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How do cold conditions help organ transplants?

How do cold conditions help organ transplants?


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Body organs are kept cold in-between explanting them from the donor and implanting them in the new host. How do these cold conditions help organs to stay viable while they haven't fresh blood, energy and oxygen supply?


This paper actually goes into the whole history of organ transplants.

In short it seems to have the following effects:

  • preservation - usually with a specific solution to help.
  • slows down extracorporeal ischaemic damage
  • slows down hypoxic damage
  • slows down the metabolism (energy consumption) and thus the need for oxygen that blood provides.

Remember that the cooling doesn't allow the organ to live indefinitely, and may only work for a few short hours depending on the organ.

I highly recommend reading the paper if you'd like to know more about organ transplant. They went into great detail about the past and present and the abstract also says they discuss new techniques about to be don't in clinical trials.


What Is The Shelf-Life Of Organs For Donation?

In every medical drama, there is at least one episode where the doctors race against time to secure an organ for someone in desperate need of a transplant. They jump into helicopters or jets, hitch rides from strangers, or heroically run to deliver a precious life-saving organ to the patient in the nick of time. But why the rush? Do organs outside the body have a shelf life?

Medical practitioners are in a constant race against time to ensure that patients receives the organs they need. (Photo Credit : Dan Race/Shutterstock)


KIDNEY TRANSPLANTATION

Despite that renal transplantation is considered the best therapeutic option for the treatment of ESRD, access to transplantation varies among centers (Ravanan et al. 2010) and countries (Stel et al. 2005). The mean percentage of ESRD-prevalent patients included in the waiting list is �%�%, but some centers and countries may have lower percentages of ESRD patients listed. Comorbidity and demographic factors may account for differences in the access to transplantation. Activation on the waiting list in the first 2 years of the start of renal replacement therapy (RRT) significantly decreases with older age, nonwhite ethnicity, and diabetes mellitus, and the probability of receiving a kidney transplant follows a similar trend. According to the United Kingdom Transplant Registry, the probability of receiving a kidney allograft is reduced by 㹀% in older recipients in comparison with young patients, and by 㸰% in nonwhites in comparison with Caucasians. Differences among centers on the time taken to activate inclusion on the waiting list and the proportion of listed patients with ESRD may widely vary, and a similar observation also applies regarding the access to transplantation (Ravanan et al. 2010). These center disparities may not be strictly explained by patient-related factors and might reflect distinct center criteria on a candidate’s evaluation for renal transplantation. A patient starting dialysis in a nontransplanting renal center was less likely to be registered for transplantation (odds ratio 0.85, 0.77 to 0.94) or receive a transplant from a donor after cardiac death or a living kidney donor (0.69, 0.59 to 0.80) compared with patients cared for in transplanting renal centers but with similar chances of receiving a transplant from a donor after brain stem death. In another study conducted in England and Wales, specific variables significantly associated with listing were age, primary renal disease, graft number, social deprivation, and ethnicity but not gender. In contrast with the previous publication, other investigators have reported that whether the renal unit was also a transplant unit was not significant (Dudley et al. 2009). A multinational European study based on the ERA-EDTA Registry (2010) analyzing the access to transplantation by country and comorbid status showed that the relative risk of receiving a first transplant within 4 years after the start of renal replacement in four European countries varies from 0.26 to 4.10 in patients without comorbidity and from 0.12 to 3.19 in patients with comorbidity. These international differences in access to transplantation were attributed to differences in the availability of donor kidneys in relation to the number of dialysis patients, and were only partly owing to comorbid variability (Stel et al. 2005). This and other previous studies (Jager et al. 2001 Miskulin et al. 2002) show that sicker patients remain on dialysis programs and the healthier patients are selected for renal transplantation to have acceptable graft and patient survivals with this therapeutic modality, taking into account the limited number of organs available nowadays for renal transplantation. Clinical guidelines for the evaluation, selection, and preparation of the potential kidney transplant recipient may help to standardize access to renal transplantation (Dudley and Harden 2011). This approach is especially relevant with the current high incidence and prevalence of patients with ESRD. According to the recently published annual 2009 renal replacement report of the ERA-EDTA Registry (van de Luijtgaarden et al. 2012), in Europe the overall incidence rate of ESRD patients was 125 p.m.p., and the overall prevalence was 730 p.m.p., with wide variations among countries. From 2005 to 2009, the relative change of the hemodialysis (HD), peritoneal dialysis (PD), and transplantation distribution (at day 91 after the start of RRT) was an overall 0.5% decrease in HD, 1.4% decrease in PD utilization, and, interestingly, a 1.8% increase of patients living on a functioning graft. The assessment of waiting list dynamics may help to provide a better understanding of the limitations and contributions of renal transplantation to the treatment of ESRD. The Renal Patients Registry of Catalonia (2010) shows that for new cases in 1990� that were not excluded from the waiting list at the start of RRT, at 10 years, 54% had a functioning transplant, 5.2% were on the waiting list, 2.3% were pending study, 8.1% were excluded, and the remaining 30.2% had died. According to the same registry, despite the older age and the increase of incident and prevalent ESRD patients in the last two decades, the waiting list size has not increased, the proportion of patients excluded because of clinical reasons remains quite constant, the exclusion for age has decreased by 50%, and the proportion of patients with a functioning transplant has increased from 30% in 1990 to 54% in 2010. These data suggest new clinical attitudes to offer renal transplantation to a larger number of ESRD patients despite their older age and comorbidity. In some European countries with very active transplant programs such as Norway, 70% of the patients on RRT were living with a functioning graft (591 p.m.p.). Also, the number of kidney transplants performed p.m.p. in 2009 widely varied among countries, the highest being in some regions of Spain (Cantabria, Catalonia) with � transplants p.m.p. These wide variations on the incidence and prevalence of ESRD and transplant activities across Europe strongly suggest that there is room for improving an integrated approach in the diagnosis and treatment of ESRD patients, including active policies to promote organ donation and transplantation.

The selection of transplant candidates with better clinical conditions may contribute to the better patient survival in comparison to the distinct dialysis modalities. In the cohort of patients between 2000 and 2004, 5-yr patient survival on dialysis adjusted for age, gender, and primary renal disease was 48%. Adjusted patient survivals for first deceased donor transplantation were 91%, and for living donor 94%. Adjusted 5-year graft survival during this same time period were 79% and 85% for deceased and living donor kidney transplants, respectively ( Fig. 1 ) (van de Luijtgaarden et al. 2012). Children have excellent transplant outcomes. In 2011, according to the Scientific Registry for Transplant Recipients, for deceased and living donor transplants, the estimated 1-year conditional half-lives were 11.9 years and 15.3 years in pediatric populations.

Survival of incident dialysis patients and first transplant recipients between 2000 and 2004, by treatment modality, adjusted for age, gender, and primary renal disease. (From van de Luijtgardeen et al. 2012 reprinted, with permission.)

According to the 2012 USRD Annual Data Report, �,000 new patients began treatment for ESRD in the United States in 2010 (incidence rate 348 p.m.p.), 10 times more patients than 30 years ago. The majority of ESRD patients started on HD (91%), 7% on PD, and 2% received a kidney allograft. The number of prevalent patients was almost 600,000. Of the ESRD population, 30% had a kidney transplant, 65% of them are on HD, and 7% are treated with PD. Importantly, the mortality of patients on dialysis has decreased 26% since 1985. However, mortality for dialysis patients is still far higher than in the general population and transplant patients (USRDS Annual Data Report 2012). In the 2005 patients’ cohort, 5-year adjusted survival probabilities were 35% for HD, 41% for PD, and 73% for kidney transplant recipients. The adjusted 10-year graft survival for deceased donor transplants has increased from 18.8% in 1980 to 42.7% in 2000, and from 46.2% in 1980 to 58.6% in 2000 for living donor transplants. This gradual amelioration of transplant results is especially relevant taking into account the permanent increase of age of incident and prevalent patients with RRT, which has augmented by � years from the mid-1980s to 2010 up to 64.8 years and 60.8 years for incident and prevalent patients, respectively (Renal Patients Registry of Catalonia 2010).

Another benefit of renal transplantation may be the reduction of hospital readmissions. Rates of hospitalization for ESRD patients are double those of the general population. Renal transplantation has importantly reduced hospitalization indexes in comparison with HD, for which the rate is 36% for all-cause rehospitalization. The total admission rates for dialysis patients have barely changed in the last decade as per 1000 patient years period-prevalent patients by age, gender, ethnicity, and primary diagnosis were 1889 in 1993 and 1856 in 2010. For transplant patients, the rates were 1020 in 1993 and 841 in 2010.

