Paolo Macchiarini

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Paolo Macchiarini (born August 22, 1958)[1]:2 is a thoracic surgeon and a former professor of Regenerative Medicine at Karolinska Institutet in Stockholm (Sweden). As of 2016 he was being investigated for research fraud.[2] Previously he was considered a pioneer in the field of regenerative medicine using both biological and synthetic scaffolds seeded with patients' own stem cells as trachea transplants.[1]:51 Macchiarini has been accused of research misconduct and unethically performing experimental surgeries, even on relatively healthy patients. Six of the eight patients who received one of his synthetic trachea transplants have died.[3] Also, an article in Vanity Fair suggested that Macchiarini had falsified some of his academic credentials on résumés.[4] Similar accusations have been published in the Swedish newspaper Aftonbladet according to which Macchiarini's claim to have been a professor at universities in Hannover and Barcelona has turned out to be false.[5]

The secretary of the Nobel Committee for Physiology or Medicine, Urban Lendahl, resigned in February 2016, owing to his involvement in recruiting Macchiarini to Karolinska Institutet in 2010.[6][7] Shortly afterwards the vice chancellor who in 2015 had cleared Macchiarini of scientific misconduct also resigned.[8] Macchiarini's employment by Karolinska is due to end in November 2016 following a decision by the institution not to renew his contract.[9] On March 23, 2016 the Staff Disciplinary Board at KI announced that his employee relationship with the institute had been effectively terminated.[10]

Education[edit]

Macchiarini obtained his medical degree (equivalent to MD) at the Medical School of the University of Pisa (Pisa, Italy) in 1986. He subsequently followed his residency in thoracic surgery at the same university between 1986 and 1991. He completed a fellowship at the departments of thoracic and vascular surgery and heart-lung transplantation of the Marie Lannelongue hospital (University of Paris-Sud, Le Plessis-Robinson, France) in 1993. In 1997, he obtained a PhD degree at the University of Franche-Comté. When the University of Barcelona appointed him professor in 2005, the Medizinische Hochschule Hannover awarded him an additional contract to ensure that Macchiarini would continue to teach and operate four days a month in Hanover. [11]

Surgeries performed[edit]

Claudia Castillo: First transplant using patient's stem cells[edit]

In June 2008, Macchiarini conducted the world's first transplant of a donated trachea colonized with the stem cells of the patient, Claudia Castillo.[12] "After a severe collapse of her left lung in March, Castillo needed regular hospital visits to clear her airways and was unable to take care of her children."[13] The only treatment left to her following conventional medicine "was a major operation to remove her left lung which carries a risk of complications and a high mortality rate."[14] Macchiarini proposed tissue engineering.

A team from Spain, the UK and Italy, collaborated on the surgery, which took place at Spain's Hospital Clinic of Barcelona.[15] They stripped the donated organ of its cells and MHC antigens (involved in helping the body recognize foreign tissues).[16] They used the remaining structure as a scaffold for the patient's own cells, which were cultured onto it.[16]

The operation was an immediate success. "The graft immediately provided the recipient with a functional airway, improved her quality of life, and had a normal appearance and mechanical properties at 4 months. The patient had no anti-donor antibodies and was not on immunosuppressive drugs."[16] The latter aspect was a significant advantage, as immunosuppressive drugs can "increase the risks of infection, malignancy, cardiovascular disease and bone marrow suppression."[17] "The technique raises the prospect of transplants for patients whose organs are damaged by cancer, who then cannot take the drugs as they increase the risk of cancer returning."[12]

Martin Birchall, then Professor of Surgery at the University of Bristol, commented on the importance of the operation's success: “Surgeons can now start to see and understand the very real potential for adult stem cells and tissue engineering to radically improve their ability to treat patients with serious diseases. We believe this success has proved that we are on the verge of a new age in surgical care”.[14]

Castillo was reported to be in good health six years after the surgery.[18] There are however conflicting statements that Castillo has had continuous, severe, complications after the surgery, with reports that "No graft found, serious complications, need for a pneumectomy but still reported as a major success by Macchiarini and Birchal" by her treating doctors in Barcelona in April 28, 2014.[19] To keep her trachea from collapsing multiple biodegradable stents has had to be inserted.[19]

Ciaran Finn-Lynch: first child[edit]

