Psyché et l’Amour, François Gérard, 1798

I log on to the Web portal with excitement and set up my profile. I browse for potential matches, reading though all their interests to see if they match my own. I send out requests to meet face to face. I wait. Have I received favorable responses? Were my short email invite and profile enticing enough? Is my dance card getting full?

It’s not a dating website, but rather the prelude to a biotech business partnering conference. In my role as a leader of business development and marketing efforts at Boston Children’s Technology and Innovation Development Office, my objective is to quickly and effectively pitch our most promising work to industry contacts, in hopes of continuing conversations after the conference is over. Attending these conferences is a great way to “break the ice”—and it is key to my success in building relationships and developing partnerships and alliances with life sciences companies.

I liken it to speed and online dating combined.

At last month’s Biotechnology International Organization (BIO) conference, I skipped a series of interesting talks on the agenda and devoted my time to the “Business Forum.” Using the forum’s software platform, I had prearranged 30-minute meetings with 30 different companies with which I saw an opportunity to do business.

Each meeting took place in a tiny temporary meeting room on the exhibit hall floor. Picture a maze of hundreds of unflatteringly lit rooms—about 8 feet by 12 feet—with grey walls, one table, four chairs, a garbage can and a black curtain for a door. They’re organized in rows and arranged in alphabetical and numerical order. For some people this is reminiscent of a recurring nightmare: What if I miss an important, life-changing event because I can’t find the right room? For me, this maze represents the main draw of these conferences: business opportunities waiting to be capitalized on.

In all, over three days, the forum hosted a staggering 25,573 partnering meetings involving 2,800 companies. Despite the grueling schedule, miles of walking, vocal strain and financial/budgetary constraints faced by all the participants, these meetings are on the up.

Why? Because they work.

In this age of Web technology and video conferencing, there’s still no substitute for an efficient face-to-face discussion with a potential partner, especially when it comes to collaborations, alliances and co-development relationships. As much as business deals are rooted in intellectual property assets and in financials, at the end of the day the people factor matters most.

Just like speed dating, not all connections are positive. As one of my colleagues from another institution remarked after a meeting that the participants voluntarily shortened to five minutes, “That was a miss.” (For a fun take on this, search Twitter for #biobreakuplines and its steamy opposite, #biopickuplines.)

My philosophy is to turn these speed-dating duds into networking hits. There might not be a fit between Company X and Boston Children’s right now, but who knows? Companies change their business strategies regularly. And with 13,594 industry leaders in attendance at BIO this year, everyone has an interesting story to tell. I can always use the time to ask about the delegate’s career trajectory. Most likely, I will cross paths with this person in the future, and by then he or she may have moved to a more compatible company.

And it takes some duds to find the right fits. I’ve been in meetings where the song or bell comes on (signaling that 25 minutes have elapsed), and I wish I could continue the meeting because I know something great is going to come out of this interaction. These few successes make the whole experience worth it. A number of lasting business relationships begin in these drab cubicles.

Once back home, follow-ups from these initial conversations continue for months. A few of these “dates” will lead to partnerships. And these partnerships create value—they help develop lifesaving technologies to benefit patients at our hospital and all patients worldwide.

Ed. Note: If you’re part of the biotechnology ecosystem and want to speed date with Maude to learn more about the innovations at Boston Children’s, email her at Maude.Tessier@childrens.harvard.edu.

Joshua Frase, who died from X-linked myotubular myopathy (MTM), with his father, Paul Frase, in 2006.

Back in the 1990s, rheumatologist Richard Weisbart, MD, of University of California, Los Angeles (UCLA), was studying lupus in a mouse model and found that the mice were making an antibody that had the intriguing ability to get inside tissues and cells.

Weisbart shifted his work away from studying lupus to studying and refining the antibody, called 3E10, and he and others showed that proteins could be delivered into different tissues of the body simply by attaching them to a fragment of 3E10.

Dustin Armstrong, PhD, a postdoc at Novartis at the time, was trying to find molecules that could activate growth in weakened muscles—without activating possibly cancerous growth in other tissues. He saw Weisbart’s work and contacted UCLA. In 2008, he obtained seed money and founded a company around 3E10-based therapeutics for muscular diseases, now known as Valerion Therapeutics (formerly 4s3 Bioscience).

