Stem Cell Clinic

Transplant for Szary Syndrome is Patient’s First Step in Returning to the Dance Floor – Dana-Farber Cancer Institute

The first time Bill Cronin Googled his own cancer diagnosis in 2016, his heart sank. He had Szary syndrome, a rare and aggressive form of cutaneous T-cell lymphoma and staring back at him were countless articles predicting a negative prognosis.

However, after receiving a stem-cell transplant at Dana-Farber/Brigham and Womens Cancer Center, Cronin is returning to the life he enjoyed before cancer.

Im at a place I never thought Id get to, Cronin says.

In 2015, Cronin, then 60, started feeling incredibly itchy and developed an accompanying rash. He went to his dermatologist, who diagnosed him with eczema and told him to return in five months. The rash continued to grow, however, and at the five month mark, Cronins dermatologist encouraged him to undergo further testing at Dana-Farber.

A blood test revealed that Cronins T-cells a type ofwhite blood cells that make up part of the immune system had becomecancerous. In the case of Szary syndrome, lymphoma cells will circulatethrough the blood stream and deposit in different areas of the skin. This willgenerally lead to a full-body rash and intense itchiness.

Cronin would need a stem cell transplant to combat the disease, but before he could receive one, his care team had to get him into remission. Patients who do not achieve remission prior to transplant have a high chance of relapsing.

When they first told me everything, I was really scared, says Cronin. But I knew I was in one of the best places in the world to figure out and treat this rare disease.

Cronins pre-transplant care was spearheaded by oncologists David Fisher, MD, and Nicole LeBoeuf, MD, MPH, clinical director of Cutaneous Oncology at Dana-Farber, with his transplant conducted by Corey Cutler, MD, MPH, medical director of the Adult Stem Cell Transplantation Program at Dana-Farber. Initially, Cronins disease was incredibly resistant; for nearly three years, mainstay drugs including steroids, monoclonal antibodies, and enzyme blockers all failed to put his disease into remission.

Ultimately, it would take a new drug, mogamulizumab (a type of immunotherapy that directly kills T-cells involved with Sezary Syndrome) to get Cronins disease into remission.

In May 2019, Cronin was cleared to undergo an allogeneic transplant, a type of transplant that uses a donors stem cells, in this case, Cronins brother. Since his transplant Cronin has remained in remission.

We had to use all of our big guns to get him totransplant, but Im pleased with where we are now, says Cutler.

I know the situation can always change, but it was great tobe able to share some good news with my family and friends, adds Cronin.

Patients like Cronin serve as a reminder of how stem cell transplants have improved and continue to impact patient outcomes, Dana-Farber experts note. Initially offered to only an incredibly small patient population when first performed at Dana-Farber in the 1970s, research advancements have, and continue to, broaden who is eligible for a transplant. In 2019, Dana-Farber/Brigham and Womens Cancer Center (DF/BWCC) surpassed 10,000 total adult transplants.

This milestone indicates our success as a program and our volume has allowed us to do the research to help move the field forward rather impressively, says Joseph Antin, MD, chief emeritus of Adult Stem Cell Transplantation at DF/BWCC.

In 1996, Dana-Farber Cancer Institute and Brigham and Womens Hospital merged their then separate transplant centers. By pooling together physical and intellectual resources, the new combined program was able to more than double the number of transplants each hospital could perform individually.

We always felt collaboration was better than competition, explains Robert Soiffer, MD, vice chair of Medical Oncology for Hematological Malignancies and chief of the Division of Hematologic Malignancies, who oversaw the merger with Antin. Each side could learn from the other, and that helped to catapult us into the leadership position we have today.

The Stem Cell Transplantation Program is also bolstered by the Connell and OReilly Families Cell Manipulation Core Facility (CMCF), which was established in 1996. The state-of-the-art center, led by Jerome Ritz, MD, not only processes the stem cells for transplant; it also assists researchers in developing new cell-based therapies for patients.

Another key component to the programs success has been the creation of the Ted and Eileen Pasquarello Tissue Bank. The Pasquarello Tissue Bank receives, processes, banks, and distributes research samplesof blood, bone marrow, and other tissues. Through a database overseen by Vincent Ho, MD, the Institute is able to log, assess, and later review every patients disease, including all complications and mutations. This technology allows researchers to explore the genetic makeup of past donors and better understand why a transplant was or was not successful.

Were still learning from biological specimens we collected 20 years ago, and it will continue to impact care 20 years from now, Soiffer says.

Today, there is a continuous push to develop new and more precise therapies to complement and improve stem cell transplants. The hope is to bring new treatment options to patients like Cronin who are facing rare and difficult diseases.

