Researchers at Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute (HSCI) have identified a drug compound that arrests in mice the progression of acute myeloid leukemia (AML), a bone marrow cancer that has not seen a new therapy in four decades.

The research, led by David Sykes and David Scadden, co-director and director of the MGH Center for Regenerative Medicine, was published today in the journal Cell.

AML develops when blood stem cells and blood progenitor cells cannot differentiate into adult white blood cells, and instead get frozen in an immature state. Those immature cells take up space in the bone marrow and crowd out healthy cells, making it more difficult for the dwindling number of healthy blood cells to keep up with the demands of the body.

Current therapies are designed to kill the cancer cells using toxic compounds — namely intensive chemotherapy — that ultimately assault the body, wipe out the immune system, and leave patients vulnerable to what could be deadly bacterial and fungal infection.

Prospect of shorter treatment and cure for chronic myelogenous leukemia

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Prospect of shorter treatment and cure for chronic myelogenous leukemia

By Robert Levy, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center Communications | September 14, 2016 |
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Chemotherapy typically used to treat younger people “is much too harsh for older patients,” which is problematic given that the average age of an AML patient is 67, said Scadden, who is also a practicing hematologist.

To find an alternative, the researchers used an approach that turned one of the most deadly subsets of the disease, acute promyelocytic leukemia, into one of the most treatable forms. Rather than bludgeoning and killing the leukemia cells, the researchers searched for a compound that would encourage the cells to differentiate. When leukemia cells differentiate, they live only a short time and die as part of their natural biology.

Sykes, a postdoctoral fellow in Scadden’s lab, engineered mouse progenitor cells to glow green once they matured. The team, in collaboration with the Broad Institute of Harvard and MIT, performed a functional screen with 330,000 compounds and found a dozen that were able to make the cells turn green, indicating those compounds forced the cells to differentiate. Of those, 11 blocked a metabolic enzyme called DHODH, effectively forcing the cells into what the researchers called a period of fasting.

“Cancer cells are metabolically different from normal cells. Our results suggest normal cells can tolerate periods of fasting or starvation, while the cancer cells cannot. In this case, the fasting triggers a change,” said Sykes

After 10 weeks of treatment with a known DHODH inhibitor, mice with AML and mice with human leukemia cells gained weight, were active, had fewer number of leukemia stem cells, and lived longer, indicating a meaningful disease remission. Notably, no animal had disease progression on therapy. The researchers hope to test the inhibitor in a clinical trial.

“We need desperately to find new therapies,” not only for the 20,000 people diagnosed with AML every year, but for all cancers, said Scadden, the Gerald and Darlene Jordan Professor of Medicine and chair of the Stem Cell and Regenerative Biology Department. “We think that an approach to overcome the differentiation blockade of cancer may be a strategy with broad application and one we should explore for other cancer types.”

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Although targeted drugs like Gleevec have revolutionized the treatment of chronic myelogenous leukemia (CML), patients generally must take them for the rest of their lives and may cease benefiting from them over time. In new research that could suggest a road to a cure, scientists at Harvard-affiliated Dana-Farber Cancer Institute and Boston Children’s Hospital have found that CML stem cells die when a protein called Ezh2 is inhibited. Drugs that target the protein are currently in clinical trials for other cancers.

The findings, reported online today in the journal Cancer Discovery, raise the prospect that Ezh2 blockers, in combination with Gleevec and similar drugs, could eradicate the disease in some patients relatively rapidly or could be an effective therapy for those who become resistant to Gleevec-like agents, the authors write.

In a paper published simultaneously by Cancer Discovery, a team of Scottish scientists report similar findings using a different research approach.

“The vast majority of patients with CML do remarkably well on imatinib [Gleevec] and similar drugs: The disease is well-controlled and side effects are tolerable,” said Stuart Orkin, the study’s senior author and a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In only 10-20 percent of patients, however, are the leukemia cells fully cleared from the body. The other 90 percent retain a reservoir of leukemic stem cells — which initiate the disease — and must stay on the drugs permanently.”

