Dr. Guy Alexandre (1934-2024), gave birth to brain death in deceased organ transplantation

 The father of brain death has died.

Here's the NYT obit.

Guy Alexandre, Transplant Surgeon Who Redefined Death, Dies at 89. His willingness to remove kidneys from brain-dead patients increased the organs’ viability while challenging the line between living and dead.  By Clay Risen

"Guy Alexandre, a Belgian transplant surgeon who in the 1960s risked professional censure by removing kidneys from brain-dead patients whose hearts were still beating — a procedure that greatly improved organ viability while challenging the medical definition of death itself — died on Feb. 14 at his home in Brussels. He was 89.

...

"Dr. Alexandre was just 29 and fresh off a yearlong fellowship at Harvard Medical School when, in June 1963, a young patient was wheeled into the hospital where he worked in Louvain, Belgium. She had sustained a traumatic head injury in a traffic accident, and despite extensive neurosurgery, doctors pronounced her brain dead, though her heart continued to beat.

"He knew that in another part of the hospital, a patient was suffering from renal failure. He had assisted on kidney transplants at Harvard, and he understood that the organs began to lose viability soon after the heart stops beating.

"Dr. Alexandre pulled the chief surgeon, Jean Morelle, aside and made his case. Brain death, he said, is death. Machines can keep a heart beating for a long time with no hope of reviving a patient. His argument went against centuries of assumptions about the line between life and death, but Dr. Morelle was persuaded.

...

"Over the next two years, Dr. Alexandre and Dr. Morelle quietly performed several more kidney transplants using the same procedure. Finally, at a medical conference in London in 1965, Dr. Alexandre announced what he had been doing.

...

"In 1968, the Harvard Ad Hoc Committee, a group of medical experts, largely adopted Dr. Alexandre’s criteria when it declared that an irreversible coma should be understood as the equivalent of death, whether the heart continues to beat or not.

"Today, Dr. Alexandre’s perspective is widely shared in the medical community, and removing organs from brain-dead patients has become an accepted practice.

“The greatness of Alexandre’s insight was that he was able to see the insignificance of the beating heart,” Robert Berman, an organ-donation activist and journalist, wrote in Tablet magazine in 2019.

###########

And here's the story from Tablet magazine, interesting in a number of respects:

The Man Who Remade Death. Guy Alexandre was the first surgeon to remove organs from a patient with a beating heart. His colleagues thought him a murderer; Alexandre disagreed and revolutionized our understanding of death.  BY ROBBY BERMAN, Feb 4, 2019

"I met Alexandre a few months ago in his home in an upscale suburb of Brussels. The octogenarian is charming, affable and avuncular but he does not mince words: The physicians who accused him of murder “were hypocrites. They viewed their brain dead patients as alive yet they had no qualms about turning off the ventilator to get the heart to stop beating before they removed kidneys. In addition to ‘killing’ the patient, they were giving the recipients damaged kidneys that suffered ischemia … oxygen deprivation. The kidneys did not work well; they did not last long.”

"Given that brain death was not well known by the public in 1963, I asked Alexandre how he succeeded in getting consent from families to donate the organs. “It was simple. I didn’t ask. I told the families the situation was grim and I removed the organs in the middle of the night. When the family returned the next morning I told them their loved one had died during the night.”

"In 1961, Alexandre was in his third year of surgical training. He left Brussels for Boston to attend Harvard Medical School where he studied under professor Joseph Murray, the surgeon famous for performing the first successful kidney transplant between twins in 1954. After Alexandre successfully executed a number of kidney transplants between dogs in the laboratory, he was invited by Murray to join him in the operating room to operate on humans. It was there that Alexandre noticed a curious phenomenon.

"Murray turned off the ventilator in order to cause the heart to stop beating and only then did he extract the organs. Alexandre felt there was no need to damage the kidneys by depriving them of oxygen. He believed when looking at a human body with a dead brain that he was looking at a corpse that was suffering from a bizarre medical condition: a beating heart. In other words, the organism was dead but the organs remained alive."

#########

Earlier:

Friday, January 18, 2019

Fifty years of "brain death"

Drug markets: the replacement of agriculture by chemistry

Labs are replacing fields as the source of addictive drugs. Here are two stories, from National Affairs, and the Financial Times.

The current issue of National Affairs has this essay on drugs, drug use, and overdose deaths:

How to Think about the Drug Crisis by Charles Fain Lehman

"A reported 111,219 Americans died from a drug overdose in 2021. That figure has risen more or less unabated, and at an increasing pace, since the early 1990s. Back in 2011, 43,544 Americans died from a drug overdose — less than half the 2021 figure. Ten years earlier, in 2001, it was 21,705 — less than half as many again. And the problem keeps getting worse: The 2021 figure is nearly 50% higher than it was in 2019.

...

"The National Center for Health Statistics estimates that there were roughly 110,000 overdose deaths in the year ending December 2022 — essentially unchanged from a year earlier.

...

"Historically, illicit drugs — heroin, cocaine, marijuana, etc. — were derived from plants grown in fields or greenhouses. But licit pharmacology has long been able to use simple, widely available precursor chemicals to synthesize the active ingredients in these substances. This sidesteps the complex processes of farming altogether. At some point in the past several decades, drug-trafficking organizations learned to use the same techniques at scale. Using precursors sourced primarily from China, they now synthesize a variety of opioids — the class of drugs that includes heroin.

"The most widely known of these is fentanyl, a synthetic opioid conventionally used in anesthesia that is 50 times stronger than heroin. Some are stronger still — carfentanil, the most potent opioid known thus far, is roughly 100 times stronger than fentanyl. In 2021, synthetic opioids were involved in roughly two out of every three overdose deaths.

...

"Complicating the story further is the increasing purity and declining cost of methamphetamine, another synthetic drug with an exploding death rate. After synthetic opioids, methamphetamine is now the second most common cause of drug overdose death. It's also the only tracked drug where deaths not involving synthetic opioids are increasing. That these two lab-produced substances are replacing "organic" drugs at the same time is not a coincidence.