Before his diagnosis, Bill, and Barbara Finney, his partner ofnearly 30 years, were avid English Country dancers. English Country dancingevolved from the court dances of Europe in the early 17th century, and Croninand Barbara have friends from all over the country who share their passion forit.

While Cronin isnt dancing just yet, as hes stillrecovering from his transplant, he says he couldnt have gotten through thiswithout his partner on the dance floor and in life.

Barbara has been amazing and has helped take care ofeverything I couldnt do, he adds. Ive been fortunate and privileged to notonly have her, but to have been able to come to Dana-Farber.

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Transplant for Szary Syndrome is Patient's First Step in Returning to the Dance Floor - Dana-Farber Cancer Institute

Eternal youth and good health from stem cells soon within reach? – Innovation Origins

Could one of humankinds wildest dreams eternal youth and eternal good health perhaps come true after all? Well, were probably not quite there yet. But a new discovery in stem cell research may well constitute a step in this direction. Researchers led by biologist Vlad Cojocaru from the Dutch Hubrecht Institute, together with colleagues from the Max Planck Institute in Mnster, Germany, have discovered how normal human cells can be transformed into stem cells.

Differentiation between cell types is based on whether the DNA is read or not read at a specific point in time. Here, proteins known as transcription factors send the signal to read DNA in the cell or to halt the process of reading. Identity transformations, whereby cells move from an undesignated cell type to a designated cell type, occur naturally during development. However, these transformations can also be reversed. Japanese researchers were awarded the Nobel Prize in 2012 after they succeeded for the first time in reverse engineering a normal skin cell back to a stem cell.

However, it is not yet fully understood how this transformation of a skin cell into a stem cell takes place on a molecular level. A thorough understanding of the processes involving atomic details is essential if we are to produce such cells reliably and efficiently for individual patients in the future, says research leader Vlad Cojocaru. It is assumed that these types of artificially produced cells could in future be part of a remedy for diseases such as Alzheimers and Parkinsons. But the production process would have to become more efficient and predictive.

A key role in stem cell formation is played by a protein known as Oct4. This triggers the activity of the proteins that reset the adult cell as a stem cell. These genes are located in the same structure that stores the DNA in the nucleus the chromatin and are no longer active in the adult cells. Known as a pioneer transcription factor, Oct4 contributes to the opening-up of the chromatin and hence facilitates gene expression.

The study data reveals how the binding of Oct4 to DNA on the nucleosomes works. We have modelled Oct4 in various configurations, explains Cojocaru. The molecule consists of two domains, only one of which is capable of binding to a specific DNA sequence on the nucleosome at this stage of the process. With our simulations, we have been able to find out which of these configurations are stable. And how the dynamics of the nucleosomes influences the binding of Oct4. The models have been validated by experiments carried out by our colleagues Caitlin MacCarthy and Hans Schler in Mnster.

More IO articles on stem cell research here.

It was the first time that computer simulations were able to show how a pioneer transcription factor binds to nucleosomes that opens up the chromatin and regulates gene expression. Cojocaru explains that this computational approach for acquiring Oct4 models could also be used to screen other transcription factors and find out how they bind to nucleosomes.

In the following step, Cojocaru plans to fine-tune the current Oct4 models in order to find a definitive structure for the Oct4 nucleosome complex. We have known for almost 15 years that Oct4, together with three other pioneering factors, transforms adult cells into stem cells. But we still dont know how they work. The scientist emphasizes that the experimental structure definition for such a system is extremely expensive and time-consuming. Thats why he and his colleagues hope to use computer simulations in combination with a range of laboratory experiments to get a definitive model for the binding of Oct4 to the nucleosome. We hope that our definitive model will enable us to pioneer the development of transcription factors for the efficient and reliable production of stem cells and other cells required in regenerative medicine.

Results of the study were published in the Biophysical Journal.

Title photo: The pioneer transcription factor Oct4 (blue) binds to the nucleosome {a complex of proteins (green) and the DNA wrapped around these proteins (orange)}. Jan Huertas and Vlad Cojocaru, MPI Mnster, Hubrecht Institute.

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Eternal youth and good health from stem cells soon within reach? - Innovation Origins

How do body parts grow to their right sizes? – The Week Magazine

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Living things just seem to know how big to grow and how big to grow their sundry parts. A human liver maintains itself at just the right volume to do its job. A fruit fly's wings, on opposite sides of its body, somehow wind up the same size as each other, correctly scaled to sustain flight.

In everyday life, we expect body parts to be in proportion, because they usually are. "You notice if somebody comes up in front of you and one leg is way bigger than the other," says Ben Stanger, a gastroenterologist and researcher at the University of Pennsylvania's Perelman School of Medicine, who has studied organ growth.