March 2010: Ciaran Finn-Lynch is the first child to receive stem cell organ treatment, and also had the "longest airway that has ever been replaced."[20] He was 10 years old when an earlier transplanted trachea (with metal stents) started to cut into his aorta, the main blood vessel coming out of his heart.[21] After several operations, there was still bleeding from the stents. With no other options in sight, the team leader thought of Macchiarini's earlier success with Castillo.[21]

Macchiarini joined colleagues at London's Great Ormond Street Hospital during the operation, which was led by Martin Elliott,[20] and included Martin Birchall of University College London.[22] Macchiarini seeded the child's stem cells to the donated trachea and applied growth factor chemicals.[22] He explained, "We told the cells to differentiate and transform naturally into the layers that make up the airway."[22]

Due to the urgency of the child's condition, surgeons weren't able to wait for the patient's stem cells to develop into trachea cells in the lab. Martin Birchall said: "To minimise delays, we bypassed the usual process of growing cells in the laboratory over a period of weeks, and instead opted to grow the cells inside the body, in a similar manner to treatments currently being trialed with patients who have had heart attacks."[22] Using this technique, "the boy's trachea was ready to be implanted in just four hours."[20] The entire operation lasted nearly nine hours.[23]

The operation was successful. On March 20, 2010, team leader Martin Elliott said, "The child is extremely well. He's breathing completely for himself and speaking, and he says it's easier for him to breathe than it has been for many years."[20] After six months, his trachea looked almost normal, and his progress continued.[21]

In April 2013, then 14-year-old Finn-Lynch was honoured with a Pontifical Hero Award for his courage, during the Second International Adult Stem Cell conference at the Vatican. He was the second person to receive the award.[21]

Macchiarini believed that the implications for future treatments went beyond organ replacement, to the healing of damaged organs with stem cell therapy. "We need to change our philosophy…. The question is do we really need to transplant the entire organ and put the patient on immunosuppression, or can we stimulate stem cells to make it function again?"[20] Martin Birchall said that more clinical trials were needed, but was hopeful that the technique could "allow not just highly specialized hospitals to carry out stem cell organ transplants."[24]

Andemariam Teklesenbet Beyene: first synthetic trachea[edit]

On June 9, 2011 at Karolinska University Hospital in Stockholm, Sweden, doctors including Macchiarini implanted a synthetic windpipe built up with the patient's own stem cells, into a 36-year-old man with late-stage tracheal cancer.[25][26] The synthetic windpipe was made at University College London, by Professor Alexander Seifalian. The implanted trachea became loose and the patient died in January 2014.

According to information uncovered by the Swedish documentary "Dokument Inifrån: Experimenten" (Swedish: "Documents from the Inside: The Experiments") the patient went from suffering an increasingly terrible and eventually bloody cough to dying, intubated, in the hospital. At that point, determined by autopsy, 90% of the synthetic windpipe had come loose. He allegedly made several trips to see Macchiarini for his complications, and at one point had surgery again to have his synthetic windpipe replaced, but Macchiarini was notoriously difficult to get an appointment with. According to the autopsy, the old synthetic windpipe did not appear to have been replaced.[27]

Christopher Lyles: first U.S. citizen to receive synthetic trachea[edit]

The second person in the world, and the first in the U.S., to receive a synthetic trachea engineered with the patient's own stem cells, was Christopher Lyles of Abingdon, Maryland. He had "exhausted the limited treatment options available in the U.S. for his tracheal cancer."[28] Mr. Lyles was operated on in Stockholm, Sweden, in November 2011, and returned home to Baltimore in January 2012. "'I’m feeling good,' Mr. Lyles said in a telephone interview from his home, where he was playing with his 4-year-old daughter. 'I’m just thankful for a second chance at life.'"[29] However, Mr. Lyles died in March 2012, nearly four months after the surgery.[30][31]

The 3D scaffold was made by an American company "Harvard Apparatus Regenerative Technology" (www.biostage.com). The material used as synthetic scaffold was polyurethane and polytetrafluoroethylene.[citation needed][relevant? ]

Hannah Warren: first baby to receive synthetic trachea[edit]