“There’s a huge need for therapies for genetic muscle diseases, and muscle was a tissue we could target well with our technology,” says Armstrong. “The 3E10 antibody requires a membrane transporter to enter cells—and skeletal muscle has 20-fold higher expression of this transporter.”

Armstrong

“There’s a clear indication from the gene therapy work that if you could replace myotubularin, you could have an immediate effect on muscle,” Armstrong says. “Alan brings a large depth of experience in the genetic aspects of congenital muscle myopathies, and his lab has animal models and experience doing physiologic testing. That creates opportunities to do drug development.”

Homing to muscles

Beggs

He and Armstrong received a venture philanthropy grant from the Muscular Dystrophy Association (MDA). In the April 15 issue of Human Molecular Genetics, they showed that injection of myotubularin—attached to the 3E10 fragment—into the leg muscles of mice reversed muscle weakness and improved muscle structure.

“We gave a dose that we thought would be sufficient for just one limb, but it circulated in the blood and treated the entire animal,” says Beggs. “Since it’s an enzyme, we don’t have to replace a lot of it—a little bit goes a long way.”

Enzyme replacement could have a relatively fast path to clinic. There’s regulatory precedent for enzyme-based drugs, notably Genzyme’s Myozyme, approved by the FDA in 2008 for Pompe disease, another rare genetic disorder.

Under a pending $1.2 million grant from the MDA, Armstrong and Beggs plan to further the animal studies and figure out questions of dosage, timing of treatment, how often treatment would need to be repeated and whether the body will tolerate enzyme replacement long-term. But Beggs wants to continue developing gene therapy too.

“The best therapy might be a combination therapy,” he says. “You could give a child gene therapy first, and wait for it to wear off, or for the immune system to reject the virus. You could try this for two to three years and follow it with the protein therapy. An alternative scenario is to do both at the same time to more fully deliver the treatment to the entire body. It’s important to have more than one way to skin the cat.”

With either approach, a big question is whether the treatment will work once muscle weakness is established. Unlike dogs and mice, which develop weakness after birth, children with MTM are born weak, often nearly motionless.

“I definitely think, having followed Alan’s work over the years, that things are getting close,” says Erin Ward, whose son Will has MTM, and who, with her husband Mark, helps direct the MTM-CNM Family Conference, which next meets in July. “We’re educating the community about how to hold onto that hope and what a clinical trial process would look like. We’re kind of on that threshold, I feel.”

“Once they get the delivery process down, it is likely this science will translate to other similar neuromuscular diseases,” says Alison Frase, whose son Joshua passed away from MTM two years ago, at the age of 15. Joshua’s favorite biblical scripture, posted on the Frase Foundation’s website, perhaps best captures that feeling of hope.

“But they that wait upon the Lord shall renew their strength. They shall mount up with wings as eagles. They shall run and not be weary, and they shall walk and not faint.” —Isaiah 40:31.

End of series.

[Ed. note: For more information about this research and to discuss partnership opportunities, please contact the Technology & Innovation Development Office, 617-919-3019 or TIDO@childrens.harvard.edu. To learn about supporting the research, please contact morgan.herman@chtrust.org.]

Will Ward at the NSTAR Walk for Boston Children’s Hospital in 2012—his family’s fifth year leading a team to raise funds for the Beggs Laboratory.

This two-part series examines two potential treatment approaches for myotubular myopathy, a genetic disorder that causes muscle weakness from birth.

Sixth-grader William Ward cruises the hallways at school with a thumb-driven power chair and participates in class with the help of a DynaVox speech device. Although born with a rare, muscle-weakening disease called X-linked myotubular myopathy, or MTM, leaving him virtually immobile, he hasn’t given up.

Neither has Alan Beggs, PhD, who directs the Manton Center for Orphan Disease Research at Boston Children’s Hospital, and who has known Will since he was a newborn in intensive care.

“From the very beginning, Alan connected with our family in a very human way,” says Will’s mother, Erin Ward. “In the scientific community, he’s been the bridge and the connector of researchers around the world. That makes him unique.”

Since the 1990s, Beggs has enrolled more than 500 patients with congenital myopathies from all over the world in genetic studies, seeking causes and potential treatments for congenital myopathies—rare, often fatal diseases that weaken children’s skeletal muscles from birth, often requiring them to breathe on a ventilator and to receive food through a gastrostomy tube.

