Ghost Organs: The Structures Left Behind by Cells

An exciting development paving the way for the next frontier of medicine focuses on replacing diseased and/or damaged tissue with new, lab-grown tissue. Instead of trying to target diseases by ingesting medication, tissue engineering is a rapidly growing field that focuses on growing tissue in a laboratory environment. A popular example of lab grown tissue made headlines back in 2013. It was the world’s most expensive hamburger, which cost about $325 000 USD and over two years to develop¹. Engineering this burger required growing enough cow muscle cells in a layered formation, starting with a very small number of cells - similar to what would be taken for a biopsy. They were obtained with minimal discomfort to the animal. It was an exciting proof-of-concept venture illustrating that large quantities of tissue can be grown in a laboratory environment. Unfortunately, organs are significantly more complicated to grow than this extremely expensive hamburger, especially since organs are most useful when alive, not grilled.

Electrical circuit of the heart

Organs are made up of tens to hundreds of billions of cells which are arranged in very specific three-dimensional orientations in order to function properly. Let’s take a look at the heart. It is a hollow organ made up of muscle, nerve, and connective tissue that separates it into four distinct chambers. The top two chambers, called atria, receive incoming blood from either the body or the lungs. The bottom two chambers, called ventricles, are responsible for pumping the blood out of the heart, either to the lungs or throughout the body. There are valves that prevent backflow so that the blood is moved in the correct direction, first to be oxygenated by the lungs, and then returning to the heart to be pumped around the body freshly oxygenated. Even muscle cell orientation is crucial, as the heart pumps in a twisting motion upwards to push the blood up and then out of the heart. The craziest part is that the heart is able to do all of this without any input from the brain! It pumps independently using its own nervous system that signals when the different chambers should contract. In fact, it is even possible to have the heart beating outside the body! This is called ex vivo heart perfusion and is used as a research method to optimize organ transplantation and study gene therapy^2,3. Essentially, an organ is hooked up to a bunch of tubing that mimics a circulation system. A solution of nutrients and oxygen, maintained at body temperature (37°C), is perfused through the organ, essentially tricking it into believing it is still inside a body. If you are interested in learning more about how ex vivo organ perfusion is being used to revolutionize organ transplants, check out the exciting NASA-awarding winning work from Dr. Darren Freed’s lab using lungs. In short, growing an organ is more complicated than growing a burger, but novel scientific techniques suggest scientists may not need to grow new organs from scratch!

The Matrix - 1999

There are two key components of an organ: its cells and its extracellular matrix. An organ’s extracellular matrix is not dissimilar from the Matrix, introduced in the iconic 1999 science fiction film titled, The Matrix. Although there isn’t any computer code (that we are aware of) in the extracellular matrix, it is crucial to the organ’s structure {spoiler alert}. The Matrix, in The Matrix, was essentially the construct that the virtual reality world was built on in order to deceive humanity into thinking they were leading normal 21st century lives instead of their post-apocalyptic energy-supplying reality. In an organ, the extracellular matrix is the scaffolding that provides its three-dimensional structure. Without extracellular matrix, cells would just pool on the floor resembling a Ditto but lacking its Pokémon shapeshifting abilities. Just like how scaffolding provides the preliminary structure of a building, the extracellular matrix provides the shape of the organ.

Examples of organs with and without their cells

The extracellular matrix is built by the cells as the organ grows. In fact, many people regularly eat one of the key components that make up extracellular matrix – collagen. Collagen is the most abundant protein in the body and provides crucial structural integrity for its organs⁴. It is present in tendons, cartilage, muscle, and skin, although most are familiar with its more digestible form – gelatin. In fact, collagen behaves in a similar manner to gelatin: when more gelatin is added to a solution, that solution solidifies proportionately harder. The more collagen that is present, the stiffer that component of the body is, although there are many varieties, called isoforms, of collagen present in the body that have different structural functions. Collagen is not the only structural protein present in the extracellular matrix, there are many others which provide various mechanical properties depending on the type of tissue. For example, the heart is a constantly beating muscular organ that requires a flexible, yet strong extracellular matrix. In contrast, the liver is a relatively still, soft organ so its extracellular matrix is different, even though they both have collagen as a component.

