Scientists create universal blood-type organs for transplant

Scientists have converted eight type-A lungs into type-O lungs. One day, these “universal donor” organs could transform organ transplantation.
Grant Currin
Enzymes convert a human lung to type O during ex vivo lung perfusion.

There are 106,435 people in the United States waiting for an organ transplant.

Most of them will be waiting for a long time.

Someone in need of a heart or lung spends an average of four months on the recipient list before a suitable organ becomes available. The wait for a kidney typically lasts five years.

These averages don't reflect the patient's blood type, a crucial factor in determining whether they get the organ they need.

Marcelo Cypel, a professor of surgery at the University of Toronto and a thoracic surgeon, tells IE that people with type O blood are 20 percent more likely to die while waiting for a lung than patients with type A blood. With 45 percent of people in the U.S. having type O blood, the odds of being on the wrong side of this problem are nearly that of a coin flip.

The reason for that disparity lies in the immune system: The immune system of someone with type O blood will attack a transplanted organ that comes from a donor of any other blood type.

The problem is so severe and fundamental that the waitlists for the various organs are separated by blood type, Cypel says. It's a biological reality that "creates a lot of inequality."

"Ideally, we would like to say, well, the sickest patient should be the one getting the next organ, but it's often not the case," he says.

The separation by blood type also leads to missed opportunities for a new lease on life if someone has the wrong blood type to the available donors.

"There are situations where we may get a B donor, but we don't have a B recipient" who can receive the organ. "In that case, today, we just don't use that organ; that organ gets buried," he says.

"If we could use that organ in any of the patients in our waitlist, then we would always have a patient to receive that organ," he says. Because, again, there are more than 100,000 people in the U.S. who are waiting to rush to the hospital to receive a life-saving organ.

In a study published on Wednesday in the academic journal Science Translational Medicine, Cypel and a large group of co-authors report a potential solution: They used a combination of technologies to convert eight type-A lungs into type-O lungs, which are far less likely to be attacked by a patient's immune system, regardless of their blood type.

One day, these "universal donor" organs could transform organ transplantation.

Blood type is a huge deal 

The immune system is constantly on the lookout for anything that doesn't seem to belong. That hypervigilance is well-suited to fighting against the harmful bacteria, viruses, protists, fungi, parasites, and toxins that frequently find their way into our bodies. But it can also cause problems. Asthma, eczema, type-1 diabetes, rheumatoid arthritis, and lupus are common diseases that result from an overactive immune system turning on the body's tissues.

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Something similar would happen if someone received a blood-type-incompatible organ.

Blood type is one way the immune system keeps track of which tissues belong to a person. It comes down to the relationship between a person's antibodies and the minuscule structures, called antigens, that are located on the outside of a person's cell, verifying that whatever wants to enter the cell is not a dangerous invader. A red blood cell, which has a diamter less than one-hundredth that of a human hair, is covered with about a million antigens that  determine if someone's blood type is A, B, AB, or O, according to Stephen Withers, an enzymologist at the University of British Columbia and another co-author on the paper.

The body uses different blood typing systems, but the most important for organ transplants is this ABO system.

Withers tells IE that our bodies probably didn't develop blood types to defend against other humans' blood. It seems far more likely they protect "against [pathogens] that happened to carry those same sugars on their surface," he says.

Researchers are still studying the evolutionary history of blood types. Still, it seems clear that people with certain blood types have an extra degree of natural immunological protection against certain diseases.

No matter how the ABO blood types came about, the differences can be fatal: A blood transfusion of just 50 milliliters of incompatible blood can kill a person.

Sugars on the outside of cells are the problem

The cells that comprise organs are also covered with antigens.

"If you're O blood type… you have a certain sugar on the surface [of your cells], which I'll represent with a circle," Withers says. Someone with an A blood type has the same sugar, "but in addition to that circle, you've got a triangle attached [to it]." Someone with a B blood type has the same circle but a square instead of a triangle.

"A and B are different only in this additional sugar," Withers says. Someone with AB blood has both a triangle and a square attached to each of the many, many circles on their cells.

People with type O blood are highly desirable organ donors because their antigens are not adorned with the type-A triangles or type-B squares that would provoke the other's immune systems. That's why they're called the "universal donor" type.

(Type AB people are in the clear when it comes to receiving an organ — their immune systems are unfazed by any of these antigens.)

The study published on Wednesday shows that it's possible to convert lungs to type O by cutting off the extra sugars. The researchers figured out how to use enzymes to remove billions of squares or triangles while leaving the circles intact.

A pungent place to start

The idea for changing blood type began about ten years ago when Withers and a new colleague at the Centre for Blood Research at the University of British Columbia, Jayachandran Kizhakkedathu, "started speculating about [whether] you could you discover enzymes that could modify these antigen structures… to convert type A or B" blood to type O, he says.

While using enzymes to cleave the squares or triangles from the circles wasn't an entirely new idea, recent advancements in genomics and new laboratory technologies had only recently made it possible to quickly (and inexpensively) sift through enough enzymes to have any hope of finding one that's efficient enough to do the job in a clinical setting.