"Why have these drugs taken over the market? Because they're a much better value proposition for sellers. Synthetic drugs significantly reduce production costs, both because chemistry is less labor- and input-intensive per unit produced than farming and because lab production is much easier to obscure from interdiction efforts that drive up costs. Furthermore, because the potency per dose is higher, drug-smuggling operations can move a smaller amount of fentanyl than heroin for the same profit.

"Of course, the stronger the drug, the higher the risk of overdose. Drug-overdose death rates used to be low in part because for the first century or so of modern American drug use, the potency of illicit drugs was constrained by what traffickers could grow in a field. Synthetic drugs remove this limit."

********

And this from the FT:

How fentanyl changed the game for Mexico’s drug cartels.  by Christine Murray

"In the last decade, fentanyl has become the leading cause of death for young adults in the US. Mexico’s illegal drug trade has also adapted to the shift from plant-based drugs towards synthetics, creating a new, streamlined and highly profitable arm of the illicit business with fewer workers and lower costs — but just as much violence.

"The change has caused friction in two of Washington’s most important relationships, with China and Mexico.

...

"Instead of employing tens of thousands of agricultural labourers, the entire fentanyl industry in Mexico could function with “cooks” estimated to number in the hundreds, who were mostly not qualified chemists, Reuter said. Fentanyl’s growth appears to have hit heroin production in particular, with poppy growing in Mexico still well below its peaks, according to the UN Office for Drugs and Crime."

Is an End to Child Marriage within Reach? Not yet... Unicef report, and Lancet summary

 Unicef has issued the following report focused on the continued prevalence of child marriage, particularly in the poorest communities:

Is an End to Child Marriage within Reach? Latest trends and future prospects. May 2023

"The practice of child marriage has continued to decline globally. Today, one in five young women aged 20 to 24 years were married as children versus nearly one in four 10 years ago. Yet progress has been uneven around the world, and in many places the gains have not been equitable, leaving the most vulnerable girls behind.

"This year marks the halfway point to the deadline for achieving the Sustainable Development Goals, and when it comes to ending child marriage, a number of challenges loom large. Despite global advances, reductions are not fast enough to meet the target of eliminating the practice by 2030. In fact, at the current rate, it will take another 300 years until child marriage is eliminated."

***********

And here's an article in the Lancet:

Child marriage could be history by 2030, or last 300 more years, by Claudia Cappa, Colleen Murray and Nankali Maksud 

"UNICEF's analysis reveals only slight declines in child marriage in west and central Africa, which is the region with the highest prevalence of child marriage.1 There has been no change in Latin American and the Caribbean, which, if the current trajectory continues, would have the second highest prevalence of child marriage worldwide by 2030.1 After steady progress between 1997 and 2012, the Middle East, north Africa, eastern Europe, and central Asia regions have all seen stagnation in reducing child marriage in the past decade.

...

"Countries in sub-Saharan Africa with the highest projected population growth have the highest levels of child marriage, meaning the number of marriages is expected to increase there.

...

"declining child marriage prevalence is concentrated among girls from wealthier households. Girls from the richest quintile are less likely to become child brides and are the first to benefit from progress in averting child marriage, resulting in a widening gap in child marriage prevalence between rich and poor.1 In south Asia, wealthier households had three times more averted cases of child marriages than poor households in the past 25 years.1 If the rate of success in the richest quintile of south Asian families had been achieved globally, only 9% of girls would be married in childhood, far less than the current 19% worldwide prevalence of child marriage.1 Further progress in reducing child marriage largely depends on reaching girls who are otherwise left behind, including girls from the poorest households living without the resources and opportunities of their wealthier peers."

Future treatments for kidney failure

 The future treatments of kidney failure are just around the corner, where it seems they have been for a long time. So it's perhaps appropriate that this optimistic look at emerging technologies was published on April 1, but I think that's just an accident.

Beyond kidney dialysis and transplantation: what’s on the horizon? by Hamid Rabb, Kyungho Lee, and Chirag R. Parikh, J Clin Invest. 2022 Apr 1; 132(7): e159308., Published online 2022 Apr 1. doi: 10.1172/JCI159308

"There are currently over 750,000 patients with end-stage renal disease (ESRD) in the United States. Globally, 2.6 million patients receive renal replacement therapy with either dialysis or a kidney transplant, which is estimated to double in number by 2030 (1). Kidney care was revolutionized by the invention of the dialysis machine in 1943 by Willem Kolff and the subsequent development of the arteriovenous fistula in 1960 by Belding Scribner. The first successful human kidney transplantation was performed in 1954 by Joseph Murray, teaming with John Merrill, and has since become the treatment of choice for patients with ESRD. Although there have been only incremental innovations since that time, recent exciting developments in kidney research have the potential to transform treatment beyond dialysis and transplantation. Here, we highlight five emerging approaches for ESRD."

They go on to briefly discuss:

• Wearable and bioartificial kidneys
• Kidney-on-a-chip
• Growing a new kidney from stem cell–derived organoids
• Immune tolerance protocols for kidney transplants
• Xenotransplantation

Adam Smith and kidney exchange, by Walter Castro and Julio Elias

 Here's a blog post with supportive quotes from Adam Smith (who if he had thought specifically about kidney exchange in The Theory of Moral Sentiments (1759) would have been not quite 200 years in advance of the first successful kidney transplant (in 1954 by Joseph Murray, between identical twins...)

Adam Smith and Kidney Exchange by Walter Castro and Julio J. Elías

"Castro and Elías return with more Smithian insights into the logic of altruism and the design of kidney exchange markets."

History and pre-history of kidney transplantation

 From the Hektoen International Journal (starting with an Egyptian papyrus from 1550 BCE):

A brief history of kidney transplantation by Laura Carreras-Planella, Marcella Franquesa, Ricardo Lauzurica, Francesc E. Borràs.  Barcelona, Spain

"The history of kidney transplantation as we know it today began in the 1950s, but other key attempts were made earlier in the twentieth century. The first successful organ transplant was performed by Emerich Ullmann from the Vienna Medical School in 1902 when he auto-transplanted a kidney in a dog from its normal location to the vessels of the neck, where it produced some urine.44,45 In the same year, dog-to-dog and dog-to-goat kidney transplants were performed by Ullmann and Alfred von Decastello, ... In 1906 Mathieu Jaboulay, with Carrel as assistant surgeon (both of them Nobel laureates), performed the first kidney transplantations from goats and pigs to the arms and thighs of humans. Each kidney worked for one hour only ... The first transplantation from a human cadaver was attempted in the USSR by Yurii Voronoy in 1939, although the organ was rejected because of blood group incompatibility and the patient died after two days.

