Organ transplantation is a miracle of modern medicine, but it has a pipeline problem: roughly 20 people die every day while waiting for an organ transplant. Scientists at Harvard Medical School think they may be able to solve that problem by sprucing up old organs from pigs and animals, giving the organs and their new owners alike a new lease on life.
Surgeon Harald Ott and his lab have developed a method that strips animal organs of their cells by washing them in a detergent, leaving behind a tissue scaffold that can be seeded with human stem cells from the patient in need. This would prevent a patient’s body from rejecting the organ, and mean that transplantees would not need to spend their lives on anti-rejection drugs. As the cells grow on this scaffold, the lab uses a bioreactor that pumps the organ, keeping it healthy by stimulating it in the same way it would move in the body.
The team has successfully refurbished lungs, kidneys, hearts, and portions of intestines from rats and pigs to make them human-donor compatible, and then transplanted those organs back into animals. Though the human cells in these transplanted organs made them incompatible with the rats’ and pigs’ bodies, the organs worked — showing significant promise for future human trials. The lab also successfully re-grew muscle within human cadaver hearts that had been similarly stripped of their cells.
“Your iPhone breaks, your battery breaks, you switch it out. Medicine, in some ways, is possibly moving in that direction,” Ott told the Wall Street Journal. “I could measure you up, basically, take an organ off a shelf, ideally make it personalized so that you wouldn’t reject it, and then I would implant it into you.”
However, Ott estimates it will be at least a decade before these organs will be ready for clinical trials in humans. In the mean time, Ott is among a wide group of scientists seeking to improve the transplantation process. From better methods of preserving donor organs, to gene editing pig organs for humans, to even bio-printing and growing human organs in the lab, the era of patients waiting endlessly on transplant lists may be coming to an end.
If someone is suffering from kidney failure, one available option is dialysis. While it may sometimes be the treatment recommended to such failed organs, it can become expensive over time, and may not be the decisive solution they were expecting.
An alternative option is to get a kidney transplant, with successful operations resulting in the extension of a patient’s life. Unfortunately, kidneys are in short supply, as the most in-demand organ: according to OrganDonor, nearly 116,000 people are on the national transplant waiting list as of August 2017, 82.9 percent of which are waiting for a kidney organ.
The main reason for the kidney shortage lies in the fact that nearly one out of five kidneys recovered are actually discarded, and in recent years, the number of discarded organs has only increased. New research suggests this probably shouldn’t be as big of a problem as it is, and many of the discarded kidneys could actually be used by patients desperate for one.
Led by Dr. Sumit Mohan, MD, and Dr. S. Ali Husain, MD, from the Columbia University Medical Center, the study analyzed information gathered between 2000-2015 on the deceased who had both kidneys recovered, but with only one transplanted.
“It is obviously impossible to tell with certainty what would have happened to any discarded kidney if it had been used instead,” explained Dr. Sumit Mohan. “As a result, it has been difficult to categorize these discards as ‘appropriate’ or ‘inappropriate.’”
Mohan continued, adding, “We therefore aimed to identify kidney donors from whom one kidney was used but the partner kidney in the pair was discarded. By doing so, we could control for donor characteristics to better understand the reasons for discard, and whether concerns about using certain kidneys were justified.”
The team analyzed information on 88,209 donors — amounting to 176,418 kidneys — and discovered the reason to discard certain kidneys was due to “unappealing” traits. However, the partner kidneys used for transplants contained some, if not all, of the same traits, and performed well in spite of that. Based on Mohan’s prior explanation, it’s possible that thousands of usable kidneys were mistakenly discarded, causing leaving many to die without a whisper of hope, according to Dr. Husain and the rest of the team:
“We therefore concluded that many of these discarded kidneys were in fact quite usable, and that systems-level changes are needed to encourage better utilization of this valuable but scarce resource,” said Dr. Husain.
According to Kidney.org, 4,761 patients died while waiting for a transplant in 2014, with another 3,668 eventually becoming too sick to receive a transplant.
In a separate paper, Matthew Kadatz, MD and John Gill, MD from the University of British Columbia noted how Mohan and Husain’s research makes a strong argument to address the policies in place that allow so many organs to go unused.
“The current discard of kidneys would be hard to explain to the families of deceased donors and is a disservice to the thousands of older age and diabetic wait-listed patients who would benefit from transplantation with these higher risk kidneys and who have consented to receive them,” the pair wrote.
Only time will tell if this work ensures that every healthy kidney is fully utilized. Such a change wouldn’t completely eliminate the demand for kidneys, but it would certainly go a long way to save thousands of lives. Especially the lives of those who have been waiting multiple years for a chance to return to a normal life.