The researchers didn't try to develop their own enzyme. Instead, they turned to the vast library of enzymes that bacteria living in the human gut have produced during our shared history of co-evolution.

"The same A, B, and O antigens [that are on blood and organ cells] are present on the on the linings of our gut," Withers says. His team "hypothesized that there probably are bacteria within our gut that are producing enzymes to forage [those] sugars, and hopefully, some of them would be working on the antigens."

"They're eating us slowly," he says. It sounds gruesome, but it isn't typically a problem.

The researchers sought out those enzymes by extracting segments of bacterial DNA from human fecal samples. They "pasted" those fragments into tens of thousands of individual E. coli bacteria.

"The hope is, and you very much have to keep your fingers crossed at this stage, that the E. coli will read that DNA as if it was its own" and produce the protein it codes for, he says.

They ended up with roughly 20,000 different versions of E. coli. High-throughput techniques enabled the researchers to quickly look for E. coli that were producing enzymes that had already evolved to cut the squares and triangles off the circles.

"We ended up with basically 10 or 12 hits that were viable," including some near-duplicates, he says. One of the enzymes turned out to be about thirty times faster than the others, meaning it would take far less of that enzyme to "get the job done."

Once they found a DNA sequence that coded for the enzyme they'd been looking for, the researchers could safely produce billions of copies without ever going near another fecal sample.

"Sometimes people get that mixed up," he says.

The research builds on another revolutionary technology

Organs are very delicate when they're outside the body. Ordinarily, doctors preparing organs for transplants "shut down the metabolism of the organ" by putting it into a special liquid and cooling it to a few degrees above freezing, Cypel says.

Fifteen years ago, his team started developing a new approach. Their "ex vivo lung perfusion" technique "brings the organ back to life," he says. They keep it at body temperature — and "moving and breathing" — by pumping liquid through the vessels, the way a heart would pump blood.

Ex vivo lung perfusion has already transformed lung transplantation. The method doesn't increase the likelihood of success over the conventional approach. The one-year survival rate is roughly 90 percent for both techniques, and the five-year survival rate is about 65 percent, says Cypel.

However, the new technology is a big deal because it allows surgeons to use lungs that couldn't have been used otherwise "because they had infections or other injuries," Cypel says. "We can repair them in the system."

According to the published results, it's also an effective delivery system for the enzymes Withers and his colleagues developed.

"We treat the organ for a [few] hours with the enzyme going to the vessels," Cypel says. After that period, "99.9 percent of the antigens are removed."

What they're left with appears to be a lung that's been converted to type O, the universal donor type.

The future is bright — but it's also uncertain

It will probably be quite some time before regular patients get organs converted using the antigen-cleaving enzymes.

While the ex vivo lung profusion technique is already being used in operating rooms worldwide, Withers and his colleagues face an unusual hurdle in getting their technology approved for clinical trials, much less for clinical use.

The problem is that the ABO blood typing system isn't found in many animals, aside from humans. That's a problem because the FDA is accustomed to using data from experiments in non-human animals as a basis for approving clinical trials.

"It's a little bit different for them to decide how to proceed," says Withers.

These new research results are an essential step in that direction. By showing that the enzymes can dramatically lower the number of antigens on lungs that weren't suitable for transplantation into human patients, the researchers have taken a big step toward proving to stakeholders — including potential investors, whose money will likely fund the experiments necessary for approval — that the research could be transformative.



Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs

Donor organ allocation is dependent on ABO matching, restricting the opportunity for some patients to receive a life-saving transplant. The enzymes FpGalNAc deacetylase and FpGalactosaminidase, used in combination, have been described to effectively convert group A (ABO-A) red blood cells (RBCs) to group O (ABO-O). Here, we study the safety and preclinical efficacy of using these enzymes to remove A antigen (A-Ag) from human donor lung using ex vivo lung perfusion (EVLP). First, the ability of these enzymes to remove A-Ag in organ perfusate solutions was examined on five human ABO-A1 RBC samples and three human aortae after static incubation. The enzymes removed greater than 99 and 90% A-Ag from RBCs and aortae, respectively, at concentrations as low as 1 g/ml. Eight ABO-A1 human lungs were then treated by EVLP. Baseline analyses of A-Ag in lungs revealed expression predominantly in the endothelial and epithelial cells. EVLP of lungs with enzyme-containing perfusate removed over 97% of endothelial A-Ag within 4 hours. No treatment-related acute lung toxicity was observed. An ABOincompatible transplant was then simulated with an ex vivo model of antibody-mediated rejection using ABO-O plasma as the surrogate for the recipient circulation using three donor lungs. The treatment of donor lungs minimized antibody binding, complement deposition, and antibody-mediated injury as compared with control lungs. These results show that depletion of donor lung A-Ag can be achieved with EVLP treatment. This strategy has the potential to expand ABO-incompatible lung transplantation and lead to improvements in fairness of organ allocation.

See the full article here: 10.1126/scitranslmed.abm7190

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