Author: Tom Ulrich

Science seen: Oral cancer up close

oral squamous cell carcinoma oral cancer lymphatic system cancer metastasis

Oral squamous cell carcinoma (OSCC), a kind of oral cancer, affects some 30,000 Americans annually. It spreads through the lymphatic system and often has already metastasized by the time it’s diagnosed. The top image here is a healthy mouse tongue; the bottom is the swollen tongue of a mouse with OSCC. The cancerous tongue is overloaded with lymphatic vessels, appearing in blue and white, which help the tumor spread to the regional lymph nodes. The Bielenberg lab in Boston Children’s Hospital’s Vascular Biology Program is studying ways of blocking the progression of this and other cancers by inhibiting their spread through the lymphatic system. (Image: Bielenberg laboratory/Kristin Johnson)

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Pediatric cancers and precision medicine: The feasibility question

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What is precision cancer medicine all about? See the full infographic at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

A family walks into their oncologist’s office and sits down. Their son’s care team is there, ready to discuss the sequencing report they received about the tumor in his leg.

“We think we have something,” the oncologist says. “We found a known cancer-associated mutation in one gene in the tumor. There’s a drug that targets that exact mutation, and other children and adults whose tumors have this mutation have responded well. We’ll have to monitor your son closely, but we think this is a good option.”

This hypothetical conversation, while common in adult oncology, happens rarely (if at all) on the pediatric side. This kind of personalized, genomics-driven medicine (where the genetic alterations in a patient’s tumor drive therapy, not the tumor’s location) isn’t a standard approach for childhood cancers yet.

Note that I said yet. The door to personalized pediatric genomic cancer medicine is cracking open, in part because three recent papers — including one out of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center — are starting to convince the field that clinical genomics can indeed be done in pediatric oncology.

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Microptosis: Programmed death for microbes?

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Trypanosoma parasites in a blood smear. (CDC)

Of the various ways for a cell to die — necrosis, autophagy, etc. — apoptosis is probably the most orderly and contained. Also called programmed cell death (or, colloquially, “cellular suicide”), apoptosis is an effective way for diseased or damaged cells to remove themselves from a population before they can cause problems such as tumor formation.

“Apoptosis has special features,” says Judy Lieberman, MD, PhD, an investigator in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It’s not inflammatory, and it activates death pathways within the cell itself.”

Conventional wisdom holds that apoptosis is exclusive to multicellular organisms. Lieberman disagrees. She thinks that microbial cells — such as those of bacteria and parasites — can die in apoptotic fashion as well. In a recent Nature Medicine paper, she and her team make the case for the existence of what they’ve dubbed “microptosis.” And they think it could be harnessed to treat parasitic and other infections.

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Lasers for on-demand local pain relief?

laser drug delivery pain relief
(Juergen Faelchle/Shutterstock)

Consider this scenario: A patient is home recovering from knee surgery to repair an ACL tear. Her pain medications are wearing off, and the surgical cuts are starting to throb. Reaching over to the table she picks up what’s essentially a souped-up laser pointer, points it at the surgical wound and turns it on. Within seconds, the pain starts to fade.

This picture isn’t as far-fetched as you might think. In a pair of simultaneous papers, Boston Children’s Hospital’s Daniel Kohane, MD, PhD, and his laboratory recently reported their efforts to create not one, but two methods for packaging long-lasting local anesthetics in microspheres that could be injected in advance by a surgeon or anesthesiologist and that would release the drugs when zapped with a laser. Both methods have one goal in common: to provide patients with durable, localized and personalized control of surgical, traumatic or chronic pain with minimal side effects.

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How can we make personalized therapy for childhood cancer a reality?

For some pediatric cancers, such as acute lymphoblastic leukemia, older forms of therapy — and older ways of defining who receives which therapy — have served well over the last few decades. But that approach is no longer sufficient. Revolutionary gains have been made in adult oncology using personalized genomic therapy — therapy based on matching treatments to the genetic makeup of a patient’s tumor. The time has come to take them to the pediatric space.

But how will pediatric oncology get there? A panel discussion at Boston Children’s Hospital’s Global Pediatric Innovation Summit about personalized cancer genomics — moderated by Bloomberg News’s John Lauerman and featuring Katherine Janeway, MD, clinical director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center — took on this question. Panelists raised four overarching concepts to consider: numbers, sharing, collaboration and incentives.

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A calmer rodent is a better rodent for pain medication research

The global market for pain medications is huge — some estimates predict it will hit $41.6 billion by 2017. However, the costs of pain medicine development are huge, too; it takes roughly $900 million to bring a new analgesic compound to market. In part, this is because some 80 percent of compounds that look promising in preclinical animal studies (largely in rodents) fail in late-stage clinical trials.

