Transplants

If there’s one single image that universally connotes death, it’s that of a skeleton. But in the living human body, bones are a beehive of activity that, at the cellular level, is as lively and intricate as any dance troupe could perform.

Within the hollows of the long bones dwells a spongy tissue called marrow, which hosts stem cells responsible for the production of both red and a variety of white blood cells. The latter are the warriors, messengers, sentries and medics that compose our immune system. White blood cells defend against microbial invaders and scour our bodies for suspicious cells showing signs of being cancerous. Without our immune systems we wouldn’t last a week.

Whether white or red, blood cells can become cancerous, giving rise to lymphomas and leukemias that, respectively, account for about 45,000 and 75,000 new cases annually in the United States. One effective method of treating these conditions is bone marrow transplantation. In this procedure, the patient’s own blood-forming stem cells are, as thoroughly as possible, wiped out, and then replaced with bone marrow from a donor. From the new bone marrow springs an entire new, cancer-free immune system.

There are two things to watch out for after a tranplant. The first is the possibility that not every single cancerous blood cell was destroyed. The second is the prospect that the new immune system, perceiving its new home in the patient’s body as foreign tissue, may turn its guns on the patient’s own organs - a condition called graft-versus-host disease, or GVHD.

The better the immunological match between donor and recipient, the smaller the chance of the recipient’s developing the unremitting, chronic, form of this syndrome (cGVHD). But when a male recipient gets bone marrow from a woman, there will always be a set of proteins produced from genes on the man’s Y chromosome that the immune cells from the female donor have never come across, says Stanford bone-marr0w-transplant researcher David Miklos, MD, PhD.

As I wrote in our release concerning Miklos’s recent discovery, just published in Proceedings of the National Academy of Sciences, of a blood-borne biomarker that predicts the onset of cGVHD after female-to-male bone marrow transplants, there’s a trade-off here that often justifies a male leukemia or lymphoma patient’s receiving marrow from a female donor:

While female-to-male bone-marrow transplants put the recipient at 40 percent higher risk of either acute or chronic GVHD than sex-matched transplants, they also reduce the male recipient’s risk of a cancer relapse by 35 percent. Cancer cells are, at heart, unstable and make all kinds of bizarre proteins, fragments of which they tend to display on their surface — a red flag to the immune system. The new immune system is therefore especially vigilant for cancerous cells that somehow survived the effort to destroy them, putting the patient at risk of a relapse.

Miklos has found that the presence of a very particular species of immune cell in the blood of men who’ve received marrow tranplants from women is a strong predictor of impending cGVHD. This early warning that the still asymptomatic condition is developing may may someday allow physicians to administer immune-suppressing drugs that nip cGVHD in the bud.

Previously: Cancer drug shortage implicated in relapses among young Hodgkin lymphoma patients, New leukemia study making waves and Stanford faculty and students launch social media campaign to expand bone marrow donor registry
Photo by Great Beyond

There were more than 1,800 lung transplants in the United States last year, and 190 of those occurred in California, according to data from the federal Organ Procurement and Transplantation Network. A recent story in the San Francisco Chronicle takes a closer look at the challenges facing lung transplant patients and explores why a significant number don’t live beyond the five-year mark, despite improvements in survival rates.

Erin Allday writes:

Only about 55 percent of patients survive five years after the transplant. Those rates are better at Bay Area hospitals, where about two-thirds of patients can expect to survive that long. Nationwide, only a third of patients live 10 years.

It’s unclear what, exactly, goes wrong after the first year. Most patients die of what’s known as chronic rejection, which causes the airways of the lung to deteriorate slowly. Doctors don’t yet know how to prevent or stop that process.

“I started doing (lung transplants) in the early ’90s, and it was really primitive then, and it’s gotten a lot better. All sorts of things have improved,” said Dr. David Weill, director of Stanford’s Center for Advanced Lung Disease. “But we haven’t solved the mystery of that slow loss of lung function.”

Previously: Regular exercise may boost lung transplant patients’ heart health, quality of life and Given a second chance, lung transplant patient moves forward with gusto

How do you catch a drug-safety problem before it trips you up in human trials? Try making a mouse with a human liver - or one close enough to human to predict what the drug you’re testing will do in a person.