Around the world, lists of patients in need of an organ transplant are often longer than the lists of those willing (and able) to donate — in part because some of the most in-demand organs for transplant can only be donated after a person has died. By way of example, recent data from the British Heart Foundation (BHF) showed that the number of patients waiting for a heart transplant in the United Kingdom has grown by 162 percent in the last ten years.
Now, 50 years after the first successful heart transplant, experts believe we may be nearing an era where organ transplantation will no longer be necessary. “I think within ten years we won’t see any more heart transplants, except for people with congenital heart damage, where only a new heart will do,” Stephen Westaby, from the John Radcliffe Hospital in Oxford, told The Telegraph.
Westaby didn’t want to seem ungrateful for all the human lives saved by organ transplants, of course. On the contrary, he said that he’s a “great supporter of cardiac transplantation.” However, recent technological developments in medicine may well offer alternatives that could save more time, money, and lives.
“I think the combination of heart pumps and stem cells has the potential to be a good alternative which could help far more people,” Westaby told The Telegraph.
An Era of Artificial Organs
Foremost among these medical advances, and one that while controversial has continued to demonstrate potential, is the use of stem cells. Granted, applications for stem cells are somewhat limited, though that’s down more to ethical considerations more than scientific limitations. Still, the studies that have been done with stem cells have proven that it is possible to grow organs in a lab, which could then be implanted.
Science has also made it possible to produce artificial organs using another technological marvel, 3D printing. When applied to medicine, the technique is referred to as 3D bioprinting — and the achievements in the emerging technique have already been quite remarkable.
Other technologies that are making it possible to produce synthetic organs include a method for growing bioartificial kidneys, the result of a study in 2016.
For his part, Westaby is involved in several projects working to continue improving the process: one uses stem cells to reverse the scarring of heart tissue, which could improve the quality of life for patients undergoing coronary bypass. Westaby is also working on developing better hardware for these types of surgical procedures, including inexpensive titanium mechanical heart pumps.
Together with 3D bioprinting such innovations could well become the answer to donor shortages. The future of regenerative medicine is synthetic organs that could easily, affordably, and reliably be printed for patients on demand.
United Therapeutics is set to take a big step forward in its plans to pursue advances in the field of organ transplantation thanks to a new partnership with the University of Maryland. The company has announced a $ 24 million research partnership that will help the school establish a center specializing in cardiac xenotransplantation research, the first of its kind in the US.
Xenotransplantation refers to the cutting-edge practice of transplanting organs between different species. Organ shortages are already a very real concern, and they could grow more pronounced in the future. If we’re able to genetically modify organs from animals, we might be able to better satisfy demand.
The center, which will be constructed in Baltimore, is set to focus on cardiac xenotransplantation. United Therapeutics is also collaborating with the University of Alabama on research pertaining to kidneys, and Columbia-Presbytarian on lung transplants.
“Xenotransplantation offers hope to thousands of patients who are currently waiting for heart transplants and most of them die waiting for the human organs,” wrote Muhammad Mansoor Mohiuddin, director of xenoheart transplantation in the Department of Surgery at the University of Maryland School of Medicine, in email correspondence with Futurism. “Xenotransplantation will provide an alternative to the current available treatment options for end stage organ failure.”
The partnership will focus on transplanting pig hearts into human bodies. This concept has been the subject of various studies, including a recent project that was centered around cloned pigs, and a Chinese effort that expects to carry out a successful transplant within the next two years.
“This grant thrusts our Transplant Division into an elite group of centers doing cutting-edge xenotransplantation research,” said University of Maryland’s chair of the Department of Surgery, Dr. Stephen Bartlett, in a press release. “We now can look forward to exponentially expanding our department’s current and new xeno initiatives, creating an even greater impact in accelerating our trajectory of discovery and innovation in medicine.”
Xenotransplantation Allows for More Organ Donors
Mohiuddin stressed that both the University of Maryland and United Therapeutics are eager to make this procedure a “clinical reality.” This isn’t a research project intended to push the limits of what might be feasible; it’s an effort to establish how cardiac xenotransplantation might be used in a practical context.
To that end, researchers will address some of the most pressing issues that are stopping people in need of organ transplants from being helped. Mohiuddin describes the human immune system’s rejection of animal organs as being a “major barrier” that has prevented the success of this method in the past. However, genetic modification is offering up ways to counteract these issues.