Beggs’s lab has helped identify many of the dozen or more known causative genes, and has studied the MTM1 gene that’s mutated in Will for many years, modeling the mutations’ effects in animals and examining their impact on children’s muscles. Now, after 20 years, he’s at the brink of seeing his work finally translated into a treatment that could help patients get stronger. If either of two approaches being tested succeeds, it would be the first directed therapy for any congenital myopathy.

“There are hurdles to clear during this last push,” says Alison Frase, whose son Joshua passed away from MTM two years ago, and who, with her husband, founded the Joshua Frase Foundation, which has supported Beggs’s lab for almost 16 years. “But the trans-Atlantic team of scientists whom Alan has brought together has accomplished some miraculous milestones.”

Moving a muscle

Normally, when a muscle needs to move, calcium rushes into the muscle cells and sets off a contraction. Stores of calcium are held at the ready in sausage-shaped structures called T-tubules, maintained by an enzyme called myotubularin that is encoded by the MTM1 gene. But in children with MTM1 mutations, like Will and Joshua, myotubularin is absent or dysfunctional. As a result, Beggs and his collaborators have shown that the T-tubules are disorganized and leaky.

“The calcium is not going where it should be,” says Beggs. “It is not available to surge into the cell. The last step in triggering a muscle to contract is disrupted.”

When T-tubule structure is compromised, as at right, the triad structure to which it belongs falls apart and calcium stores are lost. (Credit: Michael Lawlor)

In 2008, Beggs and collaborators in France reported a successful fix in mice: gene therapy, using an injected virus to carry a healthy MTM1 gene into the muscles. Muscle structure, volume and contractile force all improved, and in follow-up research, the animals’ lifespans—normally shortened to two months by MTM—were prolonged to more than six months.

Beggs needed to test gene therapy in a larger animal before it could be attempted in humans. At a scientific meeting, he heard about some Labrador retrievers that had a disease very much like MTM. He mentioned this to Frase, who had become a professional collaborator, helping raise awareness and money for MTM research while lending support to families.

“Alan told me that a researcher thought she saw Joshua’s muscle disease in a dog,” says Frase. “We had a pretty good hunch that this dog had an MTM1 mutation.”

Nibs

Hoping to do genetic studies in the Labrador retrievers, Beggs contacted the researcher, G. Diane Shelton, DVM, PhD, a veterinary pathologist at the University of California, San Diego. Shelton then introduced Frase to the vet in Canada who was treating these dogs.

“The vet located a family with two affected puppies,” says Frase. “I called the owner and explained to him about Joshua, where we were in the research, and how we needed a large animal model. Before I could even finish my story, he said, ‘I want to give you my dog Nibs.’”

Frase with Nibs

Will with Simba, one of Nibs’s descendents

Nine days later, Frase flew from Florida to Saskatoon to meet Nibs, the puppies’ healthy mother, at the airport. They instantly bonded. “She was a genetic carrier, just like me,” Frase said.

That was the start of the world’s first MTM dog colony, established at the Wake Forest Institute of Regenerative Medicine in Winston-Salem, N.C., with funding from the Joshua Frase Foundation and in collaboration with Casey (Martin) Childers, DO, PhD. Childers, now at the University of Washington, had previously studied golden retrievers with a form of muscular dystrophy.

Within weeks, Beggs, Shelton and colleagues in France confirmed that Nibs carried an MTM1 mutation, as did seven male Labs with the same syndrome. Nibs produced a litter of 12 puppies, including five carrier females and one affected male pup. Today, the colony has more than a dozen carriers, many of which have been bred. (Will Ward’s family adopted two healthy, non-carrier dogs from the colony.)

The diseased dogs are clearly benefiting from gene therapy. At a conference late last year, Beggs, Childers and colleagues in France reported improved leg strength and diaphragm function during breathing—to near-normal levels. The muscles bulked up, had larger fibers and showed fewer pathological features. “To date, the dogs that have received gene therapy have survived to four times the age of their untreated littermates with MTM,” says Frase.

As for Nibs, she eventually was returned to her Canadian owner. “I felt I needed to bring her home,” Frase says. “She did what she needed to do for me. When she took off and ran for her original owner at the airport, I knew I had done the right thing.”

Part 2 will look at the promise of enzyme replacement for congenital muscle disorders.