CML is a slowly progressing type of blood cancer that develops in the bone marrow. Primarily occurring in adults, it is rare in children.

Over time, some patients develop resistance to Gleevec and other drugs that block BCR-ABL, the misbegotten “fusion” protein that drives CML growth. Although second- and third-line targeted therapies can often return the disease to remission, some patients don’t benefit from these drugs or develop severe side effects.

The new study grew out of efforts to discover whether different types of cancer are susceptible to Ezh2 inhibitors. In laboratory experiments, the Dana-Farber/Boston Children’s researchers found that not only is Ezh2 overabundant in leukemia stem cells, but it helps them survive and give rise to full-fledged CML cells. Follow-up studies in mice showed that inactivating Ezh2 through gene-editing techniques caused CML stem cells to die, halting the disease at its source.

“The stem cells’ dependence on Ezh2 suggests they will be especially vulnerable to drugs that target the protein,” Orkin said. “Such drugs are already in clinical trials for other diseases, including lymphoma and some solid tumors.”

Epizyme, a biopharmaceutical company based in Cambridge, Mass., recently opened a pediatric trial of an Ezh2 inhibitor for children with rhabdoid and other tumors. Dana-Farber/Boston Children’s is a site in the multicenter Phase 1 trial.

Although adding Ezh2-targeting agents to the standard drug regimen for CML has the potential to dramatically shorten the treatment period for many patients, ethical considerations may lead to the agents’ first being tested in patients who don’t respond to Gleevec and similar drugs, either initially or after drug resistance develops, Orkin said. “Our findings suggest inhibition of Ezh2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant.”

Joining senior author Orkin, the study’s lead author is Huafeng Xie of Dana/Farber/Boston Children’s. Co-authors are Cong Peng, Jialiang Huang, Bin E. Li, Woojin Kim, Elenoe C. Smith, Yuko Fujiwara, Partha P. Das, Minh Nguyen of Dana-Farber/Boston Children’s; Jun Qi of Dana-Farber; James E. Bradner of Dana-Farber and the Novartis Institute for BioMedical Research; Shaoguang Li of University of Massachusetts Medical School; and Giulia Cheloni of UMass Medical School and the University of Florence in Italy.

The study was funded in part by the National Institutes of Health and Hyundai Hope on Wheels.

Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, the nation’s top pediatric cancer center according to U.S. News & World Report, brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care at Boston Children’s Hospital and most outpatient care at Dana-Farber Cancer Institute.

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When it comes to developing test questions, there’s the ordinary way and the fancy way.

The ordinary way is to just make up questions and put them on the test. However, this can lead to questions that are misleading, confusing, or simply don’t test for the knowledge you’re trying to measure.

The fancy way takes a lot of possible questions, tries them out on students, and whittles them down to the most useful. But this process is both time-consuming and expensive.

A group of researchers at the Harvard-Smithsonian Center for Astrophysics (CfA) has found a way for schools, professors, textbook publishers, and educational researchers to check the quality of their test questions that turns out to be both fast and cheap. It invokes the power of crowdsourcing.

The problematic growth of AP testing

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The problematic growth of AP testing

By Rebecca R. Hersher ’11, Harvard Correspondent | September 3, 2010 |
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“Crowdsourcing opens up a whole new possibility for people creating tests,” says lead author Philip Sadler. “And instead of taking a semester or a year, you can do it in a weekend.”

The CfA group has had a long-standing program of developing methodologically rigorous tests for various sciences and grade bands. The researchers evaluate new multiple-choice questions in a two-step process. First, they conduct pilot testing of lots of questions, developed by content experts, on a large number of students. Then they conduct field testing on 1,000-2,000 students. Using statistical analyses, they select the best questions for the exams.

Sadler and his team investigated whether it was possible to replace the first step, pilot testing, with crowdsourcing. Crowdsourcing websites, such as Amazon’s Mechanical Turk, assign thinking tasks to a global community made up of people who receive small payments in return. For this study, the task of each participant was to answer a set of 25 multiple-choice life-science questions developed for middle-school students.