...

"Investigations resumed after World War II with other attempts at human kidney transplantation, especially by two groups in Europe and the United States. In 1946 a human kidney allograft was transplanted to blood vessels in the arm under local anesthesia by a team in Boston.50 The graft only functioned for a short time, but it was long enough to help the patient recover from acute renal failure. This achievement attracted major interest, as did the first transplantation from a live donor performed by Jean Hamburger (who defined the term “nephrology”) in Paris from a mother to her sixteen-year-old son. The transplanted kidney functioned for twenty-two days.51 In 1950, Lawler in Chicago was the first to attempt intra-abdominal kidney transplantation.

"In 1954 at Peter Bent Brigham Hospital (later Brigham and Women’s Hospital) in Boston, Joseph Murray performed the first truly successful living donor kidney transplantation. He received the Nobel prize for this achievement in 1990. The transplant was performed from one monozygotic twin to the other, so there was no histo-incompatibility. This was the first time that a transplanted patient, who had been dying from renal failure, survived for years after the transplant.52 The procedure was met with growing success—one kidney recipient even had a successful pregnancy and delivery—and expanded to other hospitals. 53 The first kidney transplantation in Spain was performed in 1965 at the Hospital Clínic de Barcelona by Antoni Caralps, Pedro Pons, Gil-Vernet, and Magriñá, followed by eight additional transplantations at the same hospital that year.

"However, even though transplantation surgical techniques had greatly improved, good immunosuppressive regimens were still lacking. The use of the newly available azathioprine, prednisolone, or total body irradiation helped during the initial crucial rejection period between identical twins or siblings.54 In the mid-1960s, great improvements were made in the pre-treatment of patients with hemodialysis to enhance health before surgery; organ transportation between hospitals; identification of HLA antigens, discovered by Jean Dausset; development of tissue-typing and lymphocytotoxicity testing; and an increase in kidney transplants, which provided valuable data for improvement.55–57 Methodologies and management were consolidated in the 1970s, and saw the beginning of transplantations from cadaveric donors.

"But the most remarkable breakthrough of this period was the introduction of the calcineurin inhibitors cyclosporine A and tacrolimus. Cyclosporine A was first isolated in 1971 from a soil fungus (Hypocladium inflatum gams) in Norway and studied by Jean-Francois Borel and Hartmann F. Stähelin at Sandoz (now Novartis).58,59 The importance of this drug was reflected in the speed at which it was approved and released to the market in 1983. This small cyclic polypeptide made it possible to reduce the percentage of rejection in the first year after transplantation from 80% to 10%.60 Tacrolimus, somewhat better than cyclosporine A in reducing acute rejection and improving graft survival,61 was isolated from Streptomyces tsukubaensis in the soil of Tsukuba, Japan in 1987. The name tacrolimus derives from “Tsukuba macrolide immunosuppressant,” although it was initially called FK506 because of its target FK506 binding protein (FKBP).62,63,57 Mycophenolic acid, which was first isolated in 1893 from Penicillium glaucum in spoiled corn, was found to possess antibiotic activity but carried many adverse effects.64 A century later, its ester derivate mycophenolate mofetil was synthesized as a safer drug with immunosuppressant action.65,66 Rapamycin, also known as sirolimus and a current first-line immunosuppressant, was first found to be an antifungal metabolite of Streptomyces hygroscopicus. Discovered in Rapa Nui (formerly named Easter Island) in 1964, the name rapamycin comes from the site of its discovery.67–69 It is also abbreviated as mTOR because tor in German means door, and this protein serves as a gateway to cell growth and proliferation.70 Other analogs such as everolimus were synthesized later and are also routinely used in kidney transplantation.71 Although many immunosuppressive drugs are now in use, cyclosporine A and tacrolimus are still key in preventing organ rejection, even fifty years after their discovery."

Kidney transplant in June 1950

I'm accustomed to calling Murray's 1954 surgery the first successful kidney transplant, and indeed the first successful organ transplant.
(see my post  A transplant makes history--Joseph Murray’s 1954 kidney operation ushered in a new medical era.)

But there were earlier attempts, and there's room to disagree on what constitutes a success. Here's a recent anniversary article about an earlier kidney transplant, from a deceased donor (and also before immunosuppression--Murray's surgery involved a live donation from one identical twin to another...)

This Day In Science June 17, 1950 – First successful kidney transplant operation was performed

"On June 17th 1950 Dr. Richard Lawler performed the first successful kidney transplant. The recipient was Ruth Tucker, a 44-year-old woman who had polycystic kidney disease (PKD).
...
"A transplant was risky but the only real option for survival for Tucker, as dialysis was not yet widely available. The donor kidney was removed from a patient who had died of cirrhosis of the liver.

“Not the most ideal patient, but the best we could find,” said Dr. Lawler after the surgery. The transplant surgery was quick, and 45 minutes after removal of the kidney from the donor the operation was complete. Tucker was released from the hospital a month later.
"The kidney functioned for at least 53 days, but it was removed 10 months after the surgery as it had been rejected. This transplant was conducted well before the development of immunosuppressant drugs and tissue typing which would have helped prevent organ rejection.

"Ruth Tucker had PKD in both of her kidneys, leaving one non-functioning and the other functioning at 10%. The donor kidney gave her body the chance to resume normal kidney function, therefore when the donor kidney was removed, Ruth was able to live another 5 years with her one remaining kidney. She died in 1955 from coronary artery disease which was unrelated to PKD and her organ transplant.

"Dr. Richard Lawler never performed another transplant, saying that he “just wanted to get it started”.
***********

Here's some more detail on the website of the Little Hospital of Mary in Chicago, where the surgery was performed.