Preemptive Renal Transplantation

Among the distinct alternatives for the treatment of ESRD, renal transplantation may also be the first therapeutic option of RRT to avoid dialysis. Prolonged dialysis time is considered a detrimental factor for transplant survival (Meier-Kriesche et al. 2000 Meier-Kriesche and Schold 2005 Kasiske et al. 2010) and increases the risk of hospital admission after transplantation (Gram et al. 2012). Preemptive renal transplantation (PRT) may avoid dialysis-related comorbidity, improve quality of life, and provide better transplant outcomes. Data reported a decade ago showed that longer waiting times on dialysis negatively impact on posttransplant graft and patient survival. In a paired kidney study on the impact of pretransplant dialysis on graft survival, dialysis time before transplantation longer than 2 years was associated with 29% 10-year graft survival rates in comparison with 63% in patients with 0𠄶 months on dialysis (Meier-Kriesche and Kaplan 2002). As PRT is associated with better patient and graft survival than transplantation after dialysis, this therapeutic option might be favored in all ESRD patients at the time of initiation of RRT and has been more common in the last 15 years. It has also been performed at higher levels of estimated glomerular filtration rate (eGFR), particularly among recipients of live-donor transplants (Friedewald and Reese 2012). In the United States, preemptive listing for kidney transplantation has increased in the last decade (Davis 2010) and occurs in 16.6%�.3% of listed patients. Patients with less comorbid clinical entities, such as patients with polycystic kidney disease (41.9%) and glomerulonephritis (24.6%), were more often listed before dialysis than those with hypertension (12.2%) and diabetes (14.4%) (Keith et al. 2008).

Because of the better outcomes of pancreas–kidney transplantation (PKT), it has been claimed as the optimal therapy for patients with ESRD, especially if a living donor is available. PKT might be favored with an improved patient access to nephrology and transplant care, and better education of the community and healthcare personnel (Davis 2010). Nevertheless, recent studies have raised new concerns about the consequences of early versus late PKT (Friedewald and Reese 2012) and how to find an adequate �lance of benefit (maximization of utility) and justice (fairness in organ allocation)” (Petrini 2009).

Owing to the benefits of PKT, we might see a wider adoption of this therapeutic alternative in the coming years (Huang and Samaniego 2012).

Renal Transplantation in Older Recipients

The age of patients with ESRD initiating RRT has gradually increased in the last decade. According to the ERA-EDTA Registry, in 2009, the mean age of incident patients was 64.1 years. This implies that the proportion of patients older than 60 years on RRT in some areas may be higher than 60% and patients older than 70 years account for more than 50% (Renal Patients Registry of Catalonia 2010). This results in an increasing proportion of older patients on waiting lists and, in the last years of the past decade, 㸰% of kidney transplant recipients were 60 years or older. This translates to an increment of prevalent older patients with a functioning allograft that was very low in the mid-1980s, whereas in 2010 it accounted for 34% of patients with a kidney transplant. The growing proportion of elderly patients has also been observed in other solid organ transplant programs, especially in lung and heart transplants (Abecassis et al. 2012). Although it is well known that graft and patient survival are poorer in older suitable patients than in younger recipients, renal transplantation from deceased or living donor decreases mortality in older patients by 㸰% over those patients remaining on dialysis ( Table 1 ) (ERA-EDTA Registry 2010). Older transplant recipients frequently suffer from comorbid conditions such as cardiovascular disease, infections, malignancies, physical limitations, cognition alterations, and overall reduced quality of life. Older age is associated with an increased frequency of early readmissions after transplantation (McAdams-Demarco et al 2012). The risk of death is also exacerbated in older recipients. The mortality rate in patients older than 60 years in the first year after transplantation is more than double that in younger recipients (10.5% vs. 4.4%), which is aggravated with comorbidities and whether the patient received an ECD kidney. Nevertheless, older recipients have shorter life expectancies than younger patients and might benefit from receiving kidneys from ECD donors to increase access to transplantation. The potential utility of allocating kidneys from donors � years to recipients of the same age (old to old), regardless of human leukocyte antigen (HLA) matching and with short cold ischemia time, was addressed in the Eurotransplant organization 10 years ago in the so-called Eurotransplant Senior Program (ESP) (Frei et al. 2008). In this program, graft and patient survival were not negatively affected by the ESP allocation when compared with standard allocation, suggesting that donor/recipient age matching could increase the number of elderly recipients transplanted, which might result in a longer life expectancy compared with dialysis.

Table 1.

5-Year survival probabilities (cohort 2001�) in incident dialysis patients and transplant recipients (survival rates in %)


Yale’s lead transplant doctor on new approach that could help many more in need of organs

NEW HAVEN, Conn. (WTNH) — For years the world of organ donation has followed the same plan: Keep organs cold while transporting them to those who are desperately waiting for them on tight deadlines.

“We were limited at how many organs we could successfully transplant, and we started to learn when there were times when the damage was too much and it wouldn’t work,” said Dr. David Mulligan, Yale Medicine’s Chief of Transplant Surgery and Immunology and Director of the Yale New Haven Transplantation Center.

“A lot of times we wouldn’t know how bad it was going to be until we put them [the organs] in and we saw how the patients did, and so, that was scary,” added Mulligan, who is also a professor of surgery at Yale School of Medicine.

More recently, new technology using machines called warm perfusion devices are being tested at locations including the Yale New Haven Transplantation Center. Instead of cold storage, a warm solution, like blood, is kept circulating through the organs after removal.

“And then we measured with the organ out of the body of the donor how the organ was performing,” explained Dr. Mulligan.

He said that doctors have even found ways of tuning up the organs and improving them while they are outside of the body.

“If there was an injury to the lungs or if there was an infection like a pneumonia that could be treated with antibiotics it could go away and then the lungs could be transplanted,” explained Dr. Mulligan.

The warm perfusion could also extend precious organ travel time.

Dr. Mulligan said having organs working outside the body could open other medical possibilities.

“How drugs metabolize, how chemotherapy could work, how we can better target different types of tumors that can be in a particular organ.”

“It’s a huge opportunity for us to do something important that would actually significantly increase the number of transplants in the United States so I’m really excited to help get this through the FDA,” added Dr. Mulligan, who is on the FDA committee currently evaluating three perfusion devices. He is hoping for approval in a year.

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Icing Organs

Megan Scudellari
Feb 1, 2013

© JOELLE BOLT

A small brown frog squats motionless in a den of green moss. It inhales no breath, has no heartbeat, yet it is not dead. Rock hard and icy to the touch, this speckled North American wood frog is frozen alive at &ndash2?°C, and has been so for the last 24 hours.

Then Jon Costanzo adjusts the temperature of the terrarium, and the air around the frog begins to warm. Within 30 minutes, the amphibian&rsquos skin noticeably softens, taking on its characteristic sheen. Three hours later, one eye blinks. Then the lungs shudder to life, and the frog&rsquos sides heave. Six hours from the start of warming, one leg twitches, then the other. Finally, as the timer chimes 10 hours, the frog hops once, twice, and burrows out of sight into the moss.

&ldquoI&rsquove been doing this for 25 years now, and still, whenever we freeze the frogs.

For most animals on the planet, prolonged exposure to temperatures below freezing means death. But for the wood frog (Rana sylvatica), and for an unlikely collection of other organisms ranging from insects to plants to fish, surviving the cold is a routine part of life. The Alaskan Upis beetle survives at –60?°C in the wild and down to –100?°C in a laboratory. Species of Arctic fish swim fluidly through –2?°C water, and snow fleas hop atop snow banks at –7?°C. These animals all have tricks either to survive freezing, called freeze tolerance, or to lower their internal freezing temperature so they don’t freeze at all, called freeze avoidance.

Organ cryopreservation would transform medicine the way refrigeration transformed the food industry.

However, cooling a tissue that is not adapted to tolerate or avoid freezing—as cryobiologists seek to do with human organs—is a whole different ball game. One can expect irreversible and widespread damage from the formation of ice crystals at temperatures below 0?°C: cells shrivel and collapse, extracellular matrices rip apart, blood vessels disintegrate.

But researchers aren’t giving up. Organ cryopreservation, if possible, would transform medicine the way refrigeration transformed the food industry. Currently, human organs harvested for transplant are not frozen—they are kept in cold storage, which prevents deterioration for a few hours at the most. Human hearts, for example, can be preserved for only 4 to 5 hours. But if scientists could learn the tricks of the trade from nature, and add days, weeks, or even years to the lifetime of an organ, hospitals could bank frozen organs for transplant as needed.

Though it won’t be easy, many believe that organ cryopreservation should be possible. Indeed, thanks to chemical cryoprotectants and sophisticated freezers, scientists and companies already have techniques to freeze sperm, eggs, embryos, and pools of cells such as blood or stem cells. And in the last decade, successful preservation of some solid tissues has offered hope that the long-neglected field is not dead in the water.

In 2005, heart surgeons in Israel used an antifreeze protein from fish to preserve rat hearts at −1.3 ?C for 21 hours, then successfully transplanted them into recipient rats, where the hearts pumped away for 24 hours prior to dissection for analysis. In 2003, a California company similarly preserved a rabbit kidney at below-freezing temperatures and then thawed and transplanted it into a recipient rabbit, which remained healthy with that kidney alone for more than a month. And since 2000, researchers at the US Department of Agriculture have been cryopreserving the embryos of tropical flies for years at a time, then thawing them with ease and watching them hatch and live normal lives. (See “Glass Menagerie” sidebar below.)