Originally, the extracellular matrix was thought to be solely a supportive structure for cells. It wasn’t until pioneering work by Dr. Doris Taylor emphasized the importance of the extracellular matrix in communicating instructions to cells. Her lab discovered how important the extracellular matrix was in an experiment that removes all the cells in a rat’s heart. After washing away the cells, using detergents commonly used in the lab for a number of standard techniques, the scaffolds were repopulated with heart cells which, not only oriented themselves within the extracellular matrix, but communicated with each other enough for the heart to beat^5,6. Here is a link to Dr. Taylor discussing her research. Her lab's preliminary experiments demonstrate the importance of the extracellular matrix in guiding cells where to go, in addition to enabling them to function. Keep in mind, in these experiments the heart did not beat at full strength, but these recellularized hearts have improved from pumping at 2% adult rat heart capacity to 25% adult rat heart capacity. Since the publication of this work, nearly every organ, even limbs, have been decellularized. These decellularized organs have been coined ghost organs as they have a pale, partially translucent appearance reminiscent of how ghosts are portrayed in popular media.

This exciting discovery is more than just an exploration of how the body works. It is an opportunity to bioengineer organs without having to start from scratch. Essentially, scientists can use these ghost organs as their scaffold to build organs for transplant. There are hundreds of thousands of people around the world waiting for an organ transplant. This incredible demand for organs has led to an international organ trade which involves organ tourism and the troubling, illegal organ black market⁷. So, if there is an organ shortage, where are these scaffolds going to come from? Even though there are discussions about repurposing organs from individuals who have passed away and wish to donate them, there is another source that is currently being looked into – pigs. This may initially seem like an unusual source as pigs appear quite different from humans, but it is important to note that their organs are very very similar to humans’ in both function and size. In fact, pig heart valves are regularly used as a replacement for patients with diseased or malfunctioning heart valves⁸. Also, healthy pig hearts are far more readily available than human hearts, and because the decellularization would wash away the pig heart cells, there is minimal risk of rejection. In fact, there is ongoing research evaluating how effective decellularizing and recellularizing pig hearts could be in order to act as an additional source of hearts available to transplant into patients. But wait! What would the cell source be? That is also very exciting as the cells could be from the patient requiring the transplant! That’s right, a person’s own cells can be programmed and used to populate the scaffold for their organ which would significantly decrease many of the complications currently experienced by patients receiving organs from donors. This is possible using inducible pluripotent stem cell technology. Feel free to peruse this article to learn more about how a patients’ own cells can be reprogrammed into any type of tissue!

Ironically, even though ghost organs would imply a lifeless organ, which is essentially the case when an organ lacks cells (the basic unit of life), these ghost organs can be brought back to life with science! Unfortunately, this technique does not yet yield fully functioning organs, so it is strongly encouraged that, if you aren’t one already, please consider being an organ donor because it is the only option available for the hundreds of thousands of people waiting for this life-saving donation. Hopefully in the future, there will be more options available, but only time and science will tell!

References/More Information

1. Fountain H. Building a $325 000 Burger . The New York Times 14 May 2013.
2. Sandha JK, et al. Steroids limit myocardial edema during ex vivo perfusion of hearts donated after circulatory death . The Annals of Thoracic Surgery; 105: 1763-1770.
3. Bishawa M, et al. A normothermic ex vivo organ perfusion delivery method for cardiac transplantation gene therapy . Scientific Reports 29 May 2019.
4. Lodish H, et al. 4th ed Molecular Cell Biology. Section 22.3 Collagen: The Fibrous Proteins of the Matrix . 2000.
5. Ott HC, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 2008 14: 213-221.
6. Maher B. Tissue engineering: How to build a heart . Nature News 03 July 2013.
7. Shimazong Y. The state of the international organ trade: a provisional picture based on integration of available information . World Health Organization Bulletin 2007; 85: 901-980.
8. Bhatt DL. Valve replacement: mechanical or tissue? Harvard Heart Letter . March 2018.