First Successful Organ Transplant, Little Company of Mary, 1950

"The surgery was extremely courageous, given that it was done without anti-infection drugs, tissue typing and other advances that are now standard. A Newsweek article a week after the surgery was headlined, “Borrowed from the Dead”. The article stated, “Successful transplants have been made of bones, skin, nerves, tendons and eye corneas. But up to last week, no vital human organ had ever been moved from one person to another. Then, in a daring surgical feat, Dr. Richard M. Lawler of the Little Company of Mary Hospital, Chicago, removed a diseased kidney from Mrs. Ruth Tucker…The patient was ‘willing to gamble rather than lie back and wait for death,’ Dr. Lawler said.” A month later, Tucker was released from the hospital, a medical miracle. She lived five years before dying from a coronary occlusion following pneumonia."

Some histories of organ transplantation

I can't vouch for any of these...most are un-refereed internet pages...some starting with events reported from quite long ago, regarding skin and bones, for example.

From organdonor.gov: Timeline of Historical Events Significant Milestones in Organ Donation and Transplantation

http://www.organtransplants.org/understanding/history/


http://optn.transplant.hrsa.gov/learn/about-transplantation/history/

http://www.donatelifeny.org/all-about-transplantation/organ-transplant-history/

https://www.unos.org/transplantation/history/

http://www.mtf.org/news_history_of_transplantation.html


Here's a journal article, whose history begins with kidneys...
Organ transplantation: historical perspective and current practice

C. J. E. Watson1,* and J. H. Dark, 

Br. J. Anaesth. (2012) 108 (suppl 1): i29-i42.

doi: 10.1093/bja/aer384 

"A brief history of transplantation
Kidney transplantation
Since Jaboulay and Carrel developed the techniques
required to perform vascular anastomoses at the turn of
the last century, there has been a desire to treat organ
failure by transplantation. Jaboulay was the first to
attempt this in 1906, treating two patients with renal
failure by transplanting a goat kidney into one and a pig
kidney into the other; in both cases, he joined the renal
vessels to the brachial vessels.1 Both transplants failed
and both patients died. At that time, there was no alternative
to death if renal failure developed, and it would be
another 38 yr before the first haemodialysis machine was
invented. The first use of a human kidney for transplantation
followed in 1936 when Yu Yu Voronoy, a Ukrainian
surgeon working in Kiev, performed the first in a series of
six transplants to treat patients dying from acute renal
failure secondary to mercury poisoning, ingested by its
victims in an attempt to commit suicide. All the transplants
failed, in large part because of a failure to appreciate the
deleterious effect of warm ischaemia; the first kidney was
retrieved 6 h after the donor died.
One limitation to transplantation then, as now, was the
lack of suitable donor organs. The initial pioneers had used
animal organs or organs from long deceased humans. In
the 1950s, there came a realization of the need to avoid
excessive ischaemic injury and kidneys from live donors
began to be used. Some of these were from the relatives of
the recipient; others were unrelated patients having a good
kidney removed for other reasons. The surgical technique
also needed refinement; while a kidney based on the thigh
or arm vessels might be technically straightforward, and possibly
adequate for the short-term treatment of acute renal
failure, it was not a realistic solution for the long term.
That solution came from France in 1951 and involved
placing the kidney extraperitoneally in an iliac fossa, where
the external iliac vessels are easy to access and the
bladder is close by for anastomosis to the donor ureter;
this is the technique still used today.
Having overcome the technical issues of vascular anastomosis
and placement of the kidney, there remained the
problem of the immune response. Medawar’s work during
and after the Second World War studying the rejection of
skin grafts had demonstrated the potency of the immune
system.2 At that time, attempts to control the immune
system using irradiation had proved either ineffectual or
lethal. The first successful transplant therefore came about
by avoiding an immune response altogether, which Joseph
Murray’s team achieved by performing a kidney transplant
between identical twins.3 There then followed a series of
identical twin transplants around the world, with the first in
the UK being performed in Edinburgh by Woodruff and
colleagues4 in 1960."

The dangers of designing markets for illegal goods: Silk Road Founder Ross Ulbricht--'Dread Pirate Roberts'-- Sentenced to Life in Prison

Designing illegal markets (and shutting them down) is the story of the day, with stories about the late Silk Road, and it's successors.

The WSJ has the story on the life sentence of Dread Pirate Roberts:
Silk Road Founder Ross Ulbricht Sentenced to Life in Prison
Ulbricht was convicted of running underground online drug bazaar

"The sentence handed down by U.S. District Judge Katherine Forrest followed an emotional three-hour hearing. Judge Forrest said she spent more than 100 hours grappling with the appropriate sentence, calling the decision “very, very difficult.”

But ultimately, she gave Mr. Ulbricht the harshest sentence allowed under the law, saying Silk Road was “an assault on the public health of our communities” by making it easy for people around the world to buy illegal drugs."
...
"Prosecutors have described Silk Road as a criminal marketplace of unprecedented scope and sophistication. The site, which operated for two years, facilitated millions of dollars in transactions between buyers and sellers, who hawked illegal goods ranging from cocaine to fake driver’s licenses. At the heart of the criminal conspiracy, prosecutors say, was Mr. Ulbricht, who allegedly ran the site using the pseudonym Dread Pirate Roberts.
...
"In many ways, the Silk Road case was the first of its kind. The site operated on a hidden part of the Internet called the Tor network, and its only accepted form of payment was bitcoin, a digital currency whose movements are difficult to trace. The anonymity of the site’s transactions posed new challenges for law enforcement and forced them to depart from investigative techniques that would have been used in a traditional street drug case.

"Mr. Ulbricht is also not the typical drug kingpin. He was an Eagle Scout and grew up with a close-knit family in Austin, Texas, according to his lawyer. Mr. Ulbricht studied physics at the University of Texas in Dallas on a full scholarship and completed a master’s degree in material sciences at Pennsylvania State University."
*********

For some background, here's a long excerpt from an essay by Henry Farrell on the Silk Road and Dread Pirate Roberts
"The Silk Road might have started as a libertarian experiment, but it was doomed to end as a fiefdom run by pirate kings"
...
"This hidden internet is a product of debates among technology-obsessed libertarians in the 1990s. These radicals hoped to combine cryptography and the internet into a universal solvent that would corrupt the bonds of government tyranny. New currencies, based on recent cryptographic advances, would undermine traditional fiat money, seizing the cash nexus from the grasp of the state. ‘Mix networks’, where everyone’s identity was hidden by multiple layers of encryption, would allow people to talk and engage in economic exchange without the government being able to see.