A team led by Stanford pharmacogenomic expert Gary Peltz, MD, PhD, in a study just published in the Journal of Pharmacology and Experimental Therapeutics, designed and used just such mice to show precisely how a compound showing promise for fighting HCV (the virus responsible for hepatitis C) would be metabolized in people. Not only that, but these ‘humanized’ mice accurately predicted how the compound would interact with another, already approved HCV drug in human subjects. (With more than 30 percent of all people over age 57 taking five or more prescription drugs at any given time, drug-drug interactions are a serious concern.)

The liver is the body’s chemistry set. In this hardworking organ, batteries of enzymes (molecular machines that do most of the body’s chores) operate in careful sequences like workstations of an assembly line. Together, they manufacture myriad substances and modify existing ones. They also constitute the body’s front-lne detox unit, metabolizing potentially poisonous ingested substances. That includes drugs we consume for medical purposes.

Metabolites - the products of metabolism - can themselves be bioactive, for better or for worse. “It’s often not the drug itself, but one of its metabolites, that is responsible for a drug-induced toxicity,” Peltz told me when I interviewed him for the release I wrote on the new study. So drug developers rigorously test their drugs in animals, typically starting with mice, before moving into clinical trials.

But mice metabolize things differently from humans, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen safety problems, said Peltz. Another big problem is those unanticipated interactions between a new drug a person takes and any other drugs that person may already been taking.

The drug tested in the study, clemizole, is an old antihistamine widely prescribed in the 1950s and 1960s but left on the shelf when newer drugs came along. Stanford HCV authority Jeff Glenn, MD, PhD, has resurrected clemizole after observing that it impedes the virus’s replication. The new study advances clemizole’s prospects for development, because what the drug appears to do in human liver tissue is just what the doctor ordered.

Previously: Hepatitis C virus’s Achilles heel, Immunology escapes from the mouse trap
Photo by primeperry

Neural stem cells get plenty of good press, and understandably so. They’re the matriarchal cells of the brain, from which spring all except one type of cell populating our most highly regarded (at least by itself) organ. They can remain in their primordial state for decades, languidly dividing just enough to replace their own numbers. Alternatively, they can spawn daughter cells that depart from the primordial state.

It’s the matriarchs’ daughters - so-called neural progenitor cells - that embark on committed differentiation pathways giving rise to nerve cells and other key brain cells. Given that lofty ambition, it’s not surprising that neural progenitor cells divide much more rapidly than their parents do, outnumbering neural stem cells probably by 1,000 to 1 or more.

It turns out that neural progenitors can do more than breed. They’re excellent managers, too. In a new Nature Neuroscience study that I describe in this news release, Stanford neuroscientist Tony Wyss-Coray, PhD, and his colleagues demonstrated that neural progenitor cells squirt out substances regulating the behavior of the one type of brain cell that doesn’t call them grandma.

Microglia, which trace their lineage to the immune system, are a combination police force, clean-up crew, and nursing team. They can migrate toward the sites of brain injury, put out chemical signals, and gobble up detritus, microbes, or dead or dying cells. As I note in my release:

Microglia normally are distributed throughout the brain - rather small, quiescent cells sprouting long, skinny projections that meekly but efficiently survey large areas that, taken together, cover the entire brain. But if this surveillance reveals signs of a disturbance, such as injury or infection, the microglia whirl into action. They begin proliferating and their puny bodies puff up, metamorphosing from mild-mannered Clark Kent-like reporters to buffed Supermen who fly to the scene of trouble, where they secrete substances that can throttle bad actors or call in reinforcements. Within these activated cells, internal garbage disposals called lysosomes form in large numbers and start whirring, ready to make mincemeat out of pathogens or cellular debris.

Wyss-Coray’s group showed, in rodents, that specific factors secreted by neural progenitor cells get microglia pumped. The discovery is significant considering that in the two places in the adult mammalian brain (including the human variety) where neural stem and progenitor cells reside, they’re typically closely associated with an entourage of microglia.

Now we know who’s boss. And we may have a clue about why stem-cell transplants seem to improve brain function, even though the stem cells don’t actually engraft very well.

Previously: Old blood + young brain = old brain, Could stem cells help brain-cancer patients regains cognitive abilities? and Unsung brain-cell population implicated in variety of autism
Photo by minijack3

Speaking of the Nobels, Alvin Roth, PhD, a Stanford alum and visiting professor who will become a full Stanford faculty member at the start of 2013, and Lloyd Shapley, PhD, a professor emeritus at UC-Los Angeles, have been named winners of the 2012 Nobel Memorial Prize in Economic Sciences.

An article in today’s Stanford Report highlights the health-care applications of Roth’s work:

The Royal Swedish Academy of Sciences cited the researchers’ contributions to “the theory of stable allocations and the practice of market design” in naming them for the $1.2 million prize.