Hannah Warren of Korea was born in August 2010 with an underdeveloped trachea. She survived for 2 years thanks to a tube inserted in a bronchus through the oesophagus and an aesophagus-broncus fistula.[32] In April 2013, at the Children's Hospital of Illinois at OSF Saint Francis Medical Center (in a 9-hour procedure working with local pediatric surgeon Mark Holterman- the parents, a Newfoundland, Canada man and a South Korean woman living in her country), he gave a 3-inch long, bone marrow stem cell-cultured artificial trachea, or windpipe, to 2-year-old Hannah Warren, who had until then spent all her life in the Seoul National University Hospital in Seoul, South Korea, and was initially not expected to survive. She was the youngest patient yet to undergo that procedure, and only about 50,000 people in the world have her condition.[33] Hannah died a few months later on July 6, 2013.[34] Her family stated: "Her new trachea was performing well, but her lungs went from fairly good, to weak, to poor."[35]

The 3D scaffold was made by the American company "Harvard Apparatus Regenerative Technology" (www.biostage.com). The material used as synthetic scaffold was polyurethane, polytetrafluoroethylene.[citation needed][relevant? ]

Allegations[edit]

In 2012, Italian newspapers reported stories of transplant patients accusing Macchiarini of asking for money to expedite their procedures.[36]

Research misconduct[edit]

In two separate filings in June and August 2014 Macchiarini was accused by four former colleagues and co-authors of having falsified claims in his research.[37] The Karolinska Institute appointed an external expert (Bengt Gerdin) to review the charges, comparing the results reported to the medical record of the hospital.[37] His investigation was presented in May 2015 finding Macchiarini guilty of research misconduct and that he had exaggerated the outcome of his operations in six of the seven articles reviewed.[38] After considering the findings and a lengthy rebuttal provided by Macchiarini the vice-chancellor of Karolinska Institute Anders Hamsten decided to clear Macchiarini of the allegations.[39] The Lancet published a sharp critique of Karolinska's leadership.[40] The journal did however later publish a letter from the Swedish Royal Academy of Sciences that reiterated investigator Bengt Gerdin's fraud allegation against Macchiarini's 2011 Lancet paper.[41]

Related to the findings that emerged in the investigation Swedish MPA (Medical Products Agency) and the Health and Social Care Inspectorate decided to press charges for the three operations performed in Sweden. The charges against him, for which he is still under investigation, are manslaughter and bodily harm.[42]

Professor Emeritus at Uppsala University Bengt Gerdin who the Karolinska Institute originally brought in to review the case expressed critique of the vice-chancellor treatment of the allegations, in an interview in Swedish television.[43] These concerns were echoed by the chairman of the Karolinska Institute, Lars Leijonborg, and the chairman of the Swedish Medical Association, Heidi Stensmyren, calling for an independent investigation that would also look at how the issue was dealt with by the university management.[44]

Other misconduct[edit]

A story published by Vanity Fair mentioned disjunct versions of his academic resume. The article paints him as a serial fabulist, detailing an alleged courtship and marriage arrangements from the perspective of a NBC News producer, Benita Alexander, who was supposed to journalistically portray Macchiarini and instead began an affair with her subject, only to find out he had been married for thirty years at the time.[4] The Karolinska Institute mentioned the alleged discrepancies regarding Macchiarini's résumé(s) as part of its decision to not extend his current contract beyond 2016.[45] Macchiarini is reported to have claimed that Pope Francis had given his personal blessing for the wedding between the couple, both said to be divorcees, and would host the ceremony. The Pope's spokesman said that the Pope had no "personal doctor" named Macchiarini, knew nobody of that name, and would not have officiated.[46]

Dokument Inifrån: Experimenten[edit]

Sveriges Television investigative TV show Dokument inifrån aired a three-part series in January 2016 titled "Experimenten" where Macchiarini's work was investigated.[47] The documentary shows Macchiarini continuing operations with the new method even after it showed little or no promise, exaggerating the health of his patients in articles as they died one by one. While Macchiarini admitted that the synthetic trachea did not work in the current state, he did not agree that trying it on several additional patients without further testing had been inappropriate. Allegations were also made that patients' medical conditions both before and after the operations, as reported in academic papers, did not match reality. Macchiarini also stated that the synthetic trachea had been tested on animals before using it on humans, something that could not be verified. Following the series, Karolinska Institutet stated that they would investigate his work again.[48]

A BBC documentary reports about a second healthy volunteer operated and having his trachea replaced by an artificial scaffold soaked in stem cells by Macchiarini [49]

The fate of the patient and the long-term result of the operation are uncertain.