“Due to our ability to genetically modify the pigs to make their organs less immunogenic to humans, and the development of novel immunosuppressive drugs, we are able to prevent or delay rejection,” explained Mohiuddin. Genetic engineering also makes it possible to remove any viruses that might infect humans after the organ has been transplanted.
In 2016, Mohiuddin led a groundbreaking trial where immunosuppressive drugs were used alongside immunomodulatory antibodies to allow a baboon to support a heart inside its abdomen (with the original heart intact) for a record-breaking 945 days. Now, the challenge is how to build upon those techniques to transplant animal hearts into human patients that can endure for an even greater period of time.
When a failing heart, liver, or other vital organ proves resistant to all available forms of treatment, a dying patient’s only shot at survival may be an organ transplant. Unfortunately, there aren’t enough donor organs to save all the patients who need one. Feeling desperate with precious time running out, some patients may attempt to purchase an organ illegally. In fact, thousands of sales or purchases of black market organs take place every year, according to the World Health Organization.
In the 1980s, Iran had both a shortage of legally donated kidneys and subpar dialysis equipment to treat the growing segment of the population with end-stage renal disease (ESRD). It did have highly trained surgeons capable of performing organ transplants, though. So in 1988, the nation decided on a bold (and somewhat controversial) new strategy to eliminate the dangers that come with procuring or receiving an organ illegally: they made it legal for a living person to sell their kidney.
Given this substantial need, perhaps it’s not a surprise that people turn to the black market to save their lives. While exact figures are hard to come by (the black market doesn’t exactly have any official ways to track it), the illegal trade of all organs generates between US$ 840 million and $ 1.7 billion annually and accounts for an estimated 10 percent of transplanted organs, according to a 2017 report from Global Financial Integrity (GFI), a non-profit research and advisory organization focused on illicit financial flows.
Kidneys are the most-frequently sold organs for a fairly simple reason: humans have two and can live a healthy life with just one. Selling kidneys, then, might seem like a simple matter of supply and demand — the demand for kidneys is high, so willing donors should, in theory, be able to negotiate their price from a position of strength.
However, the population supplying the organs is nothing like the people receiving them. GFI researchers found that kidney buyers are usually middle- to high-income individuals from developed countries, while kidney sellers are typically from the world’s most vulnerable populations. For poor and uneducated citizens of developing countries, selling a kidney may seem like the only way to escape poverty or settle a debt.
Recipients may pay upwards of $ 200,000 for a kidney, but the donor may receive as little as $ 5,000 of that (a broker pockets the rest), according to the WHO. Some donors aren’t paid at all, and because the sale is illegal, they have little recourse to obtain the money they are owed.
Even worse, inadequately trained surgeons may perform the surgeries under unhygienic conditions. Donors may be left with dangerous, painful complications that could force them to miss work or require expensive follow-up care, leaving the donor in a more financially precarious situation than prior to selling his or her organ.
A Market Unlike Any Other
By legalizing the sale of kidneys from living donors, Iran has been able to avoid these pitfalls of a black market, and today, about 55 percent of all kidneys donated in the nation are from living donors, according to government statistics obtained by the Associated Press. For comparison, only about 38 percent of kidney donations in the U.S. are from living donors. The rest come from deceased donors, and those organs aren’t as likely to keep recipients healthy in the long term.
The process of buying or selling a kidney in Iran is fairly straightforward, a 2011 paper shows. A doctor writes a letter stating that a patient needs a kidney, and the patient then brings that letter to an office of the Kidney Foundation of Iran, a nonprofit organization that facilitates the nation’s kidney transplants. The organization adds the patient to a list and sorts by his or her blood type. Patients in the midst of a medical emergency and disabled soldiers are placed higher up on the list, according to the paper.
To be approved as a living donor, interested Iranians go to one of the foundation’s offices to undergo medical testing (the donor pays for the tests). If the foundation believes the kidneys are healthy enough for transplantation, they approve the donor. Next, the foundation will contact the person nearest the top of the list for that donor’s blood type, taking into consideration other factors such as the donor’s physical build — a particularly small kidney might go to a child or female patient even if they are listed below average-sized men because a closer match between the size of a donated kidney and a recipient’s original kidneys results in a better long-term outcome.
The Iranian government pays for the transplant surgery itself as well as one year of health coverage for the donor after the surgery. The recipient (or their family) pays the donor, using the foundation as an intermediary, Farshad Fatemi, a micro-economist at Sharif University of Technology and author of the 2011 paper, told Futurism. The base price is set at $ 4,600, but if the donor isn’t willing to sell their kidney for that price, they and the recipient can privately negotiate a higher amount shortly after a match is set up. In 2011, Fatemi estimated that organ recipients will sometimes pay an extra $ 530 to $ 1,060 on average.