Roth… is a pioneer in the field of game theory and experimental economics and in their application to the design of new economic institutions. As one of the first “microeconomic engineers,” Roth has redesigned the market for kidney exchange, the organization that matches medical residents with hospitals, public school choice systems and a variety of other institutions.
…

Roth’s design of the New England Program for Kidney Exchange represents [one example of a] large-scale, practical application of matching theory. In many cases, a healthy person would like to donate a kidney to a friend or loved one, but is medically incompatible. With paired kidney donation, however, that incompatible donor-recipient pair can trade their kidney to another mutually incompatible pair, while obtaining the kidney they need in return. The practice greatly increases the number of compatible kidneys available to a patient.

A press conference with Roth will be held at Stanford at 10 AM Pacific time and will be streamed live on the university’s YouTube channel.

Previously: Memorable moments from Brian Kobilka’s Nobel win captured on Storify, Image of the Week: Nobel Laureate Brian Kobilka celebrates with colleagues and friends, A busy morning for Nobel Laureate Brian Kobilka and Stanford’s Brian Kobilka wins 2012 Nobel Prize in Chemistry
Photo by L.A. Cicero

Last week we wrote about the emotions surrounding pediatric heart transplants. In a piece on Well today, a transplant doctor provides a first-hand account of what happens before and after transplant surgery - and shares his own emotions involving the heart’s origin:

Coordination and timing of a heart transplant could become an Olympic event, involving at least two teams at two hospitals – a harvest team and a donor team — each with a different set of objectives. I will make at least 10 calls before I get to the hospital. Dozens of people on our transplant team will be alerted: cardiologists, nurses, anesthesiologists, surgeons, intensivists, perfusionists. As is customary, we send our own team of surgeons to pick up the heart. Other transplant teams may also be involved, sending their own sleep-deprived surgeons in to harvest the lungs, liver or kidney.

The donor story is always horrible. The children frequently succumb to trauma, terminal illness or, perhaps most tragic of all, child abuse. The donor stories stay with me, and lately I have stopped asking how the child died. I cannot forget the father who, backing out of his driveway, accidentally ran over his child. My children still don’t understand why, whenever they are playing basketball in our driveway, I make them stop and line up where I can see them before I pull my car out.

Previously: Pediatric social worker discusses the emotional side of heart transplants and One family – and five children with same serious heart disease

It’s difficult to imagine having a seriously ill child - let alone five of them. But for a couple in Oregon, this is their reality: Each of their five children suffers from dilated cardiomyopathy or symptoms that can lead to the condition.

NBC got word of the story this summer and is now following the family as 8-year-old Lindsey Bingham awaits a heart transplant at Lucile Packard Children’s Hospital. (The eldest Bingham child, Sierra, had a successful transplant here six years ago.) Reporter Sandy Cummins recently blogged about the family and had this to say of her initial visit with them:

The Binghams are an impressive family. As we dined in the hospital cafeteria, I was struck by Stacy Bingham’s patience with her other kids, her sense of calm, and by Jason’s laser focus on helping his children. Megan, 11, asked lots of great questions about the production process. They’re not attention-seekers and agreed to be interviewed for two reasons: In the hope that it will help their children and that it will inspire people to become organ donors.

Two days after meeting the Binghams, I was back at the hospital, this time with Keith Morrison, a TODAY show producer and a camera crew. I was struck by something Stacy said, how she described the way a person’s perspective changes when it feels like the clock of your life has been stopped by a medical crisis. She talked about leaving the hospital briefly one day to pick up something she needed from a nearby mall. “It’s almost a Twilight Zone when you walk through the shopping center and there’s people going about their daily lives like what color of shoes should I buy today to match this purse. It just seems so ironic because just [across the street there are] families that are worried and sick and suffering and aching for the health of their child to be better.”

NBC plans, Cummins writes, to continue monitoring the family and telling their story as they go through the transplant process.

Photo courtesy of Lucile Packard Children’s Hospital

Mary Burge is a pioneer in a field many people have never heard of: For the last 30 years, she has been a pediatric heart transplant social worker at Lucile Packard Children’s Hospital. She started at the very beginning, assisting the family of a two-year-old who was the first young child to get a heart transplant in 1984, and is a much-loved member of the team at the hospital’s Children’s Heart Center.