Just like Goldilocks wouldn’t eat porridge that was too hot or too cold, blood vessels won't grow properly in tissues that are too stiff or too loose. (Project Gutenberg/Wikimedia Commons)

Similarly, for everything to work as it should in the body, things need to be just right. Blood pressure shouldn’t be too high or too low; organs can’t be too big or too small, etc.

Donald Ingber, MD, PhD, and his lab in Boston Children’s Vascular Biology Program take this “just right” approach when thinking about how organs and tissues are structured. Recently, he and a member of his research staff, Akiko Mammoto, MD, PhD, discovered that by changing the stiffness of the surrounding tissues—not too loose and not too tight— they could keep blood vessels from leaking. Their finding could have real consequences for people with sepsis or other diseases featuring leaky vessels.

Mechanics of health, disease and blood vessels

Mammoto and Ingber’s road to this finding started with studies of angiogenesis (the process of blood vessel growth). In 2009, they discovered a gene pathway in endothelial cells lining the walls of capillaries that links vessel growth, vessel structure and the mechanical properties of the tissues in which a vessel grows.

Tissue stiffness is one of those mechanical properties. As Mammoto notes, tissues are more rigid in many disease states, like cancer, fibrosis and arteriosclerosis. This, she thinks, creates a therapeutic opportunity.

“People usually think about soluble factors or drugs that directly affect cells when talking about treatments. But it may be possible to change the physical structure of a diseased tissue’s microenvironment, which could lead to therapeutic changes in the tissue itself.”

Just right for vessels

Somewhere between Jello-O and erasers is the right stiffness for blood vessels to grow properly. (stevendepolo/Flickr, Alex Morfin/Wikimedia Commons)

As the pair reported in Nature Communications, the gel experiments produced some intriguing results. When the gels were soft like Jell-O or rigid like a hard rubber eraser, the endothelial cells wouldn’t form tight cell-cell junctions. (These junctions’ integrity is crucial to blood vessels. When they’re too loose, they leak, causing swelling or edema.) But cells grown on gels about as stiff as muscle flattened out and joined together securely.

Their next challenge was to find the same effects in vivo. By turning up expression of lysyl oxidase (LOX)—an enzyme that crosslinks collagen and elastin in the ECM—Mammoto was able to make the lungs more rigid in a mouse model. To do the opposite, she used a LOX inhibitor called BAPN.

When she looked at the blood vessels in the animals’ lungs, she saw the same pattern as in the gel experiments. The vessels in both the over-LOXed and the BAPN-treated animals were leaky, and their endothelial cells did not form tight junctions.

Getting the lungs to loosen up

To their results to a disease state, the pair turned to a model of acute respiratory distress syndrome (ARDS), a common and fatal outcome of sepsis. “The vessels in the lungs of patients with sepsis become porous, letting fluid leak into the lungs and leading to pulmonary edema,” Ingber explains. “It’s why many sepsis patients have to go on ventilators.”

Mammoto found that the lung tissues of mice exposed to endotoxin, a powerful, sepsis-fueling bacterial toxin, grew 35 percent stiffer than normal and exhibited high levels of LOX expression. “No one knew that endotoxin damages the lungs by affecting the LOX pathway,” says Ingber. “This was a whole new finding in and of itself.”

Look at these lung blood vessels. The ones on the left are normal, the ones in the middle have been damaged by endotoxin. BAPN protected the ones on the right from endotoxin's effects. (Akiko Mammoto)

In addition, Mammoto found she could neutralize endotoxin’s stiffening effects in the mice with BAPN and other LOX inhibitors, which in turn prevented toxin-induced pulmonary edema.

It’s a discovery that, if it can be translated to humans, could be a boon for patients with sepsis. Mammoto and Ingber are now on the hunt for treatments based on what they’ve learned.

“Currently, doctors can give antibiotics to treat sepsis causing ARDS, but have no way to treat ARDS itself,” Mammoto says. “But if we can come up with a way to change the lung microenvironment and counteract the effects of endotoxin, it might give other treatments a better chance of success.”

Ingber concurs. “This could open up a new universe of agents for therapeutically targeting edema in any tissue caused by any number of conditions, such as sepsis, smoke inhalation, heart failure and more.”

Advances in medical care sometimes present challenges on the flipside. Case in point: Over the past three decades, progressive developments in pediatric cardiac care have allowed many babies born with congenital heart disease (CHD) to survive. And longevity continues to improve. This progress, however, has brought hospitals a burgeoning patient population with tremendously complex and varied disease states.