References[edit]

  1. ^ a b "Qualifications portfolio for teachers and researchers at Karolinska Institutet: Curriculum vitae", Regmedgrant.com, February 4, 2010.
  2. ^ McCook, Alison (February 5, 2016). "Karolinska orders new investigation of trachea surgeon Macchiarini". Retraction Watch. Retrieved February 11, 2016. 
  3. ^ Bäsén, Anna (January 13, 2016). "Tekniken skulle rädda liv – sex av åtta dog" [The technology could save lives – six of the eight died]. Expressen (in Swedish). Retrieved February 10, 2016. 
  4. ^ a b Ciralsky, Adam (January 31, 2016). "The Celebrity Surgeon Who Used Love, Money, and the Pope to Scam an NBC News Producer". Vanity Fair. Retrieved January 7, 2016. 
  5. ^ Ahlborg, Karin (February 9, 2016). "Skandalkirurgen ljög om sina meriter" [The scandal surgeon lied about his qualifications]. Aftonbladet (in Swedish). Retrieved February 12, 2016. 
  6. ^ "Top Nobel Prize administrator resigns in wake of Macchiarini scandal". Science. Retrieved February 9, 2016. 
  7. ^ TT (February 7, 2016). "KI-fallet: Nobelsekreteraren avgår" [KI case: Nobel secretary resigns] (in Swedish). Sveriges Radio. Retrieved February 9, 2016. 
  8. ^ "Karolinska Institute vice-chancellor resigns in wake of Macchiarini scandal". Science - AAAS. 
  9. ^ Staff (February 10, 2016). "The week in science: 5–11 February 2016". Nature. 530. People: Macchiarini out. doi:10.1038/530134a. Retrieved February 10, 2016. open access publication - free to read
  10. ^ "Karolinska Institutet dismisses Macchiarini". 
  11. ^ MHH schließt Vertrag mit Luftröhren-Spezialisten - MHH press release, 08. Dec. 2004
  12. ^ a b "Transplant first a giant leap for surgery: Patient's stem cells used to engineer new organ; UK scientists involved in pioneering technique", Sarah Boseley, The Guardian, November 19, 2008.
  13. ^ "Doctors give woman a new windpipe, using her own stem cells", The Associated Press, Daily News (New York), November 19, 2008.
  14. ^ a b , University of Bristol, November 19, 2008.
  15. ^ "Once doctors had a donor windpipe, scientists at Italy's University of Padua stripped off all its cells, leaving only a tube of connective tissue. Meanwhile, doctors at the [UK's] University of Bristol took a sample of Castillo's bone marrow from her hip. They used the bone marrow's stem cells to create millions of cartilage and tissue cells to cover and line the windpipe. Experts at the University of Milan [Italy] then used a device to put the new cartilage and tissue onto the windpipe. The new windpipe was transplanted into Castillo [at Spain's Hospital Clinic of Barcelona] in June.""Doctors give woman a new windpipe, using her own stem cells", The Associated Press, Daily News (New York), November 19, 2008.
  16. ^ a b c "Clinical transplantation of a tissue-engineered airway", Paolo Macchiarini et al, The Lancet, Volume 372, Issue 9655, Pages 2023–2030, December 13, 2008, Published Online: November 19, 2008.
  17. ^ "Long-term management of patients taking immunosuppressive drugs", Denise C. Hsu et al, Australian Prescriber (vol. 32, no. 3, June 2009), summary.
  18. ^ "A Leap Of Faith Recap: Dr. Macchiarini & Pioneering Regenerative Medicine (6/27/14)", Eileen Rillera, Nerdles: News for Nerds, June 27, 2014, reporting on the NBC news report which aired the same date (see External Links).
  19. ^ a b "Pierre Delaere, the thorax surgeon from KU Leuven, forwarded me this “No graft found, serious complications, need for a pneumectomy but still reported as a major success by Macchiarini and Birchall!! We tried to approach Dr Molins and Dr Gimferrer at several occasions since 2014 without success”… In fact, there never was a full trachea transplant, and even that lacks any lining epithelium and has collapsed despite continuously present stents, as the doctors reported: “In fact, this is not a real tracheal transplant, because only left main bronchus was replaced by a donor segmental tracheal homograft. This graft has remained open 5 years because of the insertion of multiple biodegradable stents”.""Macchiarini’s patients, the real situation", Leonid Schneider, May 7, 2016 (retrieved june 21, 2016).
