Artificial Organs that Fit in Your Hand

New technologies are now available that allow scientists to make mock human organs that can fit in the palm of your hand. These organs-on-a-chip can help test drugs and provide excellent model systems for organ function when they are healthy and when they are diseased.

Think of it: a gut-on-a-chip being developed at the Johns Hopkins School of Medicine can help determine if your heart medicine is actually causing your upset stomach or your diet. This type of technology is a high-tech approach to dealing with a scourge of the low-tech world.

“I’m interested in solving a worldwide problem of diarrheal diseases,” says Dr. Mark Donowitz, who runs this lab and studies diarrheal diseases. According to Donowitz, 800,000 children a year die from diseases like cholera, rotavirus and certain strains of E. coli.

“We’ve failed so far to find drugs to treat diarrhea using cell culture models and mouse intestine,” Donowitz says. Unfortunately. mouse digestive systems don’t react the way human s do to these germs. Therefore, they aren’t very helpful for studying diseases of the gut. Therefore, Donowitz’s team is building his gut-on-a-chip technology in what he hopes will be a superior technique for studying these these diseases.

Postdoctoral researcher Jennifer Foulke-Abel holds the gut-on-a-chip inside the lab at Johns Hopkins School of Medicine.
Postdoctoral researcher Jennifer Foulke-Abel holds the gut-on-a-chip inside the lab at Johns Hopkins School of Medicine.

When you hold one of these devices in the palm of your hand, it is little more than a thin sheet of glass, topped with a plastic microscope slide with a tiny cavity inside. Half a dozen spaghetti-size tubes extend from the device.

“The reason there are so many tubes is we have a vacuum chamber that will cause the membrane to stretch, the way the intestine stretches as it moves food along,” Fouke-Abel explains.

Cells isolated from a human intestine are placed into a tiny chamber around that membrane, and the cells divide, grow and organize themselves into a small version of part of a human gut. The device, when operating, might hold 50,000 gut cells.

The first step of this research is to determine if the cells in the chip react the same way to diseases as cells in the human gut.

“And in all three of the diseases I mentioned, we’ve been able to take that first step,” Donowitz says. “So we know that these appear to be really good models of the human disease.”

To date, the guts-on-a-chip produce digestive enzymes, hormones and mucus, but they don’t yet incorporate other parts of the human intestine, such as blood vessels or nerve cells.

“They all have to be incorporated if you want to move from a simple to a more complex system, which I think you need to do if you are going to reproduce intestinal biology,” Donowitz says.

However, Donowitz’s laboratory is moving in that direction. Once it has built a complete system, they will use it to test potential drugs for the diseases being studied. “We think this could be a real step forward in terms of reducing waste-of-time drug development,” Donowitz says.

While the Donowitz lab at Johns Hopkins is working to develop the gut, other labs scattered around the country are working on other organ systems.

“There’s going to be a brain-on-a-chip, liver, heart and so on,” says Danilo Tagle, who coordinates this overall effort at the National Center for Advancing Translational Sciences, which is part of the National Institutes of Health. The grant structure for this study section will fund the development of 10 organ systems in all.

“The goal is actually to tie them in all together,” Tagle says. To this end, the mini-organs on a chip will collectively work together, much like an entire human being on a chip.

Tagle’s hope is that scientists can build many of these systems, each one based on the cells from an individual person. This would create an array of cell-based stand-ins for research or even diagnoses.

“And so you can identify which part of the population might be more responsive to particular drugs, or identify a subset of the population that might be more vulnerable to the harmful effects of a particular drug,” Tagle says.

According to Tagle, this $75 million, five-year project took off thanks to pioneering work at the Wyss Institute for Biologically Inspired Engineering at Harvard. The research has been so promising, Wyss spun off a private company to pursue it.

“It’s called Emulate,” says Donald Ingber, founding director of the Wyss Institute. “It’s just getting its feet on the ground. We have almost 20 people out of the Wyss Institute who are moving out with it.”

Ingber says it would be too much to expect this technology to replace mice in medical research anytime soon. But he is hoping that this will speed up drug development and make it less expensive, “because if we can identify things that are more likely to work in humans, that’s going to have major impact.”

And there are so many avenues to pursue, he says, there’s plenty of room for both industry and academics to work on building and improving these organs-on-a-chip.

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.”.