Plans for cryptographic currencies led to the invention of Bitcoin, while mix networks culminated in Tor. The two technologies manifest different aspects of a common dream – the utopian aspiration to a world where one could talk and do business without worrying about state intervention – and indeed they grew up together. For a long time, the easiest way to spend Bitcoin was at Tor’s archipelago of obfuscated websites.

Like the pirate republics of the 18th century, this virtual underworld mingles liberty and vice. Law enforcement and copyright-protection groups such as the Digital Citizens’ Alliance in Washington, DC, prefer to emphasise the most sordid aspects of Tor’s hidden services – the sellers of drugs, weapons and child pornography. And yet the effort to create a hidden internet was driven by ideology as much as avarice. The network is used by dissidents as well as dope-peddlers. If you live under an authoritarian regime, Tor provides you with a ready-made technology for evading government controls on the internet. Even some of the seedier services trade on a certain idealism. Many libertarians believe that people should be able to buy and sell drugs without government interference, and hoped to build marketplaces to do just that, without violence and gang warfare.
...
"Would-be criminals on the hidden internet repeatedly complain that they have been ripped off. In the description of one commenter on the Hidden Wiki:
I have been scammed more than twice now by assholes who say they’re legit when I say I want to purchase stolen credit cards. I want to do tons of business but I DO NOT want to be scammed. I wish there were people who were honest crooks. If anyone could help me out that would be awesome! I just want to buy one at first so I know the seller is legit and honest.

This creates a market niche for intermediaries, who can become entrepreneurs of trust, supporting relationships between buyers and sellers who otherwise would not trust each other. Again, the Sicilian Mafia provides a precedent. Gambetta finds that they began as brokers of trust between buyers and sellers in a rural society without effective laws. The Mafia made money by guaranteeing transactions, threatening cheaters, and sometimes cultivating a general atmosphere of paranoia in order to ensure demand for their services. In other words, it built an informal order of its own, inimical to conventional laws, that gradually began to supplant the traditional state.

When Ulbricht began to grow hallucinogenic mushrooms and sell them on the internet in 2010, he didn’t see himself either as a Mafioso or a state builder. Instead, it appears that he was driven by enthusiasm for the libertarian thinker Murray Rothbard. On his LinkedIn profile, Ulbricht declared his intention to use ‘economic theory as a means to abolish the use of coercion and aggression amongst mankind’, and to build an ‘economic simulation’ that would let people see what it was like to live in a world without the ‘systemic use of force’. At the same time, he didn’t mind turning a profit from his activism – his diary entries show that he was pleased to make money from his first crop of mushrooms, and disappointed that he cashed out his first profits before the price of Bitcoin peaked.
...
"Seller pseudonyms provided a rough equivalent to a commercial brand. As the Stanford economist David Kreps has noted, a secured brand name with a reputation for honest dealing is an asset, and the desire to preserve its value can provide the incentive for future honesty. Not that the value is dependent on the actual owner of the name: a trademark can be sold or passed from one individual to another without losing its power. Ulbricht’s own pseudonym suggests that he had given this some thought: the original Dread Pirate Roberts appears in William Goldman’s comic fantasy novel The Princess Bride (1973), where it is a composite identity, passed from pirate captain to pirate captain as a kind of guarantee of fearsomeness.
...
"Yet market competition was no guarantee of honesty. Sometimes traders wanted to build up a reputation for honest dealing so that they could take the money and run. Several scammers gamed the system by establishing themselves as apparently reliable drug dealers, making a large number of near-simultaneous sales, demanding that customers finalise the payment before they got the goods and then disappearing with the money. Since the scammers used pseudonyms and Tor just like everyone else, outraged customers could do little except issue grandiose threats in the discussion forum.

They were vulnerable to more profound betrayals, too. Customers had to give mailing addresses to dealers if they wanted their drugs delivered. Under Silk Road’s rules, dealers were supposed to delete this information as soon as the transaction was finished. However, it was impossible for Ulbricht to enforce this rule unless (as happened once) a dealer admitted that he had kept the names and addresses. It’s likely that Silk Road dealers systematically broke these rules. At least one former Silk Road dealer, Michael Duch, who testified at Ulbricht’s trial, kept the names and addresses of all his clients in a handy spreadsheet.
"This created an obvious vulnerability – indeed, an existential threat to Ulbricht’s business. If any reasonably successful dealer leaked the contact details for users en masse, customers would flee and the site would collapse. And so, when a Silk Road user with the pseudonym FriendlyChemist threatened to do just that, Ulbricht did not invoke Silk Road’s internal rules or rely on impersonal market forces. Instead, he tried to use the final argument of kings: physical violence. He paid $150,000 to someone whom he believed to be a senior member of the Hells Angels to arrange for the murder of his blackmailer, later paying another $500,000 to have associates of FriendlyChemist murdered too.

It is unclear if anyone was, in fact, killed by anyone else. Indeed, it seems most likely that the whole affair was a scam in which FriendlyChemist and his purported assassin were associates (or possibly the same person). Still, it marked the final stage in an extraordinary transformation. Ulbricht began as an idealist, setting out to build a market free from what he described as the ‘thieving murderous mits’ of the state. He ended up paying muscle to protect the bureaucratic system that he had created."
*********

The Guardian writes about the dark markets that have sprung up to replace Silk Road: Dread Pirate Roberts may have been sentenced to life, but experts and customers say the tide has turned and internet markets for illicit products are here to stay

"James – not his real name – is the editor of DeepDotWeb, a news site which focuses on darknet marketplaces and maintains an up-to-date list of which markets are on or offline. He said the current market was “WAY bigger” than it was in the days of Silk Road.