The team evaluated a total of 110 multiple-choice questions using both traditional pilot testing and crowdsourcing, and compared the results. Since the crowdsourcing participants were adults and pilot testing was conducted with a sample of the target population (middle-school students), the researchers wondered if the results would be similar. Perhaps surprisingly, the best test questions identified by crowdsourcing turned out to be high-quality questions for students too. Low-quality questions were poor for both adults and kids.

Sadler emphasizes that crowdsourcing can’t entirely substitute for studying the target student population when producing high-quality tests. However, by using it as an early step, questions can be quickly evaluated for deletion, revision, or acceptance. The questions that survive can then undergo more rigorous testing.

“The key to creating good standardized tests isn’t the expert crafting of every test question at the outset, but uncovering the gems hidden in a much larger pile of ordinary rocks,” says co-investigator Gerhard Sonnert. “Crowdsourcing, coupled with using commercially available test-analysis software, can now easily identify promising candidates for those needle-in-a-haystack items.”

A number of test developers could benefit from this new approach. For example, some schools are moving to standardize their exams and share them across the school system. Testing questions on their own students would let students know exactly what questions to expect on future exams. Crowdsourcing offers a low-budget alternative.

In addition, curriculum developers and textbook authors can rapidly test and refine the questions they include in their materials. Educational researchers will be able to produce questions that more effectively measure changes in student knowledge. And professional development programs that now have teachers produce assessment questions for their students can, overnight, measure the performance of those questions.

The journal Educational Assessment published the full results of the study. Besides Sadler and Sonnert, the authors include Hal Coyle of the CfA and Kelly Miller of the Harvard John A. Paulson School of Engineering and Applied Sciences.

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Brenden Whittaker woke in his room at Nationwide Children’s Hospital in Columbus, Ohio, drenched in sweat.

It was 3 a.m., and his mother, Becky Whittaker, watched as the nurse tried to take his temperature with an electronic thermometer, then left to fetch an old-style mercury one that registered higher.

It read 105.

“I really thought, ‘We’re going to lose him to this disease,’” Becky recalled. “‘He’s 16 years old, and he’s going to be one of the statistics.’ … He was so, so sick.”

The nurse helped Brenden change out of his sweat-soaked clothes before leaving the two alone in the dark of that too-early morning. Becky settled into the rocking chair next to the bed.

“He started talking to me about planning his funeral, where he wanted to be buried, what kind of funeral he wanted,” Becky said. “He said, ‘Mom, if you think I’m going to die, will you tell me? I’m begging you — you have to tell me if you think I’m going to die, if I’m not going to get better.’

“I looked at him and I said, ‘It’s going to rip me apart, but, yes, I’ll tell you. … I don’t think we’re there now.’”

That night in the fall of 2009 was a new low in the course of Brenden’s disease, a rare immune disorder called chronic granulomatous disease, or CGD. The condition affects a key component of the immune system, a type of white blood cell called a neutrophil that engulfs and kills invading bacteria and fungi.

Since his diagnosis as a baby, Brenden had taken regular preventive antibiotics to fight off infections before they started, gotten thrice-weekly interferon shots to boost his weakened immune system, and avoided activities that might bring him into contact with troublesome microbes. Despite that care, he’d been hospitalized repeatedly for surgeries to drain abscesses and for intravenous antibiotics to fight infections.

“[Over the years], I’ve had hundreds of procedures,” Brenden said. “I’ve had lung biopsies, bronchoscopies, endoscopies, had ingrown toenails removed. I’ve had all kinds of stuff like that.”

Despite his fears in the hospital that night, Brenden recovered, but it cost him the infected portion of his lung, which doctors removed, and his junior year in high school. Even then, the recovery wasn’t permanent. His next downward spiral began in 2014, and in April 2015 he had the left lobe of his liver removed, before spending most of August at Nationwide Children’s to treat another lung infection.