Many of the field’s successes were spawned by the in-depth study of organisms like the wood frog, and cryobiologists argue that somewhere in nature lies the answer to prolonging—perhaps indefinitely—the shelf life of human organs. “There’s a good chance that if we study natural adaptation—how other cells and tissues have been able to tolerate the challenges of freezing—that may provide at least some ideas of directions in which to look,” says Richard Lee, who runs the Laboratory for Ecophysiological Cryobiology with Costanzo at Miami University.


MECHANISMS OF CRYOPROTECTION
View full size JPG | PDF © JOELLE BOLT

Frostbite

In the early 1960s, a graduate student at Stanford University named Art DeVries observed fish swimming in the icy waters around Antarctica and asked a simple question: If the water in the Antarctic Ocean is –1.9?°C (it’s salty enough to stay several degrees below the 0?°C freezing point of fresh water), and fish have a freezing point around –1?°C, why aren’t the fish frozen solid?

DeVries collected some fish, and from them isolated the answer: a simple protein with an unusual repeating structure that allows it to bind to ice crystals, thus preventing them from growing into larger crystals. Known as antifreeze proteins (AFPs), the compounds effectively lower the freezing point of a solution. (See illustration below.) Because the blood of Antarctic fish is chock full of AFPs, their freezing temperature is actually about –2.5?°C—just low enough to avoid turning into frozen fish sticks.

AFPs have been isolated from the blood and tissues of fishes, snow fleas, beetles, caterpillars, and other organisms. These proteins have been used in numerous experiments in agriculture, in hopes of lowering the freezing temperature of crops, but applying the same technique to mammalian cells has proven tricky, as mammals are adapted to maintain high body temperatures. “We’re trying to figure out how to make our tissues do something really bizarre: tolerate freezing,” says Lee.

In at least one case—the transplanted rat hearts—scientists have achieved that bizarre feat. In 2005, a team of researchers led by Boris Rubinsky, an ice physics expert at the University of California, Berkeley, and Jacob Lavee, director of the Heart Transplant Unit at Sheba Medical Center in Israel, removed rat hearts and preserved them in a solution of sterile water and fish AFPs. The hearts were cooled in solution to –1.3?°C for up to 24 hours, then warmed, rinsed, and transplanted into the abdomen of recipient rats as auxiliary organs—not to pump blood, but to test the hearts’ viability. After more than 200 rat transplantation experiments, the researchers confidently decreed that the procedure worked. The use of AFPs improved heart preservation time from 4 hours at 5?°C to 21 hours at –1.3?°C. 1 Buoyed by the success, Lavee preserved the heart of a 220-pound pig for 19 hours at –1.1?°C, transplanted it into another pig, and “the heart worked beautifully,” he says. To this day, Lavee retains “almost no doubt” that the procedure could work with human hearts.

Unfortunately, what looked like a new start for organ preservation turned out to be a dead end. Lavee and Rubinsky failed to find funding to continue the work, and the research ground to a halt. “Apparently, organ transplantation is not a big enough market for pharma or any company to invest the money needed to do animal and human experiments,” says Lavee.

KIDNEY ICE CUBE: A rabbit kidney that has not been perfused with vitrification solution is frozen solid at a temperature of –140° C (left). A perfused kidney is preserved, but not frozen, at the same temperature. COURTESY OF GREG FAHY

Glass Menagerie

Over the last 70 years, the technique for freezing human sperm and embryos, a mainstay of fertility clinics, has not differed much from how frogs freeze in Ohio—add a glut of glycerol and lower the temperature slowly. But today, clinics and hospitals are turning to a technique that no known organism experiences in nature—transforming tissues to glass.

Vitrification is the rapid cooling of a substance to a glass state, achieved by pumping enough cryoprotectants into cells or tissues, and cooling them fast enough, so that they transform into an ice-free glass. Through vitrification, scientists have successfully completed two of the most complex examples of cryopreservation to date: a 40,000-cell fly embryo and a rabbit kidney.

Led by entomologist Roger Leopold, a team of researchers at the US Department of Agriculture’s Agricultural Research Service (ARS) Laboratory in Fargo, North Dakota, has spent the last 20 years developing a vitrification protocol to freeze six different strains of screwworm fly embryos, each composed of an estimated 40,000 differentiated and organized cells. The project is part of a successful program that has eradicated the screwworm fly, a livestock parasite, from the US and Central America by releasing sterile flies to collapse native populations. Freezing screwworm embryos eliminates the need to continuously rear fly colonies and ensures the continuation of specific strains of the flies for future research.

Leopold’s cryopreservation procedure—which involves soaking the embryos in a cryoprotectant bath of ethylene glycol, polyethylene glycol, and trehalose, then vitrifying them in liquid nitrogen—is run by a robot that preserves up to 5,000 embryos in 40 minutes. So far, the team has kept flies “on glass” at −196 °C for more than 7 years and successfully brought them back to life. The ability to freeze 40,000-cell embryos gives Leopold “some hope that we could cryopreserve something other than an 8-cell embryo in mammals,” he says.

Greg Fahy shares that hope. In 2002, Fahy and colleagues at 21st Century Medicine, a California-based cryopreservation research company, successfully vitrified a rabbit kidney at −130 °C for 20 minutes, then warmed it and transplanted it into a recipient rabbit that lived for 48 days before being euthanized for research purposes (Organogenesis, 5:167-75, 2009).

Fahy has been unable to replicate the success, but is still optimistic that vitrification of whole mammalian organs is just around the corner. “I don’t see any reason why it can’t happen,” says Fahy. “We have a proof of principle: we transplanted a rabbit kidney and had it survive.”

But vitrification is not without challenges, Fahy admits, the greatest of which is the high concentration of cryoprotectants needed to prevent ice formation. The toxicity of such concentrations can be more damaging than ice itself, says the University of Notre Dame’s Jack Duman, yet it could be possible to add antifreeze proteins to help lower the necessary concentration. That combination of strategies, however, has yet to be explored.

But other teams working to use antifreeze proteins in cryopreservation forge ahead. South Carolina-based Cell & Tissue Systems, a cryopreservation and tissue-storage company, is currently using insect AFPs, which prevent ice formation even better than fish AFPs, to successfully cool veins and arteries without the destructive formation of ice. “We’ve found that we can go below zero with these whole tissues for days on end without significant deterioration,” says the company’s president and chief science officer, Kelvin Brockbank.

In 2010, Brockbank began using insect AFPs in collaboration with Jack Duman, an expert in insect cryobiology and AFPs at the University of Notre Dame in Indiana who has studied freeze-tolerant and freeze-avoiding insects since the 1970s. With graduate student Kent Walters and biochemist Anthony Serianni, Duman recently discovered another antifreeze compound—this time from a small black beetle—that could be even more useful than previously identified insect AFPs. The Alaskan Upis ceramboides beetle is freeze-tolerant down to –60?°C, thanks in part to the production of the only known nonprotein antifreeze—a glycolipid consisting of a complex sugar called xylomannan and a fatty acid. 2 The antifreeze appears to coat cell membranes. There, the researchers hypothesize, it not only inhibits ice-crystal formation in extracellular water but prevents ice from entering a cell, acting like armor against the cold.

“It’s phenomenal, perhaps better than any of these peptides to date,” says Brockbank. “This is absolutely going to have benefits—certainly for cells, probably for tissues, and possibly for organs.”

A delicate balance

Despite a few notable successes, scientists still lack the ability to preserve more complex tissues and organs. One of the biggest threats of freezing is not the physical damage from ice crystals—which look like tiny butcher knives under a microscope—but the effect of freezing on the flow of fluids into and out of cells.

When a tissue is exposed to below-freezing temperatures, the water between cells freezes first. As ice crystals form in the extracellular space, solutes such as metabolites, ions, and various proteins become concentrated due to the decreasing volumes of liquid water. Water therefore rushes out of the cell in an attempt to dilute the now-concentrated exterior environment, causing the cell to shrink and damaging the plasma membrane. At the same time, ion concentrations inside the cell increase, harming internal organelles. This outflux of water also puts extreme pressure on the shrinking cells: if a cell loses more than two-thirds of its water, the pressure becomes too great, and the cell collapses. “That is not survivable,” says Costanzo. “That’s damage that can’t be repaired.”

There is a way to avoid the damage from osmotic pressure, however—as the wood frog has clearly demonstrated. As summer turns into fall, and the days shorten and temperatures creep down, wood frogs begin to accumulate urea, and later glucose, in their skeletal muscle, liver, and blood. These natural cryoprotectants flow into the frog’s cells and serve to diffuse the concentration gradient between the interior and exterior of the cells as extracellular water freezes, preventing cell shrinkage. (See illustration.)