James said it could safely be assumed that the daily turnover of the biggest markets – Agora is the largest, followed in no particular order by Nucleus, Middle Earth, Abrax, and Alphabay – is in the order of more than a million dollars a day. He estimated the market cap to be in the “hundreds of millions” of dollars.

“It’s becoming bigger all the time,” James told the Guardian. “Currently there are over 40 markets, forums, private vendor shops and a higher number of product listings than ever. I can personally testify that we, as a site who is reporting the darknet, see more and more traffic from people searching for specific markets – 1000% more than we saw last year.”

He said that since Ulbricht’s arrest people had “lost the sense of being invincible”, but also that they learned from Ulbricht’s mistakes and were now more careful, and more aware both of the dangers of law enforcement and of scams.

On Reddit, the subreddit for darknet markets has almost 60,000 subscribers. Among users asked by the Guardian what they thought the future holds, opinion was split. Many were worried by the instability of the new markets, suggesting that once vendors had enough repeat custom they would move to a direct-deal model rather than advertising on marketplaces that were vulnerable to exit scams. Vendors were the biggest losers in the Evolution exit scam.

But others thought the new order was here to stay.

“As long as our customers understand that purchasing their drugs through a DNM [Dark Net Market] is WAY safer than doing it in person, this will continue forever,” said one user, who gave his name as John. “People aren’t afraid of being robbed, beaten or killed because they went to their corner drug dealer when they can go to a DNM instead.”"

Job market for new Ph.d. economists

A recent NBER working paper discusses the job market for economists:

IS IT ALL WORTH IT? THE EXPERIENCES OF NEW PHDS ON THE JOB MARKET, 2007-2010
Brooke Helppie McFall
Marta Murray-Close
Robert J. Willis
Uniko Chen
Working Paper 20654
http://www.nber.org/papers/w20654
November 2014


ABSTRACT
This paper describes the job market experiences of new PhD economists, 2007-10. Using information from PhD programs' job candidate websites and original surveys, the authors present information about job candidates' characteristics, preferences and expectations; how job candidates fared at each stage of the market; and predictors of outcomes at each stage. Some information presented in this paper updates findings of prior studies. However, design features of the data used in this paper may result in more generalizable findings. This paper is unique in comparing pre-market expectations and preferences with post-market outcomes on the new PhD job market. It shows that outcomes tend to align with pre-market preferences, and candidates' expectations are somewhat predictive of their outcomes. Several analyses also shed light on sub-group differences.

some interesting paragraphs:

"During the job-market seasons covered by this study, job candidates submitted 107 applications, completed 17 interviews and 6 fly-outs, and received 3 job offers on average. Our findings show a dramatic increase in applications compared to List (2000), who found the average job seeker in his convenience sample had scheduled just seven interviews prior to the AEA meetings in 1997.xvii It is likely that the decreased cost of finding openings and submitting applications associated with of the growth of internet job listings and web-based applications have changed norms since the late 1990s. "(p9)

"Positions in business and industry tend to be the highest paid, at $110,100 on average, while postdoctoral fellowships, the lowest-paid category, average just $57,500. The average salary for a four-year college position is $72,400, while the average new assistant professor’s salary at a university is $96,500 per year. " (p16)

Jacob Lavee on preventing transplant tourism, in the birthplace of transplantation

Jacob Lavee, about whom I've written numerous posts, was just in Boston as the 8th Annual Joseph E. Murray Visiting Professor in Transplant Surgery, to speak about "Preventing transplant tourism: A personal voyage which shaped the Organ Transplant Law in Israel."

Interview with the late Dr Joseph Murray, about the first kidney transplants and related matters

Great interview, conducted in 2000. Lots of detail. For example, he practiced on dogs, removing a dog's kidney and then transplanting it into the same dog, to practice the surgical techniques for kidney transplants without immunological complications...and discussion of repugnance... and of the generosity and courage of early transplant patients ...and the relationship between basic and applied science (18 minutes for the whole thing).

Here's the video from the Nobel site (I can't figure out how to upload it): http://www.nobelprize.org/mediaplayer/index.php?id=732 .

Here are my earlier posts on Dr. Murray who shared the 1990 Nobel Prize in Physiology or Medicine for "...discoveries concerning organ and cell transplantation in the treatment of human disease"

Dr. Joseph E. Murray, who won a Nobel for the first kidney transplant, RIP

Nobel winner Dr. Joseph Murray, famous for first successful kidney transplant dies in Boston

See my earlier posts about Dr. Murray and the first kidney transplant,

update: here's a good obit in the NY Times:Joseph E. Murray, Transplant Doctor and Nobel Prize Winner, Dies at 93

"Dr. Joseph E. Murray, who opened a new era of medicine with the first successful human organ transplant, died on Monday. He was 93 and lived in Wellesley and Edgartown, Mass."

Harvard celebrates first kidney transplant

In connection with Harvard's 375th anniversary, the Gazette is taking note of some key events:  A transplant makes history--Joseph Murray’s 1954 kidney operation ushered in a new medical era

"“If you’re going to worry about what people say, you’re never going to make any progress,” Murray said during a recent interview at his home in Wellesley Hills, Mass."
...
"After the operation, Murray’s work on transplantation continued. Despite his success with the Herricks, the problem of rejection generally still presented a high hurdle.
In the years that followed, Murray used first X-rays and then drugs to suppress the immune system and keep the body from rejecting the grafted tissue, but there were few successes. Through those dark years, he and his colleagues pressed on, inspired by the dying patients who volunteered for surgery in hopes that, even if they didn’t make it, enough could be learned that success would come one day.
“We were trying. In spite of several failures, we felt we were getting close,” Murray said. “It’s difficult to translate the optimism of the Brigham staff and hospital. The administration really backed us.”
Finally, in 1962, in collaboration with scientists from the drug company Burroughs-Wellcome, Murray tried a drug, Imuran, on 23-year-old Mel Doucette, who had received a kidney from an unrelated cadaver donor. The success of that operation and the anti-rejection drug cleared the final hurdle to widespread organ transplantation between unrelated donors, and set the stage for the many refinements and breakthroughs by others in the years to come."