Today, though, Brenden’s lungs are clear and, for the first time in his life, roughly half of his neutrophils are functioning — enough, doctors say, to keep him well. Now 23, he is working again, part time at a golf course near his home in Ohio, and cautiously looking forward to college in 2017 — if his health holds out.

The sea change came after Brenden received an experimental gene therapy treatment in December at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, a collaboration of Boston Children’s Hospital and the Dana-Farber Cancer Institute. This phase I trial, intended to test the procedure’s safety, is being conducted at three centers around the country and is led in Boston by David Williams, the Leland Fikes Professor of Pediatrics at Harvard Medical School (HMS), chief of hematology/oncology and director of clinical and translational research at Boston Children’s, and president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Williams has worked in the gene-therapy field since he was a postdoctoral fellow at Massachusetts Institute of Technology in the early ’80s.

“I’m thrilled we were able to get the trial opened so quickly and enroll our first patient,” Williams said. “I’m very thrilled everything has gone well so far.”

The trial is designed to progress in stages, so Brenden’s improved health cleared the way for a second patient to begin the same treatment, this time at the National Institutes of Health in Bethesda, Maryland. If all goes well with both patients, a third will undergo the procedure at the University of California at Los Angeles, where Donald Kohn is the chief investigator for the overall study. These three early patients will be closely monitored and, if there are no complications, more will be treated with the aim of moving to a broader, phase II trial. The ultimate goal is to create a new CGD treatment, which would be among the vanguard of new therapies based on altering a patient’s genetic code.

Where’s the bleach?

When chronic granulomatous disease was first recognized in 1950, little could be done to control the infections that plagued its sufferers, who rarely lived past 10.

“The disease was first called ‘fatal granulomatous disease,’ which gave a good impression of what happened. Prior to good antibiotics … the disease was fatal,” said Stuart Orkin, the David G. Nathan Professor of Pediatrics at HMS and who is affiliated with the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Orkin has studied the genetics of CGD for decades.

Over time, doctors learned the lesson they would apply in Brenden’s case: that the way to keep someone with CGD alive is not to let them get sick in the first place.

Though modern antibiotics have made CGD a manageable disease, control can be imperfect. Life with CGD is marked by repeated infections, large and small, and regular inpatient hospital stays to fight the worst flare-ups. Patients develop granulomas — the body’s efforts to wall off infections it cannot defeat — which cause problems of their own, blocking digestive tracts and other critical passages.

CGD affects about 1,500 people nationwide and has two major variants. A patient can inherit both copies of a defective gene from his or her parents or, as in Brenden’s case, because the defective gene is carried on a mother’s X chromosome, and boys have only one X chromosome, only one copy can cause disease.

In the body, the defective gene upsets the killing chemistry that occurs inside healthy neutrophils. These white blood cells engulf bacteria or fungi, triggering a series of chemical reactions that ultimately produce hypochlorite, the active ingredient in common household bleach. The hypochlorite, produced in tiny quantities, kills the engulfed invader.

In the 1960s, a pediatric hematology/oncology fellow at Boston Children’s named Robert Baehner devised the first diagnostic test for CGD. Baehner went on to become a professor at Indiana University School of Medicine, where part of his continued impact on the field was training the leader of Brenden’s current gene therapy trial, Williams.

“I’m here today because I had such a wonderful mentoring experience with Dr. Baehner when I was a medical student,” Williams said. “I hadn’t done research before that, so this completely changed my career.”

Baehner also returned to Children’s years later on sabbatical to work with Orkin, bringing with him a tissue sample from a CGD sufferer.

In 1986, Orkin, working with colleagues searching for the muscular dystrophy gene — thought to be near CGD’s gene — used that sample to identify the CGD gene, pioneering a technique called positional cloning.

“Working together [with collaborators], we did a number of … things, using some logic, a little luck, good reagents,” Orkin said. “It was very challenging. The extent of what we knew about the genome … was like the Stone Age compared to today.”

Baby blues

Brenden Whittaker’s CGD revealed itself only gradually.

After a family trip to the beach at age 1, Brenden developed a grape-sized swelling on the right side of his face. Routine antibiotics didn’t work, and a mumps test came back negative, so the doctor drained the infection and sent a sample to the lab for testing.

