Our organs thrive on thousands of tiny powerhouses inside every cell called mitochondria; these convert food into energy to power all essential activities, such as breathing, thinking and running, while eliminating toxic by-products. In the moments following ischemia, the cessation of blood circulation, this balance changes : Mitochondria burn dwindling nutrient stores, and create waste products that accumulate and eventually poison and kill the cell.
Although mitochondria generally produce energy with the help of oxygen, they can also switch to a less efficient, low-oxygen process and use up the body’s fuel reserves to the last. drop, i.e. for regarding five minutes. When energy levels eventually drop, the cell’s ionic balance, which controls intercellular communication and energy production, is one of the first to drop out.
(Read: Mitochondrial transplantation might revolutionize medicine.)
“Like a ship that must continuously pump water to keep from sinking, cells have pumps that constantly release calcium and sodium,” Parnia explains. If they are not supplied with energy, the pumps, located in the membrane of the cell, break down, which allows calcium, sodium and water to rush in.
The increased calcium then activates enzymes that break down DNA and destroy the cytoskeleton, which gives the cell its structure. High calcium concentrations also trigger apoptosis, the self-destruction of mitochondria. “But apoptosis is a process that takes place over a period of up to 72 hours, on average,” says Parnia.
At the same time, free radicals (unstable molecules like hydrogen peroxide and superoxide) wreak havoc by rupturing cell membranes and deactivating enzymes.
If cardiopulmonary resuscitation or another life-saving measure suddenly restores blood flow, it can paradoxically trigger a second, more devastating wave of destruction: blood vessels leak, tissue swells, and cell death accelerates.
Parnia compares this phenomenon to the devastation caused by earthquakes followed by tsunamis. The earthquake sets the scene, but it is the tsunami that often inflicts the most damage. “By instituting anti-tsunami measures, or treatments once morest the secondary injury process, we can save brain functions, which opens up a whole new field of medicine,” Parnia explains. “And it is precisely this phenomenon that the Yale group has brilliantly demonstrated”: the advantages of controlling the process of restoring blood and oxygen to the tissues.
Clinical practice, however, often lags behind science. According to Parnia, most of us have an outdated conception of death, including many doctors and scientists. “We all grow up hearing that death is a permanent end, not recognizing that it is only because we have no treatment. It is not necessarily the permanent end of the cells. »
RESUCCITATE THE ORGANS
In order to demonstrate that it is possible to recover cells and organs well following the usual delay, the Yale team caused cardiac arrest in pigs, animals chosen for their similarities to humans, and left the bodies on the operating table at room temperature.
After an hour, the researchers injected OrganEx into the animals’ circulatory system. This blue solution is a proprietary blend containing “amino acids, vitamins, metabolites and a cocktail of thirteen different compounds that have been optimized to promote cellular health, reduce stress and cell death, and suppress inflammation,” according to Andrijevic. The solution is mixed with the animal’s blood and circulated for six hours using a machine similar to extracorporeal membrane oxygenation devices (ECMO) used to provide temporary cardiovascular support to injured patients. This device, however, contains special pumps to deliver OrganEx without destroying blood vessels, a dialysis unit to filter out toxins, and sensors to monitor fluid pressure and flow.
For the experiment, some animals received no treatment. Those who received it were treated using ECMO, which pumped blood containing oxygen but not carbon dioxide through the body.
Designed with input from an external advisory committee and other experts, the experiments adhered to standards for humane treatment of animals; the pigs were anesthetized and given neural blockers to prevent them from regaining consciousness. “We wanted to see how well we might restore or reverse cell death in damaged organs. Our task was not to revive the animal,” says Sestan.
When the team examined brain, heart, liver and kidney samples treated with OrganEx under a microscope, they found that they looked more like healthy tissue than disintegrated tissue from untreated animals.
Single-cell RNA sequencing, which provides real-time insight into the molecular processes taking place inside the cell, showed that organs from OrganEx-treated pigs resumed their basic functions, such as repairing DNA and maintaining cell structure, while preventing cell death. Also, the heart cells started beating and the liver cells resumed their task of absorbing glucose from the blood.
However, Sestan invites to interpret its results with caution. “We can say that the heart is beating, but to determine whether it beats like a healthy heart or not, further studies will be needed. »
(Read: Our cells die so we can survive.)
FUTURE OBJECTIVES
Ultimately, the goal of transplant researchers is not just to save donor organs, but also to improve them before transplantation, according to Abbas Ardehali, a cardiothoracic surgeon at the University of California, Los Angeles (UCLA ), who led clinical trials of so-called “organ-in-the-box” systems, a machine that maintains the physiological conditions of an organ when it is outside the body, for the heart and the lungs. “In regarding ten years, I imagine that the organ that will be removed will be very different from the one that will be transplanted. »
Gene therapy, for example, might one day transform the donor organ to match the biology of the recipient. “Imagine the future. You will be able to come, receive your new kidney and go home, without needing to take immunosuppressants”, imagines Ardehali.
Other researchers, such as Hanane Hadj-Moussa, a molecular biologist at the Babraham Institute in Cambridge, England, turn to nature to develop organ preservation strategies. The wood frog and the rat-taupe no, for example, are able to survive in freezing cold or low oxygen environments, similar to those experienced by the human body when the heart no longer pumps blood. “To conserve energy during hibernation, they turn off many non-essential processes,” says Hadj-Moussa. Learning to stop these processes in donor organs might help preserve them.
Brandacher is investigating whether antifreeze proteins from a species of arctic fish might prevent the formation of ice crystals, which can rupture cells, in organs. With his partners, he has demonstrated that the addition of antifreeze proteins to preservation solutions makes it possible to preserve organs between -6 and -8°C. His group is also using these proteins to see if it is possible to lower the temperature of organs to minus 150°C, the temperature at which biological time stops; thus, “we might consider organ storage”. So far, Brandacher’s research has been limited to animals, but he says studies aimed at treating human organs with antifreeze proteins may be possible within a year or so.
Patients might also benefit from advances in healing damaged organs, experts say.
However, Sestan does not yet consider the potential clinical implications on living subjects, preferring to focus on organ transplants. Its next objective is to test the organs treated with Organ-Ex, in particular by transplanting them into recipient pigs in order to assess their functioning in a living animal. “When something can really affect and transform society, we have to be careful not to speculate. »
