Breaking Boundaries: Interdisciplinary Approaches to Disease Solutions
“Nobody was ever cured by injecting themselves with a paper in Nature,” Harvard Stem Cell Institute co-director Doug Melton said, kicking off HSCI’s 10th Annual Malkin Retreat.
Melton reminded the more than 300 assembled scientists from all across the Harvard Stem Cell world that while HSCI’s first decade of establishing a collaborative environment, focusing on new ideas and on young scientists – and supporting exciting new research with the Seed Grant program, has been enormously successful, the aim in the coming decade has to be not just on doing good science, but also on treating and curing disease.
HSCI scientists, Melton said, need to be working more and more in partnerships — with each other, with foundations, and with industry — to lift their science out of journals and into the clinic as quickly and successfully as possible.
One of HSCI’s greatest “strengths is bringing together people who think in different ways but are interested in the same type of questions,” said Paola Arlotta co-program leader of HSCI’s Nervous System Diseases Program and a faculty co-chairs for this year’s retreat.
The morning keynote speaker, Lorenz Studer, MD, from Memorial Sloan Kettering, addressed the various challenges of using human pluripotent stem cells to model and treat neural diseases.
Each speaker at the event discussed a different approach to solving common biological challenges, from drug delivery, to stem cell transplants as treatments, to developing therapies for diseases, to the very basic question of how to classify a cell, from a different angle.
David Mooney of Harvard’s Wyss Institute for Biologically Inspired Engineering, discussed new forms of immunotherapy for the treatment of cancer. He gave the example of a new prostate cancer therapy that provides about four months of additional life at a cost of $100,000 which involves removing antigen presenting cells from patients, exposing the cells to cancer antigens in the laboratory, and infusing them back into the patients where it’s hoped they make their way to the lymph nodes, said Mooney.
“I’m an engineer and we try to simplify things whenever possible,” Mooney said. So he tried to eliminate the complexity of working ex vivo by “moving the biology into the body.”
Mooney and his team engineered a plastic device, made from the same polymers used in biodegradable sutures, that acts as a “cell factory” in the body. The piece of plastic releases agents slowly over time that attract a certain type of cell, manipulate the cells, and then send out altered or transformed cells elsewhere in the body.
When Mooney’s team tested the device, they found some mice “showed complete regression of tumors.” Further tests showed that about one million of the altered cells made it from the device to the lymph nodes.
The device is now FDA-approved for a Phase 1 clinical trial, and has been implanted in nine patients. Presently, there is limited data, but no safety problems, Mooney said.
Merit Cudkowicz, MD, MSc, director of the Massachusetts General Hospital ALS clinic, explained to the more than 300 attendees at the retreat how she and her team are using a multidisciplinary approach to find treatments and therapies for the neurodegenerative disease ALS.
ALS has a wide range of variability in clinical phenotypes. Life expectancy averages at about two to four years after diagnosis, but ranges from six months to over forty years. Over the course of a year, some patients may not change at all, while others’ symptoms may progress at four or five times the normal rate. Additionally, some forms of ALS are heritable with one of two genes, SOD1 or C9ORF72, present in nearly half of the ALS families, while other forms don’t seem to have a heritable genetic component.
Additionally, ALS may involve more than misfiring neurons. “It’s really become apparent in the last couple of years that it’s really not a motoneuoron only illness,” Cudkowicz said; more than 50-60% of ALS patients probably have cognitive involvement, such as frontotemporal dementia.
This heterogeneity among ALS patients and their symptoms may indicate different biological mechanisms at work, which could impact the development and testing of treatments. “There are no short cuts for getting a quick read on whether a new drug works,” Cudkowicz said. A drug or therapy that might not work for one small sample of ALS patients might work for another.
“Ultimately the field thinks it isn’t one drug that will solve the problem” Cudkowicz said. “Given all the pathways that seem to be affected, we are probably going to need some combination approach.”
Aviv Regev, PhD, director of the Klarman Cell Observatory and the Cell Circuits Program at the Broad, ended the day by explaining how she uses big data sets to address the complex challenge of classifying cell types. Cells can be classified in many different ways; however, profiling single cells for their molecular content can bring the field closer to charting a universal “cell atlas.”
The retreat also included a series of hyper-speed presentations of 2013 HSCI Seed Grant recipients’ research, with the talks limited to one minute, with one follow-up question each. The presenters were as follows:
- Reza Adbi, who modified cell surface CD44 of murine MSCs in order to increase homing and trafficking capabilities to pancreatic islets and reverse type 1 diabetes.
- Suneet Agarwal, who manipulated mitochondrial genomes using TALONS to target mtDNA. The Agarwal Lab is now using CRISPR methods and additional nucleases.
- Natasha Frank, who identified normal markers that enabled researchers to isolate stem cells from limbal stem cells.
- Jenna Galloway, who established a tendon regeneration model in zebrafish in order to look at pathways regulating tendon injury response.
- Tatsuya Kabayashi, who phenotyped BMI1 cells in cartilage and investigated the consequences of losing BMI1.
- Maria Kontaridis, who generated iPS cells from patients with LEOPARD syndrome and Noonan syndrome in order to find mechanisms of clinical similarities of and elucidate the differences between these two disorders.
- David Milan, who identified causal genes and monogenetic traits using a modification of radiation hybrid mapping.
- Sangmi Chung, who generated a temporal lobe epilepsy model and injected neurons derived from human PSCs into epileptic mice, where they inhibited post-synaptic responses and suppressed seizures.
Arlotta concluded the retreat by encouraging scientists to reach out, break boundaries, and do science at the intersection of fields, which, she said, “may actually lead us to a better understanding and development of cures for diseases.”