Results brought more questions than answers. The infection was caused by a bacterium common in dirty water, Serratia marcescens, but one that a healthy immune system should be able to handle. That fall, when Brenden developed a strange, acne-like bump on his chin also caused by Serratia marcescens, it was apparent there was an ongoing problem.

The doctor quizzed Becky about her family history, looking for signs of immune dysfunction: Had anyone died young, died of infection?

“At first you’re like, ‘Well, no way this could be it. I can’t think of any child in my family with any issues or any problems like this,’” Becky said. “I grew up on a farm, shoveling out stalls with manure and whatnot, and I was never sick. But half of my white cells work.”

A DNA test of Becky’s blood was positive for CGD. So she and Brenden traveled to the National Institutes of Health, and saw Harry Malech, a CGD expert. He counseled them about Brenden’s careful way forward.

“It’s a really hard disease for a boy to have because, statistically speaking, more boys would prefer to be dirty than not,” Becky said.

Despite periodic trips to the hospital, Brenden was able to live an active life. His mother’s work as a transplant nurse ensured that someone knowledgeable about health and the health care system watched over him.

He played soccer and ice hockey, avoiding baseball, football, and their bacteria-laden dirt, dust, and grass. He backpacked with the Boy Scouts, packing all his water to avoid questionable sources on the trail. He demonstrated canoe and kayak skills in a pool’s clean waters.

But infection and illness were never far away. Pneumonia forced him to start kindergarten late and with an IV for antibiotics. In second grade, his small intestine was almost blocked by a granuloma, which stubbornly persisted until a cocktail of antibiotics, high-dose steroids, and other drugs did the trick. In sixth grade, he was back in the hospital with an ankle infection.

Brenda MacKinnon and Whittaker discuss his progress. Rose Lincoln/Harvard Staff Photographer
Whittaker discusses his progress with Pediatric Oncology RN Brenda MacKinnon. Rose Lincoln/Harvard Staff Photographer

But it was during 11th grade that things really went south. The “rip-roaring infection,” as Becky described it, settled in his lungs in September and held on. For months, the Nocardia bacteria shrugged off antibiotics until, finally, in March, surgeons removed the upper and part of the middle lobe of his right lung.

“The doctor who did the surgery brought the tissue out into the waiting room and showed it to us. He had developed a big granuloma around the Nocardia infection so the antibiotics were not going to get to it. They weren’t ever going to take care of the infection with no white cells to help them work,” Becky said. “[The year] 2009–10 was a terrible, terrible period of time. … You can’t just keep chopping away essential body parts when new infections occur.”

Brenden recovered, but had missed so much school that he repeated his junior year. By late 2014, he had graduated and started at a local community college when he got sick again. He would fight infections through much of 2015.

“I probably spent nine of 12 months of the year in the hospital. I had a granuloma in my urethra in January. I had the liver stuff kind of February through May. I had some recurring pneumonia in my right lung, or, actually, in both of my lungs,” Brenden said. “I spent the Fourth of July in the hospital and was discharged before my birthday in July. I was in the hospital by Aug. 2. I had a lung biopsy that started to bleed. I spent a week in the ICU in August, then I was admitted to the regular inpatient floor for three weeks following that, so I was in the hospital all of August. They assumed it was a fungal infection in my lungs. They never figured out what it was.”

Brenden’s doctor at Nationwide Children’s told them what had become apparent: Brenden was getting too many infections, having too many surgeries and, with so much antibiotic use, risking drug-resistant infections. They needed to explore other options.

Bone-marrow transplants can provide a source of healthy immune cells for CGD sufferers, but tests of family members and unrelated donors turned up no good matches. Finally, a specialist who had heard of Williams’ gene-therapy trial at Boston Children’s thought Brenden might be a good candidate.

“I had been so sick last year, I was willing to do anything not to be that sick anymore,” Brenden said.