About 90 percent of children born with heart defects now survive to adulthood, thanks to diagnostic, interventional and critical care improvements. Specifically, one-year survival has improved from 67.4 percent from 1979 to 1993, to 82.5 percent from 1994 to 2005.

“The number of pediatric hospital admissions for congenital heart disease is increasing relatively slowly, but as the patients live longer and develop common adult medical issues, adult patient admissions are increasing much more rapidly,” says Alexander Opotowsky, MD, MPH, cardiologist at the Boston Adult Congenital Heart (BACH) and Pulmonary Hypertension services at Boston Children’s Hospital.

In a recent research letter to the Journal of the American Medical Association, Opotowsky and colleagues reported on 8 million CHD admissions at 1,000 hospitals. Adult admission volume was 87.8 percent higher from 2004 to 2010 compared with 1998 to 2004. Meanwhile, pediatric admissions grew 32.8 percent between the two time periods.

Thus, annual adult admissions are approaching those of children, accounting for 36.5 percent of all congenital heart disease admissions, noted the authors.

This increase doesn’t simply mean an influx of additional patients, but also a new type of patient. “These adult patients have undergone more procedures and have a greater burden of prior cardiac interventions and comorbidities, as well as the additional psychosocial stresses that arise from living their lives with a chronic condition or conditions,” says Opotowsky.

As pediatric patients with CHD age, they will require services outside of cardiology, such as in obstetrics, pulmonology or psychiatry. As a result, questions have arisen about who should manage them.

“The delivery of care for these patients needs to be deeply collaborative,” Opotowsky points out. “Pediatric cardiologists are true experts in detecting, imaging and treating congenital heart disease, but adult specialists bring a broad perspective with an understanding of commonly acquired medical issues and an approach integrating other comorbidities of these patients.”

To facilitate collaborative care, Boston Children’s has developed a partnership with Brigham and Women’s Hospital. Laurence Sloss, MD, and Michael Landzberg, MD, at Boston Children’s, have been developing the BACH service over the past three decades. Partnering is particularly helpful when adult patients with CHD need to be admitted to the hospital for procedures or surgeries unrelated to their heart disease, but still require expert monitoring of their CHD.

One more common management challenge relates to adult women with CHD who become pregnant. One study of 53 pregnancies in women with CHD found substantial maternal cardiac and neonatal complication rates. Recognizing this as a growing medical management consideration, recent guidelines from the American College of Cardiology/American Heart Association (in 2008) and the European Society of Cardiology (in 2011) include pregnancy recommendations for various congenital lesions, suggesting the management plan include labor and the postpartum period.

Despite such guidelines, it is incredibly hard to develop clinical criteria that can be widely applied to the CHD population.

“While the 2008 guidelines sought to provide generally applicable guidance for these patients, over two-thirds of recommendations carry a level of evidence of C,” says Opotowsky, who continues to participate in research aimed at optimizing care for adults with CHD. “These recommendations are based on expert opinion or small case series that are typically deemed as a weak evidence base. This limitation is due to both the recent emergence of the field and the heterogeneity of the patients.

“The care has to be incredibly personalized and tailored to the needs of each patient,” Opotowsky adds. “This is what makes caring for these patients both challenging and so wonderfully rewarding.”

(Scott Foresman/Wikimedia Commons)

“There’s no doubt that tourniquets played a key role in treating the bombing victims,” says Boston Children’s Hospital Trauma Center Director David Mooney, MD.

Two children who were later treated at Boston Children’s had tourniquets applied at the site of the tragedy. One arrived with extensive lacerations caused by one of the two detonated bombs. The other was in worse condition, having suffered blood vessel damage among other problems. Both children are doing better, although one will require further treatment.

Dating back to Roman times, a simple tourniquet, encircling a limb just above a wound, was the go-to method to stop bleeding. Since then, tourniquets have been used on the battlefield and in emergency rooms and operating rooms. However, had the bombings taken place 10 or 15 years ago, those wounded might not have been treated with tourniquets, Mooney believes. In those more recent years, tourniquets were out of favor over fears that they could cause nerve damage, blood clots, ischemia and other problems. Instead, clinicians were taught to simply apply direct pressure to halt bleeding.