If the donor and recipient agree on terms, both undergo tissue testing to make sure the recipient would be unlikely to reject the new kidney. If the results are favorable, the patient and donor sign an agreement and are given a list of centers and doctors that can perform the transplant. The center will hold the check from the recipient during the surgery and hand it over to the donor afterward to ensure payment is made.
A Viable Model?
While the Iranian system does speed up the process of organ donation for patients — the average wait between reaching out to the foundation and receiving a kidney is five months — Fatemi said the legal kidney market is not without its shortcomings.
One issue is that doctors often fail to follow up with donors post-surgery. It’s important to follow donors for several decades after donation to see how the process affects them, Fatemi stressed, but said doing so would be difficult, as donors often try to hide their identity to avoid the stigma associated with selling a kidney. Educating the public on the benefits of donation, paid or not, could help solve this problem, Fatemi said.
Fatemi also noted that, just like the illegal kidney market, the poorest, more vulnerable members of society are still the ones donating in Iran’s legal market, and they typically only do so because they feel they have no other option to escape poverty. “I have been to the foundation. The people who are donating are young and full of energy, but they are poor and selling a part of their body to solve what may amount to very small problems in their everyday lives,” Fatemi said.
Given the lack of follow-up, no one even knows for sure if these vulnerable citizens benefit from the sale.
Though Iran’s market may be imperfect and only stops the illegal sale of one type of organ, Fatemi believes it’s better than the alternative of having a black market. The system protects disadvantaged donors by ensuring they are paid what they are owed and taken care of medically, and it also gives recipients a second chance at life that they may not get otherwise.
“With these transplants, people can live two, three decades longer than they would without them,” said Fatemi. “During that time, they have good times with their families. They are productive members of the economy. That’s the positive side.”
For now, Iran still stands alone in allowing citizens to legally sell their kidneys, and no other nation appears on the cusp of doing so. However, that’s not to say a new legal kidney market couldn’t emerge. A 2015 study published in the journal American Economic Review concluded that U.S. citizens were more open to the idea of organ sales when presented with information on their potential benefits, so at least one barrier to creating such a market — public disapproval — could potentially be eliminated through education programs.
Still, Iran didn’t decide to legalize kidney sales until the situation was dire, so if history is any indicator, the next nation to test a system will likely be one facing a similar situation, perhaps somewhere like India where end-stage renal disease is becoming more common and the black market is thriving. Meanwhile, nations where the frequency of end-stage renal disease has stabilized over the last decade, such as the U.S., may choose to continue with the status quo until new technologies and treatments render the kidney market, both legal and illegal, obsolete.
“Every time I go to the foundation, I wish for the day when we can clone a kidney for a person,” said Fatemi. Until that happens, he said, Iran’s system is a good one.
In a study published in the journal Nature Chemistry, the researchers showcased a purely chemical technique for gene assembly. It uses an efficient and rapid-acting chemical reaction called click chemistry that puts together multiple modified DNA fragments into a gene — a process called click DNA ligation.
In the Netherlands, Els van der Heijden has lived for over 50 years with cystic fibrosis (CF). She hasn’t let it stop her from finishing college and starting a career in consulting, rising above the many challenges that the hereditary condition involves. But despite her resilience, Heijden has described living with CF as living with “a dark cloud hanging over my head.” This was, however, before she read about a child named Fabian whose life was saved with a “mini-organ” grown from a small piece of colon tissue (the colon is one of several organs affected by CF).
The organoid, or lab-grown “mini organ,” wasn’t implanted in Fabian but, rather, was used to test the easily accessible, inexpensive drug ivacaftor (Kalydeco). Because Fabian’s CF was caused by a rare mutation, treatment options weren’t obvious. The test showed the drug to be extremely effective, giving Fabian relief within hours. After discovering this, Heijden spoke to her doctors and they agreed to have a “minigut” created for her as well. Her miniature organ was tested with the drug Orkambi — a combination of ivacaftor and another compound. Remarkably, the result was similar to Fabian’s; she responded beautifully. “I had an enormous amount of energy,” she said, “for the first time ever, I felt like my body was functioning like it should.”
This strange, life-saving medical practice was developed in the lab of Hans Clevers. Since the initial creation/discovery, Clevers has made it possible to create organoids from the stomach, pancreas, liver, and even brain. Organoids have even been created from tumor cells — a process where scientists introduce mutations into organoids made from healthy tissue, thereby allowing them to study the progression of cancer.