First live kidney donor dies at 79 (56 years after donating to his twin)

Ronald Lee Herrick became the first live kidney donor when, as a college freshman, he donated a kidney to his twin.
Here's the Globe obit: World's first organ donor dies at 79
"On Dec. 23, 1954, Dr. Joseph Murray removed a kidney from Ronald and implanted it in Richard. Years later, Murray shared a Nobel Prize for his groundbreaking work. For the Herrick twins, the results were more immediate and personal. Ronald gave Richard about eight more years of life.


"The older and more serious of the twins, Ronald Herrick didn't talk about his key role in opening a new venue in medicine unless someone asked, and even then he had to be drawn out if the conversation lasted more than a few sentences. Unassuming and modest, he taught math for decades in high school, junior high, and college. On the side, he kept his hand in farming because he grew up on a family farm and loved the physical work of agriculture.

"Mr. Herrick, who suffered from heart ailments that prompted him to retire from teaching and farming in 1997, died Monday in the Augusta Rehabilitation Center in Augusta, Maine, where he was recuperating from heart surgery in October. He was 79 and lived in Belgrade, Maine."

Here's another account: First successful organ donor dies
"Ronald Lee Herrick, who became a medical pioneer in 1954 when he donated a kidney to his twin brother in what is considered the world’s first successful organ transplant, has died at the age of 79.


"The native of Rutland, Mass., died in Augusta, Maine, on Monday, while recovering from heart surgery. A retired math teacher in Northborough before moving to Maine, he was quiet about his role in the groundbreaking operation at the former Peter Bent Brigham Hospital in Boston. His gift created a new field of medicine, as this Globe story says.

"I didn't think too much about it," Herrick said during an interview when the 50th anniversary of the operation was celebrated in 2004. "We had all kinds of meetings beforehand. I agreed, and there was no real problem."

"When the identical twins were 23 years old, Ronald’s brother Richard was dying of chronic kidney inflammation.

"Organ transplants had been attempted before, but they had failed. Kidney specialists at the Brigham believed taking a kidney from an identical twin would avoid the recently recognized problem of rejection, in which the recipient's immune system attacks the transplanted organ as foreign.

"The doctors -- including Dr. Joseph E. Murray, who later won the Nobel Prize in medicine -- were right. The operation was a success and Richard, a Coast Guard veteran who had been failing while on an early form of dialysis, recovered, married his recovery room nurse, and became the father of two children. He died of a heart attack eight years later.

"Here was a person who was near death and was able to return to normal life," Dr. Michael J. Zinner, chief of surgery at Brigham and Women's Hospital, the successor to Peter Bent Brigham Hospital, said in 2004. "This ushered in a new era, when surgery would no longer simply be used to treat acute illnesses like appendicitis or a traffic accident (injury) but now could be used to treat a chronic illness and make patients better."

HT: Steve Leider

Misc. organ transplant links: poetry and priority

Steve Leider points me to this video about all of the people who received transplant organs from Chris Henry, the wide receiver who died in a vehicle accident last year. Apparently his mother brought them all together recently.


All those organ recipients from one donor made me thing of this kidney transplant poem that (along with others by the same author) is reported by the Los Angeles Examiner:  Los Angeles Poet G. Murray Thomas, an essential voice in a city where noone is ever doubting Thomas (HT gtaniwaki )

“YOUR KIDNEY JUST ARRIVED AT LAX”

"The doctor told me as I lay in pre-op prep.
I envisioned a special chartered flight,
an entire airplane filled with organs.

"Hearts with little heart shaped carry-ons.
They always watch the inflight movie
and cry all the way through.

"Livers splurging on one last drink;
they don’t think they’ll be allowed
where they’re going.

"The lungs eye the spot
where the oxygen masks drop.

"Corneas stare out at the passing countryside;
they always get a window seat.

"The spleens are always complaining

about security
about the length of the flight
about the lack of leg room
(although they have no legs).
"The gall bladder always gets in line
before his row is called.

"And there’s my kidney,
no doubt reading a book to pass the time
something classic: As I Lay Dying,
or Great Expectations,
or The Stranger.

"All of them wondering
about the journey ahead,
about their new home,
about their new life."

-G Murray Thomas


In other news, the Israeli priority rule is going into effect: Registered donors to get preference if they need organ

"...the Health Ministry’s Israel Transplant will “give priority” in the receipt of organs to people who previously signed an ADI card and gave consent to donate organs after their deaths.

"Their immediate family members will also be entitled to this benefit.

"The new policy, which is being promoted by a twoweek media campaign that began on Sunday, is aimed at narrowing the gap between the 10 percent of Israelis who are registered as potential donors with ADI and the 62% who, when polled, said they were willing to donate lifesaving organs after they die.

"The 2008 organ transplant law included a unique section that gives priority to ADI card holders and their immediate relatives who need a transplant organ. However, due to the need for many technical and other preparations, it has taken more than two years to launch the new policy, which was approved by a majority of experts.

"Anyone already registered with ADI or who signs up before December 31, 2011 will be entitled to the priority benefit starting on January 1, 2012, while anyone joining after December 31, 2011 will be entitled to the benefit from three years after the date of signing, according to Israel Transplant, which is chaired by Rambam Medical Center director-general Prof. Rafael Beyar.

"Tamar Ashkenazi, Israel Transplant’s long-time coordinator, said that she hopes the “bonus” will induce hundreds of thousands of people – from the age of 17 – to register with ADI as potential organ donors. Today, only 547,000 people, or 10% of the population of the requisite age, are registered. ADI is an organization named for Adi Ben-Dror, who died decades ago from the lack of a donor kidney.

"Ashkenazi noted that there are two computerized lists of people who need organ transplants, one of those in hospital who urgently need an organ and the other living at home who need one less urgently. Having an ADI card would give “additional points” that are allocated and, through computers, automatically calculate who is most suited for a specific organ among those of a compatible blood type. “The extra points will be a significant addition to those who urgently need an organ,” she said.

"For a few weeks after the media campaign ends, stands will remain in public places for signing up new ADI members."

