Using Patient Stem Cells to Make “Heart-Disease-on-a-Chip”


Personalized medicine is a new but quickly advancing innovation in medicine that tailors the diagnosis and treatment of a particular patient according to their specific genetic and physiological idiosyncrasies. As an example, if a patient has high blood pressure, which treatment would work the best? If the patient is an African-American, it is unlikely that a group of drugs called ACE inhibitor or another group called ARBs would work terribly well because African-American patients tend to lack sufficient quantities of the targets of these two type of drugs for them to work properly. Therefore, diuretics or beta blockers are better drugs to lower the blood pressure of such patients.

Other examples include the enzymes that chemically modify drugs are they circulate throughout our bodies. Some patients have excessive amounts of a liver enzyme called CYP2D6, and this enzyme modifies the painkiller codeine.  Codeine, you see, is not given in an active form.  It only becomes active after the liver enzyme CYP2D6 modifies it.  People with large amounts of CYP2D6, which includes about 10% of Arabs, over-activate codeine, which causes side effects like profound sedation and stomach cramps (codeine or hydrocodone is a form of morphine).  Therefore, before the patient is prescribed codeine, which is present in several different types of prescription painkillers (e.g., Norco, Lortab, Tusnel-HC, Canges-HC, Drocon-CS, Excof-SF, TriVent-HC, etc.), it would be immensely useful to know if your patient had this condition in order to cut their codeine dose or prescribe an altogether different pain-killer.

Now that you have, hopefully been convinced that personalized medicine can potentially save lives, I hope to tell you about a new advance that brings stem cells into the personalized medicine arena.  Kevin Kit Parker and William Pu have used stem cell and “organ-on-a-chip” technologies to grow functioning heart tissue that carries an inherited cardiovascular disease.  This research appears to be a big step forward for personalized medicine.

Parker and Pu modeled a cardiovascular disease called Barth Syndrome, which is caused by mutations on a gene that resides on the X chromosome called TAZ, which encodes the Tafazzin protein.  Barth Syndrome is also affects heart and skeletal muscle function.  Skin biopsies were taken from two male patients who suffer from Barth Syndrome.  These cells were de-differentiated into induced pluripotent stem cells (iPSCs) that were further differentiated into heart muscle cells.  To differentiate the iPSCs into heart muscle cells , the cells were grown on small slides known as chips lined with human extracellular matrix proteins that mimicked the environment of the human heart.  The cells were tricked into thinking that they were in a heart and they differentiated into heart tissue.  Not surprisingly, the heart tissue made on a chip contracted very weakly compared to normal heart tissue.

To confirm that they were not barking up the wrong tree, Parker and Pu used normal cells that had been genetically engineered to possess mutations in the TAZ gene.  When these engineered cells were used to make heart tissue on a chip, they too contracted very weakly.  This told Parker and Pu that they were definitely on the right track.

“You don’t relay understand the meaning of a single cell’s genetic mutation until you build a huge function,” said Parker, who has spent over a decade working on “organs-on-a-chip” 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.”.

The TAZ mutation disrupts the activity of the powerhouse of the cell, a small structure called the mitochondrion.  Even though the TAZ mutation did not affect the over all energy supply of the cells, it seems to affect the way the heart muscle constructs itself so that it can properly contract.

Since mitochondria use a process known as oxidative phosphorylation to make the lion share of their chemical energy in the form of the molecule ATP (adenosine triphosphate), mitochondria also generate toxic byproducts called reactive oxygen species or ROS.  Cells have mechanisms to squelch ROS, but these mechanisms can be overwhelmed if cells make excessive quantities of ROS.  Heart muscle that contains the TAZ mutation seems to make excessive quantities of ROS, and this affects the integrity of the heart muscle.

Can drugs that quench ROS be used to retreat patients with Barth Syndrome?  It is difficult to say, but this chip-on-a-dish is surely an excellent model system to determine if such an approach can work.  Already, Pu and his colleagues are testing drugs to treat this disorder by testing those drugs on heart tissue grown on chips.

“We tried to thread multiple needles at once and it certainly paid off,” said Parker.  “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.”.

Authors Agree to Retract One STAP Paper


Embattled stem cell scientist Haruko Obokata from the Riken Center for Developmental Biology in Japan has agreed, albeit reluctantly, to retract one of the two Nature papers that describes a controversial technique for generating pluripotent stem cells by stressing adult cells with acid or pressure.

Obokata and her colleagues pioneered the STAP protocol that generates Stimulus-Triggered Acquisition of Pluripotency or STAP cells in two papers that were published in the international journal Nature in January, 2014. When these papers appeared, they were regarded as a revolutionary finding in the field of stem cells. Nevertheless, these papers also generated more than a fair share of suspicions, and rightly so. After all, these papers challenged many previous observations. Therefore, many laboratories tried to repeat Obokata’s results, without any success. While in and of itself this was not a definitive refutation of these papers, further mining of the data in these papers revealed discrepancies and inconsistencies. Again, while this is not a definitive refutation of the results in the paper, it was enough to implement further investigation. Therefore an internal investigation by the Riken Center was conducted.

In their investigation, Riken found evidence of misconduct.  According to the Riken report, two pictures of electrophroresis gels were spliced together, and that data from Obokata’s doctoral thesis was reused in two images despite that fact that these data came from experiments that had been conducted under different conditions.

Obokata apologized for her errors, but insisted that these mistakes were unintentional and that they did not detract from the validity of her work in general. She also said she would be appealing the findings. That appeal, however, was rejected earlier this month.

Now, Obokata has agreed to retract one, but not both, of two Nature papers. According to the Nature News Blog, which is editorially independent of the research editorial team, the “Bidirectional developmental potential in reprogrammed cells with acquired pluripotency” paper is to be retracted. Riken told the Nature News Blog that each co-author either agreed to the retraction or did not oppose it.  According to the Japan Times:

Of the three researchers, her lawyer said University of Yamanashi professor Teruhiko Wakayama is responsible for the paper Obokata has agreed to retract. He was engaged in all experiments, and Obokata wrote the paper under his guidance, lawyer Hideo Miki said.

She e-mailed the other main co-author, Yoshiki Sasai, deputy director of the Riken Center for Developmental Biology in Kobe, that she would have no problem if Wakayama wants to retract it, Miki said.

Both papers were published in the Jan. 30 edition of the journal, one as a “letter” and the other as an “article.”

However, the journal Nature couldn’t confirm the request. “Nature does not comment on corrections or retractions that may or may not be under consideration, nor does it comment on correspondence with authors, which is confidential,” a spokesperson tells the Nature News Blog. “We are currently conducting our own evaluation and we hope that we are close to reaching a conclusion and taking action.”

According to the Japan Times, Obokata has said that she will not retract the other paper.