Stories like Heijden’s show just a fraction of the potential organoids hold. According to Rudolf Jaenisch, a stem cell scientist at the Massachusetts Institute of Technology in Cambridge, “It is highly likely that organoids will revolutionize therapy of many severe diseases.” While Clevers “was always driven by curiosity,” the real-world applications of this curious endeavor are becoming not just feasible, but potentially life-changing.
Organoids are created from incubated tissue samples and can be used to repair tissue, test drugs (as was demonstrated with Fabian and Heijden), test toxicity, study microbial interaction, model infection, and study the progression and development of cancers. One thing that sets these types of studies apart is how effective the use of organoids is for patients with less common mutations. Heijden shares her mutation with only two others in all of the Netherlands. But because the mini-organ that the drug was tested on was made with her own tissue, it was possible to show the potential effects on Heijden herself. It will be interesting to see how this method progresses through continued testing and regulatory approval. For now, it certainly has Heijden’s approval, who described her recovery: “It was as if someone opened the curtain and said, ‘Look, the sun is there, come out and play. And I did.”
This year, novel organ transplant procedures have been getting a fair amount of attention. While some may seem rather bizarre — like that human head transplant currently in the works — others could be the beginning of a new era in organ transplantation. Chinese researchers have been working on using genetically modified pig organs for human transplantation, and they expect it to be available in the next two years.
In order to confirm these effects, researchers from more than 10 institutes in China have asked permission from the government to conduct human clinical trials use pig organs for transplants. These trials are part of a a national xenotransplantation project funded by the Chinese central government.
Piggy Organ Bank
China seems to be leading the way in this field, producing more genetically modified pigs than any other country. For pig organ transplants to work, modifying pigs by removing certain genes are necessary to prevent the human immune system from rejecting the donated organs. The South China Morning Post (SCMP) reports that cloning farms in China produce a total of 1,000 cloned pigs a year, according to one researcher.
That’s potentially a huge pig organ bank, assuming the government manages to approve clinical trials soon. For Zhao Zijian, director of the Metabolic Disease Research Centre at Nanjing Medical University in Jiangsu, the government seems to be taking too long.
“We have patients dying from organ failure and their desperate relatives pleading for them to have the chance to live,” Zhao, who’s also a senior scientist at a xenotransplantation lab, told the SCMP. “But when we turn to the authorities in charge of approving the clinical trials, all we get is silence. We understand it must be very hard for the government to make a decision, but it’s time we got an answer.”
Pig organs could speed up the process of getting transplants. In China, for instance, over 300,000 patients require organ transplants, but only less than 10,000 organs are donated each year. Moving forward, initiative when it comes to coming up with the necessary regulations are needed. “Someone has to take the first step – whether it’s the US Food and Drug Administration or the China Food and Drug Administration,” Zhao said.
A team of engineers at the University of Toronto have created a way to fix damaged organ tissue without surgery. The method involves a needle, a patch the size of the postage stamp, and a bit of time.
The patch itself has shape-memory capabilities, meaning it will always return to its default state when introduced to the right temperature. Once inserted into the needle and injected into the body, the patch unfolds and expands before proceeding to repair and replace missing tissue. Made using a biocompatible, biodegradable polymer, the patch will dissolve over time, and in its wake, leave behind newly-made tissue.
Biomedical engineering Professor Milica Radisic and her team have been working on the project for nearly three years, with a lot of their work devoted to creating a tissue patch that could work via injection. Miles Montgomery, a PhD candidate in Radisic’s group, finalized the patch’s design after a dozen attempts.
“At the beginning it was a real challenge; there was no template to base my design on and nothing I tried was working,” said Montgomery in an interview for Eureka Alert. “But I took these failures as an indication that I was working on a problem worth solving.”
Fixing More Than Hearts
The expanding tissue patch was initially made to treat those that have suffered from heart attacks, and could be used instead of open-heart surgery. And while it could have been an implant, Radisic explains that the risks outweigh the benefits. If the implant required surgery to be implemented, it wouldn’t be easily accessible to everyone that needed it. Since heart attacks are extremely traumatic on the human heart, leaving it in a vulnerable and precarious condition, surgery after the fact could risk the patient’s survival.
Going forward, Radisic and her team are working with researchers from the nearby Hospital for Sick Children. They intend to study the long-term benefits of the patches, as well as their stability. The patch has been tested on rats, to great success, but there is a long way to go before clinical trials. But if things pan out, the patch might also be used for other traditionally damaged organs, such as the liver. To buy more time for these studies, patents on their patch and the injection process have been applied for.