Burge, who is profiled in a fantastic story in the San Francisco Chronicle, usually meets families soon after they’ve gotten the news that their child will need a new heart. They may be frightened, overwhelmed with medical information, worried and exhausted. Often, they haven’t had time to think about - let alone meet - their immediate needs. That’s where Burge comes in. The Chronicle story describes her first interaction with 7-year-old transplant recipient Abi Morgan-Mendoza and her mom, Jazmin Mendoza:

Amid a barrage of doctors and nurses, Mary Burge, the hospital’s heart transplant social worker, entered Abi’s room. Abi hid from her.

“I was afraid she was going to give me a poke,” Abi said.

Instead, Burge brought an empty canvas tote bag for Jasmin Mendoza - for all the medical gear and paperwork she had already accumulated.

“Do you need a toothbrush?” Burge asked Mendoza. “Money for food? A bed at the hospital? Do you need underwear?”

Burge said she first tries to meet the most basic needs of families who have come from around the world seeking heart transplants. After that, she can begin to address more daunting questions: Does the family have medical insurance? A long-term place to stay near the hospital? Does the family have a phone? Reliable transportation? At least one adult who can care for the child and manage dozens of daily medications? If the answer to any of these questions is no, Burge jumps into action.

The California Institute for Regenerative Medicine today granted cardiothoracic surgeon Robert Robbins, MD, $20 million to lead a team of researchers in an investigation of the use of human embryonic stem cell-derived heart muscle cells in patients with end-stage heart failure, and $20 million to oncologist Judith Shizuru, MD, PhD, to develop an antibody-based method to deplete diseased or dysfunctional blood and immune stem cells in patients with severe combined immunodeficiency. In the video above, cardiologist and co-investigator Joseph Wu, MD, PhD, describes the research proposed in the first grant.

From our release:

“This will be first time anyone has implanted cells derived from human embryonic stem cells into a human heart,” said Robbins, professor and chair of cardiothoracic surgery and director of Stanford’s Cardiovascular Institute. “We’re excited to assess this potential treatment for patients who currently have very few options other than heart transplant.”

Robbins and his colleagues hope to move into human clinical trials within four years, after first testing the transplantation approach extensively in animal models. They plan to enroll about 10 patients in the proposed phase-1 trial.

The two four-year awards were part of CIRM’s second round of disease-team grants. All told, the agency awarded $150 million to eight teams. Stanford investigators received $57.1 million during the first disease-team award round in October 2009.

More from our release about the Shizuru award, which builds on previous work from Stanford’s Irving Weissman, MD:

The Shizuru grant focuses on the use of a monoclonal antibody previously tested in mice by Weissman’s group to remove, or deplete, diseased or dysfunctional blood and immune system stem cells in patients with severe combined immunodeficiency. Currently these cells must be killed by high-dose chemotherapy or radiation, a process that itself can be life-threatening, prior to transplantation with healthy donor cells. Shizuru and her collaborators plan instead to use an antibody that will specifically recognize and eliminate the faulty cells without the use of toxic treatments, enabling patients to more readily accept cells from a healthy donor.

If shown to be effective, the technique could potentially been used to treat many other types of diseases, including sickle-cell anemia and cancers of the blood cells such as leukemias and lymphomas.

A full list of CIRM-funded institutions and descriptions of the disease areas targeted are available on CIRM’s website.

Previously: Stem cell-based heart-attack therapy approved for clinical trials, Lab-made heart cells mimic common cardiac disease in Stanford study and Nature News examines CIRM’s public funding uncertainties

Organ transplantation is never simple, particularly when the procedure involves a living donor, and even more so when the transplant is being done on the liver. The liver is difficult to operate on, its consistency like that of wet tissue paper. There are also the added wrinkles: Among them, the living donor’s liver must be partitioned just right and surgeons must control bleeding in an organ that’s rich with blood vessels.

So, it’s not surprising that Stanford patient Judith Lattin, despite years of suffering from liver failure, was not thrilled at the idea of her younger sister donating a portion of her liver to save Lattin. It’s the role of a big sister to ensure that her little sister stay out of harm’s way, and Lattin had concerns about her sister, Christine Webb, undergoing such a risky and rare procedure. (Only a handful of hospitals in the U.S. even do the surgery.) In fact, when Webb first volunteered to help save her sister’s life, Lattin said “no.”

As you’ll see in the video above, Lattin put her faith in her sister’s decision and in her transplant team. The procedure was successful, returning Lattin to health and bringing the two sisters closer than they thought they’d ever be.

Lattin and Webb’s full story can also be found on Stanford Hospital’s website.