Another Ohio freeze-tolerant frog, the Cope’s gray treefrog (Hyla chrysoscelis), accumulates glycerol, instead of urea or glucose, as a cryoprotectant. Glycerol, it turns out, is a very effective cryoprotectant for many types of animal cells: in 1949, English biologist Christopher Polge first used glycerol to preserve fowl semen at −79 ?C, and within a year produced the first chicks from eggs fertilized with frozen sperm. Since then, glycerol has been used to safely freeze bacteria, mammalian embryos, and more. Other useful cryoprotectants have been identified in freeze-tolerant and freeze-avoiding animals, including trehalose, sucrose, and sorbitol.

However, testing these compounds for their ability to preserve larger human tissues has produced disappointing results. Alone, cryoprotectants have been unable to sufficiently protect a human organ from freezing damage: even if they protect individual cells from damage, they do not block the formation of ice between cells that interrupts vital cell-to-cell interactions in a tissue. In addition, cryoprotectants that are nontoxic for one species or tissue may be highly toxic for another. Glycerol, for example, damages human heart tissue. As yet, there is no known universally nontoxic cryoprotectant.

An additional risk of cryopreservation is the damage that can occur when a solution rapidly moves into and out of a cell, such as injuring the cell membrane or destabilizing the cytoskeleton. But Carissa Krane of the University of Dayton and David Goldstein of Wright State University in Ohio may have found a solution to that problem: a cell membrane protein that humans share with our distant freeze-loving frog relatives.

Goldstein takes a midnight stroll through the swamps of Ohio every year in late spring. Wading through water and mud, he listens for the shrill mating call of the Cope’s gray treefrog. During the night, Goldstein and his students capture 30 to 40 frogs and haul them back to his lab. The next morning, Goldstein calls Krane to tell her that her frogs are in.

About 5 years ago, Krane was busy using mice to study aquaporins—a class of membrane proteins discovered in the 1990s that regulate the flow of water into and out of cells—when Goldstein contacted her about a project on how glycerol and water move through cells in Cope’s gray treefrogs. She jumped onboard, and right away one of her graduate students identified an aquaporin in the frogs’ cells that allows the transfer of both water and glycerol through the cell membrane—an aquaglyceroporin. Last year, the team implicated the aquaglyceroporin, called HC-3, in freeze tolerance: blood cells from cold-acclimated frogs—those held in conditions simulating the approach of winter, and thus building up their glycerol stores—have a higher abundance of HC-3 than those of warm-acclimated frogs. 3

Krane’s team sequenced the HC-3 gene and found a close ortholog called Aquaporin 3, or AQP3, in the human genome. The protein AQP3, surprisingly, is present in the same tissues in humans as HC-3 is in frogs—blood, liver, and skeletal muscle. “We actually have these proteins expressed in the same cells, but we don’t freeze,” says Krane. “If we can just understand how this natural process happens in a frog, maybe we can imagine a scenario down the road where we could prepare an organ harvested from a human donor by perfusing it with glycerol under cold conditions that upregulate these proteins,” she says.

Breaking records

The list of scientific challenges for cryopreserving organs is long, and that’s not even including the trouble of thawing tissues, which is “potentially more stressful than freezing,” says Goldstein. Ice crystals melting in the extracellular spaces of a tissue create pools of water, which can upset the osmotic balance and, this time around, cause cells to swell.

All told, the days of freezers full of human organs are still a ways off. “When I first started in the field in the ’80s, I thought there would be a couple different variants on a theme, and that we would solve preserving mammalian cells and tissues for medical applications forever,” says Brockbank. “But here I am, 20 years later, and we’re still far from it.”

But neither he nor other cryobiologists are giving up. One organism that might hold the answer is a small, flightless fly called the Antarctic midge (Belgica antarctica)—the world’s southernmost insect. The midge is the only known insect that spends its entire life in Antarctica. It survives for 2 years as a larva, frozen throughout the continent’s 7-month winters, then metamorphoses into a 5-millimeter-long adult that lives only 10 to 14 days in a rush of mating and laying eggs before it dies.

Over the last 8 years, Lee at Miami University has identified numerous ways that the Antarctic midge survives freezing, including elevated levels of glycerol, glucose, and trehalose—and aquaporins. But in this case, the aquaporins appear to help the flies, not to accumulate glycerol, but to move large amounts of water into and out of cells. To freeze without the dangers of ice, the midge simply gets rid of most of its body water.

Losing 15 percent or more of our body water is fatal to humans. Midge larvae, however, can survive a 70 percent water loss. “You can dry these little fly larvae out until they look like little raisins. They look terrible,” says Lee. “Then you add water, and they plump up and wriggle away. You can practically hear them laughing at you. They can handle this—it’s no big deal.”

Aquaporins may be at the heart of the midge’s unique dehydration ability. With David Denlinger at Ohio State University, Lee and colleagues recently sequenced the midge genome and have already identified a key aquaporin involved in the insect’s rapid dehydration. 4 When they blocked aquaporin channels in midge tissue, the cells failed to survive freezing. “In hindsight, it’s a real clear thing,” Lee says. The ability to freeze without damage is “all about water moving around.”

THAWED ALIVE: Larvae of Antarctic midge survive for 2 years, though they are frozen throughout the continent’s 7-month winters. COURTESY OF RICHARD LEE Taking a cue from the midge, Lee’s team found that slightly dehydrating other insects increases their cold tolerance. The same might be true for mammalian organs: in the early 1990s, researchers at the University of Rochester in New York found that dehydration helped cryoprotectants reduce freezing damage in rat hearts. 5 Still, dehydration stresses cells, especially the cytoskeleton, and there is little to no effort underway to apply this strategy to human organ cryopreservation.

Lee and Denlinger were surprised to find yet another midge adaptation to the cold: the larvae keep heat shock proteins (HSPs) turned on, in high production, all the time. 6 “They didn’t read the textbook,” says Lee. In most organisms, HSPs, which help proteins fold and maintain their shapes, are turned on only when an organism is under severe stress. But continuous production of HSPs may be a common way to deal with continual cold stress: an Antarctic fish, Trematomus bernacchii, and an Antarctic ciliate, Euplotes focardii, also constitutively express such proteins.

“We think that when you’re living in a constantly cold environment . . . that it is necessary for you to maintain these chaperone proteins to help protect your proteins against abnormal aggregation and degradation,” says Lee. Activating HSPs in transplanted human organs, therefore, might be another strategy for cryopreservation, but it also remains untested.

From antifreeze armor to dramatic dryness to syrupy cryoprotectants, organisms use a catalog of molecular strategies to survive the cold. In fact, if there is one constant in the field, it is that there is no single way to freeze a frog—or any organism, for that matter. “Ever since people have been doing cryopreservation work, they’ve been looking for a magic bullet,” says Duman. “Maybe there is no real magic bullet. There certainly isn’t one for insects. They do lots of different things. Maybe that’s what we’ll need to do as well.”

Correction (February 6, 2013): This story has been updated to correctly reflect that Greg Fahy and colleagues vitrified a rabbit kidney at −130 °C, not −22 °C. The Scientist regrets the error.

References

1. G. Amir et al., “Improved viability and reduced apoptosis in sub-zero 21-hour preservation of transplanted rat hearts using anti-freeze proteins,” J Heart Lung Transplant, 24:1915-29, 2005.

2. K.R. Walters et al., “A nonprotein thermal hysteresis-producing xylomannan antifreeze in the freeze-tolerant Alaskan beetle Upis ceramboides,” PNAS 106:20210-15, 2009.

3. V. Mutyam et al., “Dynamic regulation of aquaglyceroporin expression in erythrocyte cultures from cold- and warm-acclimated Cope’s gray treefrog, Hyla chrysoscelis,” J Exp Zool A Ecol Genet Physiol, 315:424-37, 2011.


How Fecal Transplants Work

Unless you're a detective, a thief or a strangely nosy person, you wouldn't take your neighbor's trash and dump it in your kitchen, let alone consume it. On the other hand, if you were dying of scurvy, those limes they threw away after last night's margarita party might look surprisingly appetizing.

Accepting a transplant of someone else's stool, however carefully tested, might sound just as extreme, but -- thanks in part to its effectiveness in treating the intractable bug Clostridium difficile -- fecal microbiota transplantation might just be the next big thing in medicine [sources: Grady Hudson Mayo Clinic].

C. difficile, an emerging epidemic in hospitals and nursing homes, primarily affects older patients during long stays in care facilities. Like opportunistic weeds, the bacteria move into areas of the gut decimated by the very antibiotics intended to oust infections (antibiotics don't distinguish bacterial friend from foe). Once in the gut, C. difficile cranks out toxins that damage the intestinal lining, causing symptoms ranging from diarrhea to life-threatening colon inflammation. To make matters worse, C. difficile has grown increasingly virulent and antibiotic-resistant in recent years [sources: Grady Hudson Mayo Clinic].