A recent study in the Annals of Surgery found those concerns to be largely unfounded. In addition, the experiences of soldiers over the past 10 years in Iraq and Afghanistan strongly indicate that tourniquets can be highly effective when used properly.

Combat injuries, Mooney notes, have “changed from shooting injuries to injuries caused by improvised explosive devices (IEDs).” Like the bombs used in Boston, IEDs are detonated on or in the ground, and they are loaded with shrapnel, which causes lower-extremity injuries. Because of the increase in serious lower-body wounds suffered on the battlefield, Mooney reports that the use of tourniquets in the military is now “standard practice. Most every soldier is given a tourniquet and is trained on how to use it.”

Proper use of a tourniquet is central to success. “A tourniquet must be applied tight enough, so the bleeding stops,” Mooney explains. In some situations, a second tourniquet is needed. But tourniquets must not be left on for too long. “When we see a patient with a tourniquet, the clock is ticking,” Mooney says. “We know that this person has a severe injury, and we get them to the operating room as quickly as possible.”

On Marathon Monday, the 260+ victims were only minutes away from Boston Children’s and the city’s other trauma centers, so tourniquets applied at the finish line could be removed within an appropriate amount of time, and the people who were severely injured could be brought quickly into surgery. In the case of the two children with tourniquets who came to Boston Children’s, Mooney reports that “they were in the OR within minutes.”

The successful use of tourniquets on these two young patients is instructive and encouraging, but many questions remain about the impact the devices have on pediatric patients. There is a wealth of information on how tourniquets help those hurt in combat and on injured civilian adults, but very little data on children.

In situations like the marathon bombings, Mooney says, “we’ve been forced to use ‘combat therapy’ on kids, but we don’t know the long-term effects.” For example, if a child treated with a tourniquet develops a problem with an arm or leg as they grow older, how can we tell if the tourniquet was to blame? “There may never be enough kids to study for us to really know the impact,” Mooney says.

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Lin28, a known player in cancer, is hard to suppress with drugs. But two related enzymes present highly druggable targets. (Emw/Wikimedia Commons)

In 2008, Gregory and his colleagues showed how a factor called Lin28, which is associated with numerous cancers, makes a cell more prone to revert to a less specialized, stem-like state.

Lin28 acts by preventing maturation of Let-7—an ancient family of microRNAs found in creatures from humans to worms. Let-7 is the yin to Lin28’s yang: it causes stem cells to differentiate (embryonic stem cells, which are completely unspecialized, have very low levels of it). If a cell’s Let-7 can’t mature, it can’t differentiate; instead, it remains stem-like and can potentially become cancerous.

Suppressing Lin28 with RNA interference (RNAi) has been shown to suppress tumor growth. But Lin28 is difficult to target with drugs. Gregory’s lab, part of the Stem Cell Program at Boston Children’s Hospital, has now identified two other key players that work in tandem with Lin28. Both are associated with loss of Let-7 and with tumors, but what’s exciting is that they are enzymes, presenting far more “druggable” targets.

Gregory

Dis312 hasn’t been looked at systematically in cancer, but there’s one rare, highly lethal disease, known as Perlman syndrome, in which Dis312 is known to be mutated. Perhaps not coincidentally, Perlman is associated with fetal overgrowth and a predisposition to Wilm’s tumor, the most common form of renal cancer. Few people born with Perlman syndrome survive infancy.

Meanwhile, the team has shown in the journal Cell that when you use RNAi to suppress production of the TUTase, you can inhibit tumor growth. “That was a nice proof of principle,” says Gregory.

With funding from the National Cancer Institute, Gregory and colleagues will soon start screening some 5,000 small-molecule compounds to find ones that might block TUTase. Dis312 could eventually be tested in drug screens too, and if either search pans out, we could have a new weapon against cancer.

To learn more about Lin28/let-7 pathway collaboration opportunities at Boston Children’s, please contact Abbie Meyer, PhD, in the Technology & Innovation Development Office, abbie.meyer@childrens.harvard.edu. To learn about supporting the research, please contact kathleen.corcoran@chtrust.org.

There are a couple of ways by which aspirin might affect cancer. (cpradi/Flickr)

Aspirin does a remarkable number of things in the body, enough that it’s said it would never win approval today from the Food and Drug Administration as an over-the-counter drug.