Gene therapy

After a sputtering start, gene therapy has gathered momentum. Its promise was illustrated in 1990 when a 4-year-old girl named Ashanti DeSilva became the world’s first successful gene-therapy patient. The treatment did not cure the near-total immune dysfunction that Ashanti suffered, but nonetheless it pulled her out of danger, allowed her to enroll in school, and illustrated the merit of treating genetic diseases at their most basic level.

Progress stalled in 1999, when 18-year-old Jesse Gelsinger became the first person to die in a gene-therapy trial. Gelsinger, who had a genetic liver disease, had a massive immune reaction to the virus, called a vector, that was used to shuttle the corrected gene for his condition into his DNA.

“Gene therapy has had a number of setbacks along the way,” Orkin said. “Those setbacks probably have delayed things somewhat. … Each one of those steps takes five years to recover from … so it’s taken a long time.”

In 2008, researchers successfully treated Leber’s congenital amaurosis, which causes blindness. In 2010, a French patient was treated for beta-thalassemia major, a blood disease. In 2013 and 2014, children were treated for ADA-SCID, or “bubble boy syndrome.” Other trials have targeted hemophilia, the inherited eye disease choroideremia, HIV, sickle cell disease, and cancer.

Venture capital firms have taken notice of the progress, and money has flowed into gene therapy-based startups, a good sign, according to Williams — who, with colleagues at Boston Children’s and three other academic institutions in the United States and United Kingdom, recently started a gene therapy company — since such firms expect short-term returns that flow from clinical success.

“I think things are progressing,” Williams said. “You get a sense of that by the number of trials that are open, and you get a sense of that by the number of new companies that are starting.”

Though Brenden later admitted some apprehension at being the first to undergo the procedure, he agreed to the trial and traveled to Boston last November for screening tests. Physicians also extracted blood stem cells to freeze as backup in case the procedure went awry.

In early December, Brenden returned so doctors could take more blood stem cells, this time to be engineered for the trial at a cell-manufacturing facility run by Dana-Farber.

There, the cells were isolated and mixed with a virus containing a functioning copy of Brenden’s malfunctioning gene. The virus inserted the working gene into the cells’ DNA, creating a population of Brenden’s own stem cells with an extra gene. The hope was that these stem cells, which would be infused back into Brenden later that month, would develop into properly functioning white blood cells.

On Dec. 13, Brenden returned to Boston and the next day began a three-day, six-dose course of chemotherapy, which killed cells in his bone marrow to clear space for the new, engineered cells to take hold. On the 18th, the corrected stem cells were infused into his blood to begin their migration to the marrow.

Brenden doesn’t remember much of his nearly month-long stay, little of Christmas or college football’s Bowl season. The nausea after chemo was unforgettable, though, as were the sores in his mouth and the hair that was falling out.

Ohio State beat Notre Dame in the Fiesta Bowl. “I have been told I watched the game in my hospital room, and I asked a few days later when they were supposed to play,” Brenden said. “I didn’t know it was the new year for a week.”

He was discharged in early January, but stayed in Boston for outpatient checkups until the end of the month. At home in Ohio, he had three more months of forced inactivity while his immune system rebooted.

“I was definitely apprehensive about it before,” Brenden said. “Looking back now, I’m glad that I did it.”

In the months since, Brenden has resumed his old job at the local golf course, gone running, and played some golf himself. He’s also gotten regular checkups and taken periodic trips back to Boston.

The results have been encouraging, with one spring follow-up test showing nearly half of Brenden’s neutrophils working properly. That level is well above the trial’s target of 10 percent and enough for researchers to go ahead with a second patient.

“At 10 percent, our expectation is it will provide the person protection to make them essentially normal,” Williams said. “We’re not looking for partial protection, we’re looking for full protection. We think that will be the case.”

No promises

Gene therapy’s ultimate goal is to make a one-time fix, correct a genetic disease’s underlying cause, and let people get on with their lives.

In this case, however, Williams said it’s too early to talk about a widespread CGD cure. Though promising, this therapy is at the proof-of-concept stage. If it succeeds in additional trials, initially it would be reserved for the sickest patients — like Brenden — who are having difficulty managing their illness and aren’t good candidates for bone-marrow transplants. If the therapy proves itself over time, its use could expand to aid patients before serious complications develop.