Sending bacteria to fight bacteria makes good sense. Far from being a mere batch of bugs, many bacteria and other microbes are not only our friends, they are part of us. Our bodies contain nine to 10 times as many microbial cells as human ones we each play host to 100 trillion bacteria. It's all part of a microbiome, an ecosystem of microbial communities that perform all kinds of useful work, from enabling digestion to aiding our immune systems [sources: Khoruts Zimmer Zimmer].

The recognition of microbial contributions to health has given rise to the growing field of medical ecology, which approaches the body's microbiome as a garden to be nurtured and, if necessary, weeded. Fecal transplantation extends this philosophy to "organically mulching" the gut garden: Stool from a healthy donor contains beneficial gut microorganisms, aka flora, 60-80 percent of which will take up residence in the recipient's gut, replacing those destroyed by antibiotics and infections, and overthrowing harmful communities like C. difficile [sources: Borody Hudson].

Driving the need for such novel techniques are the ever-increasing numbers of people, particularly the elderly, who die each year from gastrointestinal infections. In the U.S. such deaths more than doubled from 1999 to 2007, rising from 7,000 to more than 17,000 a year [source: CDC]. Eighty-three percent of those fatalities occurred among patients over 65, two-thirds of whom died from C. difficile infections [source: CDC].

Fecal microbiota transplantation might sound outlandish or even a bit disgusting, but it restocks the body with some of the many microbes it needs to recover, live and thrive.

Bacteria: Flush With Success

Bacteria are arguably the most successful life-forms on Earth. You can find them clustered around deep-sea vents, buried far underground or teeming throughout larger organisms, including us. Our mouths alone contain hundreds to thousands of species, divided into colonial neighborhoods across our teeth, gums and tongue. Our lungs, once thought microbe-free, house 2,000 per square centimeter, and our guts could host as many as 25,000-30,000 different species [sources: Grady Zimmer].

While we might think of them as microscopic menaces -- the sources of such delights as bacterial meningitis, urinary tract infections and food poisoning -- without bacteria, life as we know it would not exist. Starting 2.7-2.8 billion years ago, cyanobacteria released the first oxygen into the atmosphere today, bacteria convert atmospheric nitrogen into something plants can use and recycle nutrients from dead organisms into the ecosystem [sources: Biello Ingham Farquhar, Bao and Thiemens].

Bacteria and other microbiota perform similar functions in our bodies. Gut microbes produce vitamins and reduce tough plant compounds into digestible slurry [source: Zimmer]. Within the immune system, bacteria help maintain skin's protective qualities, and nasal microbes produce an antibiotic shield against airborne germs. Moreover, microbes keep the immune system in check by limiting harmful swelling. It isn't a stretch to see how they might therefore play a role in inflammation-associated disorders, such as obesity, cardiovascular disease, type 2 diabetes and inflammatory bowel disease (IBD) [sources: Gewirtz Zimmer Zimmer].

Microbes also make healthier babies. Breast milk packs 600 species of bacteria and provides sugars that feed a baby's developing gut bacteria [sources: Hunt et al. Zimmer Zivkovic et al.]. According to a June 2011 PLoS One study, a woman's vaginal microbiome changes drastically when she becomes pregnant. Among other effects, this new environment might prepare newborns to digest breast milk [sources: Aagaard et al. Zimmer]. Some studies suggest children born via cesarean section might be more prone to skin infections from methicillin-resistant Staphylococcus aureus (MRSA), a staph germ that resists first-line antibiotics such as penicillin and amoxicillin. Such children could also face greater risk of developing allergies or asthma [sources: CDC Zimmer].

Exposure to certain microorganisms trains a child's developing immune system [source: Zimmer]. It also probably provides a natural defense against inflammatory bowel disease (IBD), a chronic or recurring inflammation of the gastrointestinal tract caused by a haywire immune response [sources: Olszak et al. Zimmer]. IBD, which includes ulcerative colitis and Crohn's disease, ranks among the five most widespread gastrointestinal diseases in the United States and racks up health care costs of $1.7 billion annually [source: CDC].

When the stakes are so high, particularly for patients with life-threatening intestinal maladies, doctors have started thinking outside the box -- and inside the colon.

Numerous studies suggest links between certain disorders and a lack of exposure to particular microbes. Children raised on farms, for example, develop fewer autoimmune disorders than urban children [source: Zimmer].

Along similar lines, people with asthma possess a different set of microbes than nonasthmatics. Reduced microbe exposure rates in the developed world could explain the recent uptick in occurrences of asthma and atopy -- a genetic predisposition toward developing allergic reactions [sources: Olszak et al. Reibman et al. Zimmer].

Although something like it might have been practiced as far back as fourth-century China, modern fecal transplantation was pioneered in 1958 by Dr. Ben Eiseman at Denver General Hospital [sources: Allen Brandt Eiseman]. Fecal transplants saw only sporadic use for decades afterward, but began coming into their own around 2000 [sources: Allen Brandt].

Here's how they work: After screening a donor for HIV, hepatitis and other disease-causing germs, the doctor dilutes a stool sample with saline or 4 percent milk, and then blends it into a milkshake-like slurry [sources: Allen Bakken et al. Floch Silverman, Davis and Pillai]. The mixture is then fed into a patient's digestive tract via nasogastric or nasoduodenal tubes, through a colonoscope or via a retention enema [sources: Allen Bakken Hudson]. A nasogastric tube feeds matter through the nasal passage, down the throat and into the stomach a nasoduodenal tube extends a bit farther.

The patient prepares for the procedure via the traditional take-no-prisoners, date-with-the-thunder-bucket ritual used by colonoscopy patients [sources: Allen Stein]. Stool donations usually come from family members or spouses, but some facilities have tried unrelated, prescreened donors [source: Allen Brandt].

If a fecal transplant sounds like a great DIY project, it isn't. First, stool is a level 2 biohazard second, if you don't test fecal samples for communicable diseases, you could end up in a world of hurt third, remind us to never drink frozen margaritas at your house [source: Bakken et al. Floch Silverman, Davis and Pillai].

As of October 2012, U.S. insurance does not cover fecal transplants, but some doctors believe billing codes for the procedure will exist by early 2013, with Medicare coverage following a similar schedule [sources: Allen Brandt Gewirtz]. Dr. Andrew Gewirtz of the Georgia State University Center for Inflammation, Immunity & Infection agrees.

"I would guess it might be insurable soon -- although it is possible that use of specific, defined bacterial cocktails may supplant it eventually," he says.

The procedure's legal status may pose a greater challenge. According to Dr. Lawrence Brandt of the Albert Einstein College of Medicine, the U.S. Food and Drug Administration (FDA) has declared feces for fecal microbiota transplants a drug, which makes transplants -- already a fringe therapy -- illegal until the FDA approves their use. While doctors are unlikely to do time for performing the procedure, its dodgy status could work against them should a malpractice suit arise [source: Brandt].

On the plus side, drug classification could move fecal transplants further into the mainstream. To become a widely accepted medical practice, the process must be subjected to large-scale clinical trials, but gaining funding for such trials from, say, the National Institutes of Health (NIH), hinges upon the FDA granting a substance "investigational status." Classification as a drug places feces in a category that the FDA recognizes for this purpose [sources: Brandt Khoruts McKenna].

Once they work the bugs out, bacteriotherapy and fecal transplantation could offer hope to a lot of sick people.

Feces consumption occurs throughout nature, from the dung beetle to the ringtail possum. Animals primarily nosh on stool for its nutrient content. Some eat the excrement of herbivores, whose inefficient digestive tracts leave nutrients behind, while others -- particularly non-ruminating herbivores -- eat their own droppings to give their bodies another pass at the buffet. Some young animals also gain valuable gut microbes by consuming their parent's feces [sources: BBC Encyclopaedia Britannica Hirakawa Saylor]. Bon appetit!

We stand on the threshold of a microbiotic renaissance, according to some physicians and microbiologists. As our understanding of this long-neglected field expands, so too will our treatment options.

As we mentioned, the place to start -- at least where fecal transplantation is concerned -- remains Clostridium difficile. According to the CDC, C. difficile infections kill 14,000 people in the United States annually, and its occurrence among hospitalized patients more than doubled from 2000 to 2009 [sources: Hudson Zimmer]. One long-term follow-up study of 77 fecal transplant patients reported a 91 percent cure rate after just one fecal transplant, and a 98 percent cure rate with additional probiotics, antibiotics or fecal transplants [source: Brandt et al.].

Fecal microbiota might also hold answers for people with metabolic syndrome -- a collection of co-occurring risk factors, such as insulin resistance and extra weight around the middle, that increases the chance of coronary artery disease, stroke and type 2 diabetes [source: A.D.A.M.]. In some studies, fecal transplantation in metabolic syndrome patients reduced triglyceride levels and improved insulin sensitivity [source: Allen Gewirtz].

Scientists have also tied obesity in rats to changes to the gut's microbiome. The intestines of obese persons contain a different set of microbes than those of non-obese persons, and clinical trial results suggest lean donors might help obese recipients lose weight by changing how they metabolize sugars [source: Zimmer].