The first kidney exchange in the U.S., and other accounts of early progress

The Student BMJ (a student run affiliate of the British Medical Journal) has an article interviewing the pioneering surgeons who conducted the first kidney exchange in the U.S., in 2000. (It's gated, but you can register for free.)

Anthony P Monaco and Paul E Morrissey: a pioneering paired kidney exchange
Transplant surgeons Anthony P Monaco and Paul E Morrissey performed the first paired kidney exchange in the United States
By: Prizzi Zarsadias
Published: 24 March 2010, Cite this as: Student BMJ 2010;18:c1562

The article is in interview form. Some highlights:
"When two patients found they were ABO incompatible with their live kidney donors it seemed that a long wait on the organ donor list awaited them. But by coincidence the donors were a match for each other’s recipient. Rather than lose this chance for both patients to receive a live kidney donation Anthony P Monaco and Paul E Morrissey saw an opportunity, and in 2000 they performed the first paired kidney donation in the United States. "

How did the first paired kidney donation come about?
Paul E Morrissey: We knew about paired donation from an experience in Korea. We had encountered articles about paired donation. Then these pairs simultaneously presented to us; it just clicked that we could exchange the donors. I wouldn’t attribute the idea to myself or Dr Monaco but to the entire team. We discussed it with 15 of our doctors and nurses, social workers, and various other people, and we agreed that it would be something that we would propose to the family.

How did the patients in the first exchange fare?
PEM: The surgeries were uneventful. One recipient had great kidney function. The second had recurrence of the original disease and a bad acute rejection shortly after the transplant and went back onto dialysis several weeks after the transplant. One outcome was not good. The other patient did fantastically. Any time that a living donation doesn’t work is sad. And in this circumstance, to have had a child make a donation for a parent and to have it work out for the person she donated to but not work out for the parent was sad and unfortunate.

What was the worst case scenario?
PEM: This would be close to it; the success rate for a live kidney donation is in the neighbourhood of 98% or so. This might happen once in every 50. It’s an extremely unusual circumstance for any living donation, and in this setting it adds to the unhappiness. There was a lot of hand holding for the recipient with the failed kidney but also for the donor. There was a lot of follow-up on a longitudinal basis. They are both alive and well today but who knows exactly what emotion they harbour, and I hope that the other patient is enjoying the outcome of her operation.
APM: The worst case scenario for any living transplant would be that the recipient or donor die because of surgery. We haven’t seen that, but that’s the risk in this scenario. We’ve had recipients who have died a week or two later, but that has not happened with swap transplants.
PEM: We inform the patients more of the adverse outcomes. It was, of course, at the forefront of our minds when we proceeded the second time.

During the first exchange did you envisage the technique’s success?
APM: We did not envision it, but we were not surprised that it has grown because it works well. There is a natural evolutionary process to extend it into other situations. We do swaps that involve not just ABO incompatibility; we also swap kidneys between pairs that are incompatible because of HLA antibodies. We are also currently working on a five-way swap.
PEM: The credit obviously goes to countless groups throughout the country that have pushed it forward. In particular the group in our organ procurement organisation, the New England Organ Bank, has really been a leader in taking this forward nationally but at the time that we did this, we didn’t have thoughts about expanding it beyond the reaches of our own programme. I think that they’ll continue to grow out of necessity.

The article begins with these biographical details:
Anthony P Monaco
Peter Medawar professor of transplantation surgery, Harvard University, emeritus director of the Beth Israel Deaconess Harvard Medical Center Transplant Program, and director of the Rhode Island Hospital Transplant Services
Biography—After graduating from Harvard Medical School in 1956 his career has spanned five decades. In that time he has published more than 470 papers and has held the post of editor of Transplantation for 32 years until 2001 and has been the special features editor for the same journal ever since. He is also a trustee of the New England Organ Bank.

Paul E Morrissey
Associate professor of surgery and transplant surgeon at Rhode Island Hospital and assistant medical director for the New England Organ Bank
Biography—Trained at the University of Massachusetts and held residencies and research fellowships at Yale and Harvard Medical Schools. He has been a transplant surgeon at Rhode Island Hospital since 1997 and has been surgical director of the Division of Organ Transplant since 2002. He has been awarded many honours, including the Thomas Murray award from the Rhode Island Organ Donor Awareness Coalition. "

As the article indicates, an earlier exchange had been carried out in S. Korea. Another country that has been active in kidney exchange is Holland, and a recent report of their experience is in the April 2010 issue of the American Journal of Transplantation: "Altruistic Donor Triggered Domino-Paired Kidney Donation for Unsuccessful Couples from the Kidney-Exchange Program" by Roodnat, J. I.; Zuidema, W.; van de Wetering, J.; de Klerk, M.; Erdman, R. A. M.; Massey, E. K.; Hilhorst, M. T.; IJzermans, J. N. M.; Weimar, W.

The New England Program for Kidney Exchange (the institutional descendent of that first U.S. exchange by Monaco and Morrissey) maintains a page listing Kidney Exchange:A Chronology of Scientific Contributions (scroll to the bottom of that page).

While I'm on the subject of important firsts, donating a kidney became much easier with the introduction of laproscopic kidney nephrectomies for donor kidneys (taking the kidney out via a small incision instead of a big one). Here's the article by Lloyd Ratner et al. reporting the first one:

Laparoscopic live donor nephrectomy.
Ratner LE, Ciseck LJ, Moore RG, Cigarroa FG, Kaufman HS, Kavoussi LR., Transplantation. 1995 Nov 15;60(9):1047-9.

"A laparoscopic live-donor nephrectomy was performed on a 40-year-old man. The kidney was removed intact via a 9-cm infraumbilical midline incision. Warm ischemia was limited to less than 5 min. Immediately upon revascularization, the allograft produced urine. By the second postoperative day, the recipient's serum creatinine had decreased to 0.7 mg/dl. The donor's postoperative course was uneventful. He experienced minimal discomfort and was discharged home on the first postoperative day. We conclude that laparoscopic donor nephrectomy is feasible. It can be performed without apparent deleterious effects to either the donor or the recipient. The limited discomfort and rapid convalescence enjoyed by our patient indicate that this technique may prove to be advantageous."