But as much as we take this basic aspect of life on Earth for granted, scientists don't fully understand it. How do body parts know when to start and stop growing?

In some cases, cells seem to follow an intrinsic program carried out by the activity of their genes. At other times, cells appear to react to a cacophony of messages they receive from other cells and their environment, turning growth on and off as needed.

A lot of times, they seem to do a little of both. And when they're cancer cells, the whole business has gone awry.

"We don't get it," says Stanger, author of a 2015 article in the Annual Review of Physiology that described mechanisms that control liver growth.

Starting with salamanders

Scientists have been trying to "get it" for a long time. In the 1930s, Yale zoologists Victor Twitty and Joseph Schwind conducted experiments in salamanders, cross-transplanting limb buds from a smaller species, Ambystoma punctatum, with those of a larger but closely related species, Ambystoma tigrinium. In some experiments, the researchers found that taking a limb bud from the small salamander and grafting it onto the larger salamander resulted in an animal with three large limbs and one small one (and vice versa). This suggests that "the information for size was embedded in that group of cells very early on and didn't care what was happening in the animal," Stanger says.

But Twitty and Schwind found in other experiments that nutrition an external regulator also affected limb size. "It's nature and it's nurture," Stanger says. "In biology, it's never either/or."

Developmental biologists soon discovered a variety of ways that organs and structures achieve their ultimate sizes. In one famous 1960s experiment, researcher Donald Metcalf implanted 6 or 12 fetal mouse spleens into individual adult mice whose own spleens had been removed. He found that each implanted spleen grew to a proportional fraction of the size of a normal adult spleen leaving the animal with a normal total amount of spleen material. This suggests that spleen tissue has a way of understanding how much of it there is in relation to the body, says Jamie Davies, an experimental anatomist at the University of Edinburgh in Scotland. But "really annoyingly," Davies says Metcalf also found that multiple thymus grafts implanted in an adult mouse behave completely differently: Each grows to its full adult size.

Decades later, Stanger found similar growth differences in the mouse liver and pancreas: Cells that give rise to the liver use environmental cues to determine how much the developing organ should grow, while those that form the pancreas follow an "autonomous trajectory" they always achieve a preprogrammed size, no matter what is going on around them.

Pumping the brakes on growth

Scientists have sussed out a reasonable amount of detail about some of the feedback-based programs that direct growth. A protein called myostatin, for instance, helps to suppress muscle growth. When the tissues get large enough to pump out a threshold amount, muscle cells stop growing. The molecular processes that dynamically regulate liver size seem to involve tissues in the gut: When levels of bile acid fall (a sign of reduced liver function), those gut tissues produce factors that disengage a brake on liver growth known as the Hippo pathway. As a result, growth kicks into gear allowing the liver to grow to its proper size. When bile acid levels rise to normal, Hippo comes back on, and liver growth turns off again. And so on.

The Hippo pathway is a super-popular subject of study today, both because of its job in regulating organ size and because of its potential role in controlling cancers. Many questions about it remain unanswered.

Mysteries also remain for cases where instructions for size are baked in, as seen in those early experiments with salamander limbs, says Laura Johnston, a geneticist and developmental biologist at Columbia University Medical Center. Labs are delving into a number of inputs that may play a role in directing cells to grow, from information about cell fates and cell organization that are hardwired in the DNA, to mechanical forces on tissues.

Johnston's own research, some of which she and her coauthors described in a 2009 article in the Annual Review of Cell and Developmental Biology, focuses on a phenomenon known as cell competition interactions that lead to the deaths of unfit or unneeded cells. It seems to play a role in stabilizing organ size. When researchers in her lab blocked cell-death mechanisms in the cells that give rise to fruit fly wings, they found that the bell-curve-shaped distribution of wing sizes normally seen in fly populations broke down. A larger-than-usual number of flies developed overly large wings, or overly small ones. It's as if, she says, "the precision of size regulation is lost if the cells can't do these competing interactions."

There's still much to learn out about the deceptively simple, fundamental questions of how an arm matches its corresponding limb or how a liver ends up just the needed size. But the questions have practical ramifications too. Many growth studies today, including myriad explorations of the Hippo pathway, are conducted in the service of understanding and treating cancers. "Researchers are saying, 'Look cancer is development gone wrong, and it's obviously growth-connected, so we really need to understand growth on its own,'" Davies says.

Also interested in organ growth are researchers who want to engineer tissues using stem cells. "There's always the worry that if you build something that will grow up inside the body," Davies says, "will it know when to stop?"

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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How do body parts grow to their right sizes? - The Week Magazine