"The composition and activity of gut microbiota is different in lean and obese individuals," says Dr. Alexander Khoruts, associate professor of medicine at University of Minnesota. "We know that animal energy metabolism can be changed by fecal microbiota transplantation. It is possible there will be something along these lines in humans."

"However, it is also clear that diet and lifestyle choices influence the composition of gut microbiota."

Indeed, we're only beginning to grasp the possibilities for fecal transplants and macrobiotics in general [source: Khoruts]. Don't confuse the two, however. Gut flora, though numerous, represent only a portion of total body microbes. Moreover, we do not yet fully understand the relationships between microbiota, health and disease, whether in the intestines or outside of them.

For example, a number of medical conditions may be linked to the intestine, including liver disease, migraines, chronic fatigue, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease and Parkinson's disease, but how (or if) they relate to microbial therapy or fecal transplants remains unclear and will require substantial studies to answer [sources: Allen Borody Borody Khoruts].

In the meantime, don't be too quick to "poo-poo" the idea of fecal transplantation. It's effective, fast and seems to have no side effects. But, as with any new therapy, we'll have to wait and see how it comes all out in the end.

In June 2012, around 200 scientists published the results of the Human Microbiome Project (HMP), a landmark genetic survey of the trillions of microbes composing the human microbiome. The $150 million initiative, begun in 2007 by the NIH, has followed hundreds of healthy people and sequenced genetic material from their bodily bacteria -- a harvest of more than 5 million genes [sources: HMP Zimmer Zimmer].

The HMP currently funds 15 projects with potential to show correlations between the microbiome and human health and diseases such as psoriasis, Crohn's disease, ulcerative colitis and esophageal cancer, among others [sources: Borody HMP Stein].

Authors Note: How Fecal Transplants Work

No matter how long I report on science, it never ceases to surprise. Perhaps there is nothing new under the sun, but what about where the sun doesn't shine?

Vulgarities and terrible puns aside, few things are as fun for a science journalist as when scientists or doctors point to something we take for granted and say, "Hmm, maybe this is more important than we thought," or, "Perhaps our assumptions are completely out of whack and we need a paradigm that's less than a century old."

Such cycles are a natural part of science. Research, after all, runs hot and cold, and yesterday's apparent dead-end can later open up into today's road to discovery. All it takes is a pair of fresh eyes and the context provided by time and further research.


Readers Also Love

Cold, soulless people work in the medical world. If an organ is falling apart in your body it could be because you have abused your body. I do not agree with ripping out organs from live people in order to save someone else. Far better to use stem cells and rebuild new organs with no rejection.

If we have organs of others in our body, we take on their information, and there have been many reports where this happens. What this means is because a part of the dead person's body is being kept alive, they are harmed and held back from moving on.

Organ donations are a racket and it is wrong. It promotes laws that the governments can have you killed for your organs. Once again we are responsible for our bodies and if we use drugs and don't look after ourselves, then who is to blame? Organ murder is a billion dollar racket. anon990940 May 17, 2015

I thank God that my child was 16 and he never signed an organ donor card. I had all the say in the world to say no and the team hated that. They tortured me beyond what you could imagine. They were licking their chops over my son. He was a healthy outdoorsman, never smoke or drank, didn't do drugs and they didn't have to worry about STD's. Amanda96 October 29, 2012

I think one of the key points is, it needs to be 'donation' under free will. When it goes into forced live organ harvesting, it is something totally different and shall never be allowed.

It is quite horrifying to know people get killed on purpose only because their organs can be used for transplant. Even worse, this seems to be a business in today's China, with large numbers of innocent people as victims where the state hospitals and state military are involved.

For those who receive these organs, do they really know this situation? Look up 'forced live organ harvesting.' We just can't accept this kind of thing is happening under the name of 'ethical ways to help others.' anon291543 September 14, 2012

All of you people who totally agree with organ donation, I hope you get to experience what all of the poor, helpless victims have experienced in this horrific donor operation. I hope you get to know what it feels like when your heart will suddenly start to beat 220 seconds per minute. I hope you get the chance to hear the doctors play their hard rock music as they discuss how they are going to begin dissecting your thoracic cavity, and saw your sternum in half. I hope you get to feel that cold liquid that they shoot into your heart to preserve it for some 60 year old or seventy year old.

I hope you try to move but can't because they have paralyzed limbs. I hope you get to feel the skin as they slice it off with a big cheese slicer. All of you who are for the slaughter of your loved ones, I hope you get to feel and experience all that your loved one has gone through, and for what? To make an anti rejection drug company and donor entities the richest people in the world. Shame on the medical entities for not paying for the hospital care that your loved one did not get, for when the donor is identified, he does not get hospital care. You are foolish for allowing this operation to be done on your loved one for what? So an ailing population can live maybe ten years longer? anon282214 July 27, 2012

Are you sure you want to be an organ donor? Since my daughter’s care at the hospital, I began to ask some questions and this is what I found out. I will back up, to tell you what led me to this discovery. My daughter Melissa was hit by a car as she was crossing the street. She suffered from acute brain trauma. A miracle happened moments after the accident. The miracle was an ambulance just happened to pass by within minutes of the accident. My daughter was given care immediately. She arrived at the hospital within 18 minutes. Later I found out that treatment, such as Mannitol and hypothermia therapy for acute brain trauma could have been given by the EMTs. She should have been carried to a level 1 trauma center because of her multiple traumatic injuries, vitals, and the GCS score. But the medical director of the Medical Center of the Rockies did not advise the EMTs to give my daughter

mannitol or hypothermia therapy.

They did not call for the neurosurgeon until 23:33, almost one hour after my daughter’s accident, nor

did they transfer her to a level 1 facility that had the expertise to take care of her multiple traumatic injuries.

Instead, my daughter was taken to Medical Center of the Rockies. She was evaluated and a CT scan was done. But what I have learned is there is a golden hour of opportunity to stop the intracranial brain pressure from rising. There are many aggressive treatments that can be done for acute brain trauma. Surgery is what my daughter needed immediately. She got mannitol and her ICP came down from 80 to 25. Then the doctor made the decision not to do advanced care. He said, “she her a poor prognosis and poor outcome” So my daughter, who was breathing and had a weak cough, all signs of brain stem function, was allowed to lie there in pain with no treatment except supportive care while they waited to harvest her organs.

We were asked within two hours for her organs over the phone. I must say this is our word against the doctor's. He denies this now. But they can’t deny what is on the medical report. It said our daughter was coughing up until 3:00 a.m. and that the ongoing plan was to harvest her organs. The doctors and hospital had an option. They could have operated on my daughter and hoped for a miracle, or call it quits, and let my daughter’s life benefit the federal government in passing out her organs to the world. If there had not been an option, my daughter would have gotten medical care because the doctor and hospital need to make money despite the futility of their efforts.

This was the first heartbreaking thing that I found out: A doctor and hospital can withhold care from you if they think it is futile. This is a contradiction to all the care that cancer patients get. I guess it is where the money is that deems whether you are given care, not whether your case is futile or not.

The whole reason for our suspicion of this hospital and doctors is the careless and aggressive way in which we were approached for our daughter’s organs. First, they called us within two hours, and over the phone. Second, moments after I arrived, and was standing by my daughter’s bed, it seemed as though they were shouting from the nursing center about the designation on my daughter’s license. It was thought at that time, that her Colorado license had a donor designation on it, but maybe not her Oklahoma. They had to make sure both complied with being a donor. So I was standing by my daughter, feeling pretty good, because my daughter looks amazing for just being hit by a car. All her limbs were intact, she were breathing, and I was told that all of her major organs were unharmed.

I was excited, because I thought there was a possibility that my daughter might make it. So I started talking to Melissa. I ask her to move her toe to let me know that she knew I was here. She moved the left baby toe and the one next to it. She did this four times when I asked her to. I know it was purposeful and a direct response to my asking her, because she did it four times when I asked her to. Every time they scraped the bottom of her feet she pulled them away. Yet they said, “This is insignificant. It is spinal.” My first thought was “Why do it, if it is insignificant?” Later, I read that my daughter “contracted her thigh muscle to toe nail bed pressure.” This is significant because the thigh muscle is a skeletal muscle and is only activated by the cortex of the brain. Other signs of life were that my daughter started her menstrual cycle, which is controlled by the hypothalamus part of the brain. My daughter kept her temperature constant this is regulated by the brain. The beating of the heart is regulated by the brain. My daughter lifted her body off the bed three times. The nurse even said he thought my daughter breathed over the machine. The head nurse dismissed it and said, “It was probably the machine.” The ventilator does not function as the brain it is just a machine that pushes air through the lungs. Everything else, like temperature, heartbeat and contractions are controlled by the brain. They said my daughter had doll‘s eyes, but it says on the medical report that it was not checked. I cannot remember them checking for the supra-orbital reflex. I do not remember them checking her hands for nail bed pressure or her chest, either.