But among those functions are some that may explain something that doctors have recognized for some time: patients with cancer who have been taking aspirin tend to have better outcomes.

Coming to resolution

Aspirin’s anti-inflammatory role has piqued the interest of Dipak Panigrahy, MD, PhD, of Boston Children’s Vascular Biology Program, who studies cancer development and progression.

“Chronic inflammation underlies many diseases, and the links between cancer and inflammation were first identified in the 1860s,” says Panigrahy, who will soon open his own laboratory at Beth Israel Deaconess Medical Center. “There is growing body of evidence linking pathologic inflammation of the kind associated with cancer to a failure in resolution.”

The resolution Panigrahy refers to has nothing to do with New Year’s, but rather with what should happen after an inflammatory response. After an injury and infection, inflammation is a good thing, but over time it should start to resolve—swelling should go down, inflammatory immune cells called neutrophils should die off and other immune cells called macrophages should digest the debris. Panigrahy believes that a failure of inflammation to resolve could be a significant factor in cancer development.

The resolution process relies on a new family of fatty molecules (lipids) called resolvins that the body produces to tamp down the acute inflammatory response. Together with Charles Serhan, PhD, at Brigham and Women’s Hospital (BWH)—one of resolvins’ discoverers in 2002—Panigrahy has been studying how these molecules act in the contexts of both inflammation and cancer, and how aspirin may manipulate those actions. Their work was funded last year by the National Cancer Institute’s Provocative Questions initiative, an effort to answer 24 questions raised by the cancer research community that address the broad scope of cancer biology, control, treatment and prevention.

“Aspirin triggers specific resolvin pathways,” Panigrahy explains. “We know resolvins keep white blood cells from being recruited in excess to sites of inflammation. They also counteract cytokines and chemokines, two kinds of immune system signaling proteins, which promote inflammation.

“So it could be,” he continues, “that aspirin’s anti-tumor capabilities are in part a product of its capability to reduce inflammation and activate resolution.”

Unclotting cancer

Schematic of a platelet. The alpha granules hold factors that affect blood vessel growth (angiogenesis). (Dr Graham Beards/Wikimedia Commons)

There’s another route by which aspirin could impact cancer: coagulation (aka clotting), which depends largely on platelets. “Aspirin irreversibly inhibits platelets,” says Elisabeth Battinelli, MD, PhD, a BWH researcher associated with our Vascular Biology Program. “That is why surgeons tell you not to take aspirin before surgery, so you don’t affect your ability to clot.”

With BCH’s Joseph Italiano, PhD, Battinelli is investigating links between platelets and cancer progression. “Tumor cells in the bloodstream hide from the immune system and migrate to metastatic sites in part by coating themselves with platelets,” she says.

Batinelli explains that platelets also carry factors that affect blood vessel growth, or angiogenesis, important in cancer growth. The factors, both pro- and anti-angiogenic, are packaged in bundles called alpha granules; platelets release these granules when activated.

“The question is,” she asks, “are there different triggers for platelets to release either set of factors?”

Evidence suggests the answer is yes. Two years ago, Battinelli and Italiano showed in the journal Blood that platelets do indeed respond to different triggers by releasing granules containing different factors. Platelets exposed to an activating molecule called ADP or to breast cancer cells release VEGF, one of the original and most potent pro-angiogenic factors known. However, those exposed to a different platelet activator, thromboxane, release endostatin, a peptide that the late Judah Folkman, MD, found to be a potent blocker of angiogenesis.

More intriguing, Battinelli and Italiano found that treating platelets with aspirin before exposing them to ADP or breast cancer cells stopped them from releasing VEGF. Battinelli was also part of a team that, in 2012, reported in Cancer Discovery that aspirin could interrupt chemical crosstalk between platelets and breast cancer cells. She now wants to see whether other anticoagulants can have similar effects on platelets’ angiogenic potential as well as on tumor progression in patients.

A note of caution: We are not suggesting that patients with cancer, or healthy people trying to avoid cancer, should start taking aspirin as a preventive measure. This research is all in its early days, and because cancer knocks the blood’s clotting capabilities off kilter, it likely wouldn’t be safe to self-medicate with what really is a powerful anticoagulant.

But both these lines of research add credence to the idea that to better treat and maybe prevent cancer, we have to look beyond tumor cells to the environments they set up for themselves.

