofit organizations working to improve health, human rights and education.

And:

[The Herzenbergs] encouraged minority teenagers to pursue a college education by establishing a program to bring high school students from East Palo Alto to Stanford to learn about medicine, biology and the multiple benefits of higher education. In addition, from the 1960s onward, Leonard Herzenberg conducted a behind-the-scenes campaign to expand career advancement opportunities for women in immunology and in science in general.

Please feel free to leave your thoughts and remembrances about Len Herzenberg, or messages to his family, on our online guestbook. The family requests that, in lieu of flowers, donations in Len’s memory be made to the Len and Lee Herzenberg endowed fund at the Stanford School of Medicine. Gifts may be sent to Stanford Medical Center Development, 3172 Porter Drive, Suite 210, Palo Alto, CA. 94304, or made online. Plans for a memorial service will be announced at a later date.

Photo by Steve Gladfelter