After our stand that our daughter deserved first rights to her organs, they took us before an ethics committee. We invited a lawyer to sit in on this ethics committee meeting. The ethics committee ended by saying, we could keep our daughters organs, and they were now off the table. I never knew they were on the table, but the medical report says that there was an ongoing plan to donate her organs even before brain death was documented. In fact, brain death was not documented. They blame this on me, but the truth is they had ten hours before I arrived to do any test they wanted. But they did not do it.

Why? I believe they did not do it because my daughter was still coughing up until 3:00 a.m. This is a brain stem function. Brain death can only be declared when all brain stem function is absent. My daughter was alive when the decision to withhold care from her was made. This is equivalent to performing CPR on a drowning victim and in the middle you stop and say, “This is a poor prognosis and poor outcome. Let’s stop in the mist of resuscitation.”

When I was there, they could have done anything they wanted. I was just the mother, watching. Really, the nurses were taking care of my daughter. It says on the medical report that doctors were talking to us, but this is not true. Most of our communication was with the nurses. Later, we spoke with three doctors, and with the doctor, I had to beg blood in exchange for an EEG. Can you believe this? I, a mother, had to barter for blood products in a hospital. When the organs were taken off the table, I thought everything was going to be okay. Later, after reviewing the medical records, I realized that my daughter only got supportive care while they were waiting for her to die. At that time, I did not know she was not getting food. If you do not get food, you will die, especially when you are weak, in trauma and shock. One treatment for brain trauma is nutrition it needs to be started within 24 hours. My daughter was anemic, the doctor reports, “It is probably due to a loss of blood.” But blood products were not given to relieve the anemia. The medical doctors knew that my daughter was going to have cardiac failure. But they did not try to prevent this from happening by implanting a defrillbilator in her to keep her heart beating. My daughter died because she did not get care because the doctors deemed her futile, and brain dead without documentation. My daughter was never brain dead. She showed the doctors many times that she was alive, by coughing, withdrawing her legs, contracting her thigh, and lifting her body off the bed.

Now this is what I have found out about organ donation, and the donor operation. First, I found out there are critics of brain death diagnosis and organ donation. These critics believe that brain death was concocted for one reason: to obtain profuse organs. Organs have to be oxygenated for a successful transplant. You can only get these organs from live patients. The ad hoc committee had to think really hard. Where can we get oxygenated organs? We have to get them from people who look dead, who can’t communicate with the outside world whether they are alive or not. So this was their plan to take organs from a suffering humanity. The only problem is that these organs are being taken from brain alive patients.

I have read that the donor operation goes like this. The patient is wheeled to the operating room. He is hooked up to a ventilator, he is breathing, his heart is beating, and his blood his flowing. Transplant teams from all over the world are there. Each team is there for their piece of the donor. Some are there for thoracic cavity, others are there for the abdominal region, and the others are there for leftovers. And the poor nurses are there to watch in horror and for the clean-up. Now that everyone is there, the donor’s hands are tucked under his side, to provide a better opening for the thoracic cavity and the abdominal region. The anesthesiologist is there to make sure the “rule of 100s” is being managed. He is not there to provide anesthesia. Anesthesia is not given, so the brain dead donor could be conscious when this surgery takes place. It is said that a neuro (brain)muscular blocking agent is given to keep the brain from transmitting to the tummy not to tighten up to the approaching knife. It is said that the blood pressure will rise from 100 to 220 as the knife is inserted into the thoracic cavity. The blood pressure is controlled by the brain. It is said that the donor will begin to move his limbs and may even do more complex moves like sit up. They say this is all spinal. But I say it is the adrenaline rush that we humans get when we face death. The adrenaline gland is a function of the brain. The donor’s body temperature will go down. This is regulated by the brain. The medical community explains all of these functions away. But these are clear functions of the brain. It is said they have to convince the novice nurses that after this display of life that this patient is really dead.

I am not a medical doctor or nurse, but I know what is living and what is dead. I do not have to be convinced. There is a propaganda machine that has been promoting this lie for over 32 years now. It has been adopted worldwide, even through all this controversy. This machine wants to force us all to be donors. The most prevalent is the presumed consent law. But I am going to challenge the designation to be a donor on the driver license as invalid for four reasons:

It is a contract, and a contract has to benefit both parties, but this contract benefits only one: the United States federal government. The organs of a donor can be sold for a million dollars.

Before signing a contract, you must be able to read the contract. The donor needs to know the surgery to donate his organs will be done on the basis of a brain death diagnosis, that he will not get anesthesia, that he might suffer a heart attack and that his organs might not even be used.

The official at the driver’s license bureau is not qualified to determine who is of a sound mind before signing this important document. The federal government is asking a minor to consent to a surgical operation without the permission of his parents. The presumed consent law will be challenged before the supreme court. It takes our freedom away to choose or give a gift. It is discrimination against the poor and uneducated. Only the rich who can afford to go to a lawyer to get living directive will be able to be excluded from being a donor. Only the educated and informed will be able to make a decision on the basis of informed knowledge.

More facts that I found out: The number one donor will be a 24 year old male, and will likely be uninsured. The government demands the hospital and doctor to notify the donor entity of a potential donor.

I think this should be challenged because it violates HIPPA. No one, not even the federal government, should be able to share your medical history without your permission.

With advancees in treatment for brain trauma, only 20 percent or less will die. So how does the government get organs? How can there be so many donors if 80 percnet will survive and recover with a good outcome? Who gets the money? Who are the recipients? Are they rich and just want to live longer? Most recipients are over the age of 50, the majority over 60.

So the government gets the organs free, sells them for a million dollars, and then we the taxpayers pay the bills from Medicaid and Medicare through our taxes.

The family or the insurance company has to pay for the medical care that the potential donor did not get up until the deal is sealed to be a donor. Shame on all of you who are in this business. You get almost a million dollars for this donor and then you make him pay the hospital bill.

I hope the whole world hears my cry. This donor operation is horrific, and it is potentially the disembowelment of a live human being who does not get anesthesia. This is not a dignified operation. The nurses say they “feel sad” because they are left to rinse the blood out of a hollow shell. It is a numbing feeling. We would not even treat the bodies of our animals like this. There has to be a better way to prolong life than this.

My daughter chose to be a donor. Unfortunately, like so many others, I do not believe she knew exactly what that would entail. Also, she wasn't planning on being a donor at the age of 30.

I live in another state, made my wishes clear that I would like to see her first and jumped on the first plane. I was there in a little over 12 hours after getting the devastating news. It was the mortuary who had to inform me that my daughter had been harvested and did not understand why my request to hold her hand could not be granted.

It was very obvious she had no eyes. There was a lot of bruising and swelling due to the harvesting and my 20 year old son had to see his beloved sister this way for the last time! I'm sure it was her deadbeat father who OK'ed this. I'm not sure yet, since it just happened. But he is the one who called and I said no to him.

I later learned from my husband that the mortuary explained to him why I couldn't hold my daughter's hand. She was "longboned". I'm sorry. I understand it was her wish and that it did great things, but I know she would've changed that if she knew it was at the cost of totally devastating her brother and rest of her family.

Please make sure everyone is aware of what happens. I would have been able to handle this much better if I had made myself more aware of what exactly happens. anon92385 June 28, 2010

My son died of an aortic dissection three months ago and he wanted to be a donor. Because the cause of death had to be determined first, they had to perform an autopsy. That made all his organs unusable. They did the tissue, long bone and corneas. I am grateful for people like him as I will need a cornea transplant in the near future. It is a brave and unselfish thing to do. anon89308 June 9, 2010

I'm curious to know about "face transplants" after last year's chimpanzee attack. How does that occur? Also, if I'm (donor) in a three unit family and die and my daughter and mother are all who are left for for decision making, one says okay donate and the other says absolutely not, what happens? anon86954 May 27, 2010

In reply to anon28192. We could view our daughter after organ harvest this was all handled by the funeral home that took charge of her funeral. Cost of the funeral was ours, and the transplant division paid all hospital costs from the moment she was declared brain dead (ICU, theatre costs for harvesting and transfer of the body to the police mortuary).

I was afraid of what she would look like, but there were no obvious signs of harvesting. --Wilmap amypollick May 26, 2010

@Anon86693: As far as I know, unless other arrangements have been made, the donor's family would contact their mortuary of choice and the mortuary would then handle all the arrangements, including preparing the body for viewing, if the family wanted an open casket visitation and/or service. anon86693 May 26, 2010

Is the body embalmed and prepared for viewing by the harvesting entity or its assignee? Any information would be appreciated. anon86036 May 23, 2010

Harvesting organs is the best thing to save many lives. if you calculated it you will find that one dead body can help many people because it has two kidneys, skin, bone marrow, heart, lungs, and the liver which can be used for more than three.

For me I don't mind that if my organs are useful when I am dead to be harvested. what encouraged me to this is I am an o negative blood group which is very rare so i imagined if I was the person who needs an organ wouldn't I agree and ask every body to donate their organs.