(Jerome Gerrior Racing/Flickr)

In the hours and days following the Boston Marathon bombings, the first concern for the victims was literally life and limb—stabilizing the survivors and treating wounds suffered in the blasts.

But as the survivors begin the road to recovery—a road that promises to be long and complicated—subtler effects of the blast may become apparent, including traumatic brain injuries (TBIs).

“The difference between traumatic brain injuries and the other injuries we’ve seen is that the extent of other injuries can be readily seen,” says Mark Proctor, MD, a neurosurgeon and director of Boston Children’s Brain Injury Center. “You can have a traumatic brain injury without any external signs.”

TBIs have been a major concern among soldiers serving in war zones like Iraq or Afghanistan who have experienced the concussive force of bomb or improvised explosive device (IED) explosions—not unlike the explosions on Marathon Monday.

“There were runners and spectators who were knocked down by the blast and were otherwise uninjured,” Proctor observes, “but may have experienced enough of the blast to have suffered a concussive TBI.”

Typically rated as mild, moderate or severe based on the extent of damage done, TBIs can have lasting effects on memory, concentration, behavior and attention.

(Gray's Anatomy/Wikimedia Commons)

William Meehan III, MD, who directs Boston Children’s Sports Concussions Clinic, and has worked with veterans returning from Iraq and Afghanistan, says that anyone with a TBI would know fairly quickly. “The signs and symptoms appear either the moment of injury or within a few hours, occasionally out a few days,” he explains. “At this point, anyone who isn’t experiencing TBI signs should be relatively unaffected.”

Proctor cautions, however, that many TBI symptoms—such as headache, emotional shifts, difficulty sleeping and sensitivity to light or noise—can be confused with those of post-traumatic stress disorder, which many survivors may also be experiencing in the aftermath of the blasts.

Because untreated TBIs can have lasting effects, Proctor believes loved ones and caregivers of survivors and anyone who was in the vicinity of the blast should keep an eye out for TBI warning signs.

“Many people are behaving differently now just because of the stress of the situation, but if you know someone who was in close proximity to the blasts and you notice significant behavioral changes, they should be assessed for a possible TBI.”

On that point, Meehan concurs. “If you notice signs, bring them to the attention of your doctor.”

In mice, boosting amounts of a microRNA family called miR-17-92 led to dramatic enlargements of embryonic and postnatal hearts, with thicker ventricle walls.

Now, we have a potential therapeutic target to accomplish this: a family of microRNAs called miR-17-92 that regulates cardiomyocyte proliferation. In Circulation Research earlier this month, a team led by Kühn’s research colleague Da-Zhi Wang, PhD, demonstrates its potential.

“One of the major problems with the heart is that it cannot naturally regenerate,” says Wang. “The death of mature cardiomyocytes in pathological cardiac conditions and the lack of regenerative capacity of adult hearts are primary causes of heart failure and mortality.”

So Wang and his team took a closer look at how heart cells grow. They were interested in the miR-17-92 cluster, because it had been shown to promote cell proliferation in other studies.

Their research, in normal and damaged mouse hearts, produced several important findings:

• Deleting the miR-17-92 cluster from embryonic and postnatal mouse hearts sharply decreased cardiomyocyte proliferation.
• Adding more miR-17-92 than normal to embryonic, postnatal and adult hearts induced cardiomyocyte proliferation. In adult hearts, the additional miR-17-92 actually protected the heart from injuries resulting from a heart attack, or myocardial infarction.
• Certain members of the miR-17-92 cluster, such as miR-19, were required for and sufficient to induce cardiomyocyte proliferation in cell cultures.

These findings, Wang believes, “will allow us to identify specific targets for drug development to treat heart failure,” and could guide research on regeneration in other organs.

Next up for Wang and his team are tests in mice and larger animals to determine whether direct delivery of these miRNAs in the heart can prevent or reduce the risk of developing myocardial infarction or chronic heart failure.

“This is very exciting work and may lead to therapeutics that can replace or repair damaged hearts,” says David Clapham, MD, PhD, chief of the Basic Cardiovascular Research Laboratories at Boston Children’s Hospital. “If similar mechanisms exist in lung or brain, these tissues might also be regenerated after infection, pulmonary embolism or stroke.”

Editor’s note: For more information, or to learn about partnership opportunities related to this technology, please contact the Technology and Innovation Development Office at Boston Children’s by email or phone at (617) 919-3019.