“It’s very, very early, of course,” Williams said. “It’ll be an evolution with time, of a broadening indication, if everything goes well.”

For Brenden, if all goes well he’ll be back in school in January. He plans to return to community college with an eye to transferring to Ohio State, and perhaps medical school after that.

For his mother, each encouraging neutrophil count is exciting, but experience has taught her caution.

“I don’t think Brenden and I are under any illusions that this is a cure,” Becky said. “People ask what I’ll do with the time [if Brenden stays healthy]. There are things I’d like to do, but I’m cautious about starting them because part of me is wondering when the other shoe is going to drop and what it will be when it does.

“I tried to think about how I’d feel if at some point this isn’t working, the cells reverting to their defective ways. I can’t predict how I’ll feel when that happens, so I just dwell on each measurement and, OK, this is just another period of time when the measurement is good. Let’s just go about what we’re doing. I think that’s just about all we can do.”

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Some loss of memory is usually considered an inevitable part of aging, but new research reveals how some people appear to escape that fate. A study by investigators at Harvard-affiliated Massachusetts General Hospital (MGH) examined a group of older adults with extraordinary memory performance and found that certain key areas of their brains resembled those of young people.

The study, published in the Journal of Neuroscience, is the first step in a research program aimed at understanding how some older adults retain youthful thinking abilities and the brain circuits that support those abilities. The program is led by two senior authors of the new study — Bradford Dickerson, a Harvard Medical School (HMS) associate professor of neurology and director of the Frontotemporal Disorders Unit in the MGH Department of Neurology, and Lisa Feldman Barrett of the hospital’s Department of Psychiatry.

While most older adults experience a gradual decline in memory ability, some researchers have described “super-agers” with unusually resilient memories. For the new study, the investigators enrolled 40 adults ages 60 to 80 — 17 of whom performed as well as adults four to five decades younger on memory tests, and 23 with normal results for their age group — and 41 adults ages 18 to 35.

“Previous research on super-aging has compared people over age 85 to those who are middle-aged,” said Alexandra Touroutoglou of MGH neurology and HMS, who co-authored the research with Dickerson and Barrett. “Our study is exciting because we focused on people around or just after typical retirement age — mostly in their 60s and 70s — and investigated those who could remember as well as people in their 20s.”

Imaging studies revealed that super-agers had brains with youthful characteristics. While the cortex — the outermost sheet of brain cells that is critical for many thinking abilities — and other parts of the brain typically shrink with aging, in the brains of super-agers a number of those regions were comparable in size to those of young adults.

“We looked at a set of brain areas known as the default mode network, which has been associated with the ability to learn and remember new information, and found that those areas, particularly the hippocampus and medial prefrontal cortex, were thicker in super-agers than in other older adults,” Touroutoglou said. “In some cases, there was no difference in thickness between super-agers and young adults.”

Barrett, who is also University Distinguished Professor at Northeastern University, added: “We also examined a group of regions known as the salience network, which is involved in identifying information that is important and needs attention for specific situations, and found preserved thickness among super-agers in several regions, including the anterior insula and orbitofrontal cortex.”

Critically, the researchers showed not only that super-agers had no shrinkage in these brain networks but also that the size of these regions was correlated with memory ability. One of the strongest correlations between brain size and memory was found in an area at the intersection of the salience and default mode networks. Previous research has shown that this region — the para-midcingulate cortex — is an important hub that allows different brain networks to communicate efficiently.

“We believe that effective communication between these networks is very important for healthy cognitive aging,” said Touroutoglou.

Understanding which factors protect against memory decline could lead to important advances in treating age-related memory loss and possibly even various forms of dementia, said Dickerson.

“We desperately need to understand how some older adults are able to function very well into their seventh, eight, and ninth decades. This could provide important clues about how to prevent the decline in memory and thinking that accompanies aging in most of us.”

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