To face the facts: either we are going to hell or heaven and we are not going to need these organs. we might get some benefit and go to heaven because we helped other people to stay alive. anon82295 May 5, 2010

I'm not trying to sound mean or heartless. i believe that something wonderful happened at one time of our lives. We were all given the chance of life. We also know that it has an end at one point. It is nothing to be ashamed of death it is as wonderful as life. As long as we have God in our lives and we have done good. anon76315 April 9, 2010

answering the homeless man question, i believe so, considering that harvesting organs is underhanded. wilmap January 19, 2010

Our daughter was declared brain dead on Christmas day 2009. We gave permission for everything that could be used for donation.

We had a call from the transplant division that during harvesting a malignant growth was discovered on one of her ovaries. It was decided not to use her vascular organs (a.k.a. heart, kidneys and liver) due to the risk it would cause to the already immunosuppressed recipients. They did use both corneas, skin and bone. I still have awful visions of a deflated doll after the removal of her bones. But I still think the benefit for those who needed it outweighs it. anon60313 January 13, 2010

It is evident that there are many people in the world, who would like a new organ such as a heart or a kidney.

If we promote people to donate their organs, it will decrease the number of deaths within a county. Although a person may agree to have their organs "harvested", the family may not agree with the person's wishes. At this point, the family has the right to refuse to have the patient's organ "harvested".

There is problem in this matter: what if the patient shares different values and beliefs from his/her family? Will their organs be harvested? Is it right to proceed with harvesting these organs, even if the family refuses to get do so? anon54763 December 2, 2009

i totally agree with organ harvesting. anon53184 November 19, 2009

who pays for the harvesting of the organ, the patient receiving the organ or the patient that is deceased? anon52639 November 16, 2009

Would body parts from a young, healthy homeless man who was murdered be harvested if no family could be contacted? anon28192 March 12, 2009

What kind of stitches should we expect to see after your daughter donates skin, tissues, long bones, valves, etc? Should we expect that she would be lying in her own blood? Thank you, Nashville


Introduction

Transplantation of marginal organs from donors after circulatory arrest is an important option to reduce the waiting period for recipients. Progress has been made in perfusion of donor organs with diluted donor blood [1], but there are few methods that can be easily used at many sites where donors may be found.

Hydrogen gas has been shown to have various biological effects, including suppression of ischemia-reperfusion injury in animal studies [2–5]. Ischemia-reperfusion injury is an inevitable complication of solid organ transplantation and limiting this type of injury can increase graft survival. Use of hydrogen gas has been reported to be effective in transplantation models of various organs, including the small intestine [6–7], lung [8–14], liver [15–18], heart [19, 20], osteochondral tissue [21], and kidney [22]. It is possible to expose the excised organ to hydrogen gas ex vivo without the donor and/or recipient inhaling the gas, and various methods have been devised to dissolve hydrogen gas in organ preservation solutions, including use of a hydrogen gas cylinder [6], electrolysis [18, 20, 21, 22], or a hydrogen-generating agent [17]. However, these methods require bulky equipment and dangerous high-pressure cylinders with strict regulations for handling, resulting in the need to expend considerable time and effort for preparation. Therefore, it is probably unrealistic to attempt the introduction of such methods into the clinical setting. Accordingly, a simple technique for rapidly dissolving hydrogen gas in organ preservation solutions is required.

A hydrogen-absorbing alloy is a compound that absorbs hydrogen when it is cooled or pressurized and then releases hydrogen when it is heated or depressurized. A hydrogen-absorbing alloy canister is filled with such an alloy, and these canisters have been used to supply hydrogen for fuel cells. We have developed a method of using a hydrogen-absorbing alloy canister to rapidly and conveniently dissolve hydrogen in organ preservation solutions at high concentrations. The canister storing hydrogen can be safely transported anywhere and can be easily connected to a bag containing conventional organ preservation solution, allowing hydrogen to be dissolved in organ preservation solution within a few minutes at the site of donor organ harvesting.

In the present study, the efficacy and safety of cold organ preservation solution containing hydrogen dissolved by this method were tested in a miniature pig model of kidney transplantation from donors with circulatory arrest. Previous studies were performed in juvenile domestic pigs, but we used miniature pigs to more closely reflect the clinical setting [23]. After circulatory arrest for 30 minutes, kidneys were harvested from the donor, flushed out, and stored in either hydrogen gas-containing organ preservation solution or conventional organ preservation solution. Then early kidney function after transplantation was compared between the two methods of preservation.


Keeping the liver warm

The new device is the size of a small shopping cart. Inside, the major blood vessels of a donor liver connect to tubes that infuse the organ with blood &ndash as if the liver had never left the donor&rsquos body. The liver makes bile and processes medications to the whooshing &ldquopulse&rdquo of the blood circulating through the organ.

Dr. Parsia Vagefi, Associate Professor of Surgery and Chief of the Division of Surgical Transplantation, explained some of the current challenges: &ldquoThe longer a liver sits on ice, the more likely it is to have problems after transplant. The liver will become unusable if it has been stored for too long. With many patients waiting for organs, this new way of treating organs may expand the number of donated livers that can be used for transplant.&rdquo

One recent beneficiary of the new method is Greg Nielsen, a swimming pool construction worker in Dallas. At age 59, his liver was failing due to cirrhosis and liver cancer. His feet, ankles, and belly were swollen from water retention. When he reached UT Southwestern in June, his options were running out.

When a liver quickly became available, Dr. MacConmara and the transplant team traveled to the donor hospital, carefully placed the liver in the OCS TM , and returned to UT Southwestern. Dr. MacConmara&rsquos team continued to monitor the liver as it produced bile and ensured it was functioning well. Dr. Vagefi led the liver transplant surgery team.


What happens to your body when you're an organ donor?

With organ donation, the death of one person can lead to the survival of many others. But when a donor dies, how do doctors save their organs for transplantation?

"In order to be an organ donor, you have to be in a hospital, on a ventilator, and have some type of neurologically devastating injury," said Heather Mekesa, the Chief Operations Officer of Lifebanc, Northeast Ohio's organ procurement organization.

There are two ways that this can happen: brain death and cardiac death. Cardiac death occurs when the patient has such severe brain damage that they would never make a full recovery. This damage can be to different parts of the brain. They may have a small amount of brain functionality, but the physician determines that they will never be able to recover. The donor is only kept alive by a ventilator, which their family may choose to remove them from. This person would be considered legally dead when their heart stops beating.

Most donated organs come from cases of brain death, in which the donor has no brain function, according to a 2020 study in the journal BMJ Open. This patient has irreversible loss of function of all regions of the brain, including the brain stem. A doctor diagnoses a person as "brain dead" when that patient is in a coma, has no brain stem reflexes, and fails an apnea test that serves to show if all brain stem function has been lost. A person who is brain dead is legally dead, even if they are still breathing with a ventilator. The physician, not the organ transplant team, makes that call.

While the donor's body is kept alive through life support, the organ procurement team tests whether their organs are safe for transplantation. If the donor has cancer or an infection such as COVID-19, their organs may not be usable, but not all diseases prevent organs from being used. For example, an HIV-positive donor can donate to an HIV-positive recipient. "They are transplanting organs on a regular basis that are hepatitis A-, B-, C- positive," Mekesa added.

Routine blood tests can reveal whether organs such as the liver and kidneys are healthy. The organ procurement team sometimes inspects the donor's heart for damage or blockage by sticking a thin tube into an artery or vein and threading it through their blood vessels to the heart. The team can also use a chest X-ray to evaluate the lungs for size, infection, or signs of disease. They may do further testing by sticking a thin tube into the lungs to further evaluate infection and determine if antibiotics are needed. Brains are never transplanted, but all other organs can be donated in the case of brain death in the case of cardiac death, the heart is likely too damaged to donate, according to the 2020 study.

After testing the organs, the organ procurement team finds and confirms recipient matches from the national transplant waiting list. The recipient's surgeons set up a time to meet and fly to the donor. Depending on how many organs are being donated, "you might be organizing surgeons from three to four states," Mekesa told Live Science.

In the case of brain death, the doctors start to recover the organs by clamping the circulatory system to stop the ventilator from pumping blood around the body. In the case of cardiac death, they remove the ventilator and wait until the heart stops beating, which can take anywhere from about a half hour to two hours, then an additional five minutes to ensure the donor's heart doesn't spontaneously restart, Mekesa said. The surgeons may decide not to recover the organs if it takes too long for the heart to stop and the other organs begin to die. For both types of organ donors, the surgeons then drain the donor's organs of blood, refill them with a cold preservation solution, and remove the organs.

The surgeons fly the organs back to the recipients and begin the transplantation. They must act quickly the heart and lungs can last 4 to 6 hours outside the body, the pancreas 12 to 24 hours, the liver up to 24 hours and the kidneys 48 to 72 hours, according to the Health Resources and Services Administration (HRSA). Meanwhile, the donor's body, with organs removed, is prepared for a funeral or other memorial service.



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