Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Patient stem cells used to make 'heart disease-on-a-chip'

12.05.2014

Cross-Harvard collaboration explores new possibilities for personalized medicine

Harvard scientists have merged stem cell and 'organ-on-a-chip' technologies to grow, for the first time, functioning human heart tissue carrying an inherited cardiovascular disease. The research appears to be a big step forward for personalized medicine, as it is working proof that a chunk of tissue containing a patient's specific genetic disorder can be replicated in the laboratory.


Researchers use modified RNA transfection to correct genetic dysfunction in heart stem cells derived from Barth syndrome patients. The series of images show how inserting modified RNA into diseased cells causes the cells to produce functioning versions of the TAZ protein (first image: in green) that correctly localize in the mitochondria (second image: in red). When the images are merged to demonstrate this localization, green overlaps with red, giving the third image a yellow color.

Credit: Gang Wang and William Pu/Boston Children's Hospital

The work, published in Nature Medicine, is the result of a collaborative effort bringing together scientists from the Harvard Stem Cell Institute, the Wyss Institute for Biologically Inspired Engineering, Boston Children's Hospital, the Harvard School of Engineering and Applied Sciences, and Harvard Medical School. It combines the 'organs-on-chips' expertise of Kevin Kit Parker, PhD, and stem cell and clinical insights by William Pu, MD.

Using their interdisciplinary approach, the investigators modeled the cardiovascular disease Barth syndrome, a rare X-linked cardiac disorder caused by mutation of a single gene called Tafazzin, or TAZ. The disorder, which is currently untreatable, primarily appears in boys, and is associated with a number of symptoms affecting heart and skeletal muscle function.

The researchers took skin cells from two Barth syndrome patients, and manipulated the cells to become stem cells that carried these patients' TAZ mutations. Instead of using the stem cells to generate single heart cells in a dish, the cells were grown on chips lined with human extracellular matrix proteins that mimic their natural environment, tricking the cells into joining together as they would if they were forming a diseased human heart. The engineered diseased tissue contracted very weakly, as would the heart muscle seen in Barth syndrome patients.

The investigators then used genome editing—a technique pioneered by Harvard collaborator George Church, PhD—to mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue. On the other hand, delivering the TAZ gene product to diseased tissue in the laboratory corrected the contractile defect, creating the first tissue-based model of correction of a genetic heart disease.

"You don't really understand the meaning of a single cell's genetic mutation until you build a huge chunk of organ and see how it functions or doesn't function," said Parker, who has spent over a decade working on 'organs-on-chips' technology. "In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly. Being able to model the disease from a single cell all the way up to heart tissue, I think that's a big advance."

Furthermore, the scientists discovered that the TAZ mutation works in such a way to disrupt the normal activity of mitochondria, often called the power plants of the cell for their role in making energy. However, the mutation didn't seem to affect overall energy supply of the cells. In what could be a newly identified function for mitochondria, the researchers describe a direct link between mitochondrial function and a heart cell's ability to build itself in a way that allows it to contract.

"The TAZ mutation makes Barth syndrome cells produce an excess amount of reactive oxygen species or ROS—a normal byproduct of cellular metabolism released by mitochondria—which had not been recognized as an important part of this disease," said Pu, who cares for patients with the disorder.

"We showed that, at least in the laboratory, if you quench the excessive ROS production then you can restore contractile function," Pu added. "Now, whether that can be achieved in an animal model or a patient is a different story, but if that could be done, it would suggest a new therapeutic angle."

His team is now trying to translate this finding by doing ROS therapy and gene replacement therapy in animal models of Barth syndrome to see if anything could potentially help human patients. At the same time, the scientists are using their human 'heart disease-on-a-chip' as a testing platform for drugs that are potentially under trial or already approved that might be useful to treat the disorder.

"We tried to thread multiple needles at once and it certainly paid off," Parker said. "I feel that the technology that we've got arms industry and university-based researchers with the tools they need to go after this disease."

Both Parker and Pu, who first talked about collaborating at a 2012 Stockholm conference, credit their partnership and scientific consilience for the success of this research. Parker asserted that the 'organs-on-chips' technology that has been a flagship of his lab only worked so fast and well because of the high quality of Pu's patient-derived cardiac cells.

"When we first got those cells down on the chip, Megan, one of the joint first authors, texted me 'this is working,'" he recalled. "We thought we'd have a much harder fight."

"When I'm asked what's unique about being at Harvard, I always bring up this story," Pu said. "The diverse set of people and cutting-edge technology available at Harvard certainly made this study possible."

###

The researchers also involved in this work include: Joint first authors Gang Wang, MD, of Boston Children's Hospital, and Megan McCain, PhD, who earned her degree at the Harvard School of Engineering and Applied Sciences and is now an assistant professor at the University of Southern California. Amy Roberts, MD, of Boston Children's Hospital, and Richard Kelley, MD, PhD, at the Kennedy Krieger Institute provided patient data and samples, and Frédéric Vaz, PhD, and his team at the Academic Medical Center in the Netherlands conducted additional analyses. Technical protocols were shared by Kenneth Chien, MD, PhD, at the Karolinska Institutet.

Kevin Kit Parker, PhD, is the Tarr Family Professor of Bioengineering and Applied Physics in Harvard's School of Engineering and Applied Sciences, a Core Faculty member of the Wyss Institute for Biologically Inspired Engineering, and a Principal Faculty member of the Harvard Stem Cell Institute.

William Pu, MD, is an Associate Professor at Harvard Medical School, a member of the Department of Cardiology at Boston Children's Hospital, and an Affiliated Faculty member of the Harvard Stem Cell Institute.

George Church, PhD, is a Professor of Genetics at Harvard Medical School and a Core Faculty member of the Wyss Institute of Biologically Inspired Engineering.

The work was supported by the Barth Syndrome Foundation, Boston Children's Hospital, the National Institutes of Health, and charitable donations from Edward Marram, Karen Carpenter, and Gail Federici Smith.

Cited: Wang, G., McCain, M., et. al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-a-chip technologies. Nature Medicine. May 11, 2014

Joseph Caputo | Eurek Alert!
Further information:
http://www.harvard.edu/

More articles from Life Sciences:

nachricht New method opens crystal clear views of biomolecules
11.02.2016 | Deutsches Elektronen-Synchrotron DESY

nachricht Scientists from MIPT gain insights into 'forbidden' chemistry
11.02.2016 | Moscow Institute of Physics and Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Production of an AIDS vaccine in algae

Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.

The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...

Im Focus: The most accurate optical single-ion clock worldwide

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...

Im Focus: Goodbye ground control: autonomous nanosatellites

The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.

Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...

Im Focus: Flow phenomena on solid surfaces: Physicists highlight key role played by boundary layer velocity

Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.

The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

Im Focus: New study: How stable is the West Antarctic Ice Sheet?

Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels

A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Travel grants available: Meet the world’s most proficient mathematicians and computer scientists

09.02.2016 | Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

From intelligent knee braces to anti-theft backpacks

26.01.2016 | Event News

 
Latest News

New method opens crystal clear views of biomolecules

11.02.2016 | Life Sciences

Scientists take nanoparticle snapshots

11.02.2016 | Physics and Astronomy

NASA sees development of Tropical Storm 11P in Southwestern Pacific

11.02.2016 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>