David Roberson, MBA, a neuroscience graduate student in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, wants to make those preclinical studies better at predicting whether a new compound will work safely in people — by studying rodents at “home.”

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Putting structure around the genetic basis of some immune diseases

The saying in the design world is that form follows function. But in biology, and protein biology in particular, it would be more correct to say that form begets function. Shape and structure are the foundation for most protein-based interactions in cells, and are why basic functions like receptor binding, antibody neutralization and gene transcription work.

Two enzymes in the immune system’s B cells, called RAG1 and RAG2, are a perfect example. Together, they form a complex that splices antibody-producing genes together in unique combinations through a process called V(D)J recombination. They do a similar job in T cells to build antigen-binding T-cell receptors (TCRs). In either case, the enzymes are essential to a robust immune response.

In a recent Cell paper, a team led by Hao Wu, PhD, of the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s Hospital and Maofu Liao, PhD, at Harvard Medical School used electronic microscopy to reveal how RAG1 and 2 interact at a structural level, both with each other and with DNA. The structural biology images they’ve created show plainly what mutations in the genes for these proteins do to cause disease.

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Mapping antibiotic resistance near you: ResistanceOpen

antibiotic resistance mapping ResistanceOpen

At the moment, it would appear the bacteria are winning. Antibiotic resistance is on the rise globally (in part because much of the public may not really understand how antibiotics work), threatening doctors’ ability to treat bacterial infections and potentially making surgery, chemotherapy and other medical procedures whose safety depends on antibiotic prophylaxis more risky.

Mapping antibiotic resistance — which bacteria are resistant to which drugs, and where — can help clinicians and public health officials decide how best to focus their control efforts. The challenge to date has been compiling resistance data in geographically useful ways.

“The data about antibiotic resistance are fragmented across laboratories and hospitals globally,” says Derek MacFadden, MD, a doctoral student at the Harvard T.H. Chan School of Public Health who is working with the HealthMap team in Boston Children’s Computational Health Informatics Program. “Most of the data that are available are very high level, so you can’t get an understanding of regional-level antibiotic resistance.”

This is where ResistanceOpen could come in handy. This new tool, launched by HealthMap team this week during the World Health Organization’s World Antibiotic Awareness Week, provides a window into regional and local antibiotic resistance patterns across the globe.

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Siddhartha Mukherjee: Have we lost the fire to tackle childhood cancers?

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Siddhartha Mukherjee, MD, PhD, takes his audience on a tour of 60 years’ worth of successes in cancer. What does the future hold?

We’ve all heard the George Santayana quote, “Those who cannot remember the past are condemned to repeat it.” But there’s another way of thinking about the lessons that the past holds for the future: Those who do remember the past can recapture and harness earlier feelings of energy, urgency and possibility to overcome new problems, now and in the future.

That line of thinking threaded its way throughout the keynote address oncologist Siddhartha Mukherjee, MD, PhD, author of The Emperor of All Maladies, delivered today at Boston Children’s Hospital’s Global Pediatric Innovation Summit + Awards 2015.

In taking the audience on a tour through the last 60 years of advances in cancer biology, genomics and treatment, Mukherjee highlighted the central role pediatrics played as the starting point for the cancer successes we see today. How, he asked, did children come to play such a central role? What can we learn from the successes in the 1950s and ’60s, when pediatric cancer started to evolve from a death sentence to a treatable, even curable disease?

And how, he asked, can we recapture and harness the energy and urgency of that time today?

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Improved cell cloning technique makes the jump from mice to humans

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(Lonely/Shutterstock)

Roughly a year ago we told you about Yi Zhang, PhD — a stem cell biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine — and his efforts to make a cloning technique called somatic cell nuclear transfer (SCNT) more efficient.

With SCNT, researchers take an egg cell and replace its nucleus with that of an adult cell (such as a skin cell) from another individual. The donated nucleus basically reboots an embryonic state, creating a clone of the original cell.

It’s a hot topic in both agriculture and regenerative medicine. SCNT-generated cells can be used to clone an animal (remember Dolly the sheep?) or produce embryonic stem (ES) cell lines for research. But it’s an inefficient process, producing very few animal clones or ES lines for the effort and material it takes.

Zhang’s team reported last year that they could boost SCNT’s efficiency significantly by removing an epigenetic roadblock that kept embryonic genes in the donated nucleus from activating in cloned cells. Now, in a new paper in Cell Stem Cell, Zhang and his collaborators report that they’ve extended their work to improve the efficiency of SCNT in human cells.

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