  20. ^ a b c d e "Boy's windpipe replaced in pioneering stem cell operation", Sarah Boseley, The Guardian, March 19, 2010.
  21. ^ a b c d "Vatican honors boy for courage during trachea transplant", Estefania Aguirre, Catholic News Agency, April 12, 2013.
  22. ^ a b c d "Ciaran Finn-Lynch's windpipe transplant success", BBC News Northern Ireland, July 26, 2012.
  23. ^ "'Milestone moment' as boy undergoes transplant to regenerate trachea", BioCentre. Retrieved July 1, 2014.
  24. ^ "Windpipe transplant success in UK child", BBC News, March 19, 2010.
  25. ^ Macchiarini P (2011). "Bioartificial tracheobronchial transplantation. Interview with Paolo Macchiarini". REGENERATIVE MEDICINE. 6 (6 Supplement): 14–15. doi:10.2217/rme.11.81. PMID 21999257. 
  26. ^ "Using a Lab-Grown Trachea, Surgeons Conduct the World's First Synthetic Organ Transplant", Clay Dillow, Popular Science, 07, 07, 2011
  27. ^ "Experimenten - Experimenten - avsnitt 2: Varje kirurg har sin kyrkogård - SVT Play". SVT Play. 
  28. ^ "First U.S. Patient Gets Stem Cell Trachea Transplant", Lara Salahi, ABC News via World News, January 13, 2012.
  29. ^ "Synthetic Windpipe Is Used to Replace Cancerous One", Henry Fountain, The New York Times, January 12, 2012.
  30. ^ "Christopher Lyles, Got Synthetic Trachea, Dies at 30", Henry Fountain, The New York Times, March 7, 2012.
  31. ^ "Harvard Bioscience tracheal transplant patient dies", Julie M. Donnelly, Boston Business Journal, March 6, 2012, updated December 28, 2012.
  32. ^ "Hannah Warren | Help Hannah Breathe". Giveforward.com. Retrieved August 12, 2015. 
  33. ^ Pam Adams (May 1, 2013). "Toddler youngest in world to get lab-made windpipe in Peoria operation – News – Journal Star – Peoria, IL". Pjstar.com. Retrieved August 12, 2015. 
  34. ^ "Youngest Girl Given Bio-Engineered Windpipe Dies". nbcbayarea.com. Retrieved October 2, 2013. A nearly 3-year-old toddler who was the youngest person ever to receive a bio-engineered organ died Saturday in Illinois, surgeons involved in her treatment said. 
  35. ^ "Hannah Warren Dead: Toddler Who Received Windpipe Made From Stem Cells Dies", Karla K. Johnson, The Huffington Post, 07/08/13.
  36. ^ RICCARDO GUIDI: Prof. Macchiarini arrested in Italy – driven justice? September 28, 2012
  37. ^ a b [1]
  38. ^ "Artificial Windpipe Surgeon Committed Misconduct". nature.com. Retrieved February 1, 2016. 
  39. ^ Keisu, Claes (August 28, 2015). "Visiting Professor at Karolinska Institutet cleared from suspicions of scientific misconduct". Karolinska Institutet. Retrieved February 12, 2016. 
  40. ^ Paolo Macchiarini is not guilty of scientific misconduct Editorial 932 www.thelancet.com Vol 386 September 5, 2015.
  41. ^ Claesson-Welsh, Lena; Hansson, Göran K (2016). "Tracheobronchial transplantation: The Royal Swedish Academy of Sciences' concerns". The Lancet. doi:10.1016/S0140-6736(16)00520-1. 
  42. ^ Bäsén, Anna (January 13, 2016). "Tekniken skulle rädda liv – sex av åtta dog" [The technology should save lives - six of the eight died]. Expressen (in Swedish). Retrieved February 12, 2016. 
  43. ^ Hallbom, Johannes; Moberger, Karin (January 13, 2016). "Utredaren står fast – KI:s stjärnkirurg har forskningsfuskat" [The investigator stands firm - The KI's star surgeon accused of research fraud] (in Swedish). Sveriges Television. Retrieved February 12, 2016. 
  44. ^ Andersson, Carl V (February 1, 2016). "KI:s ledning granskas av oberoende utredning" [KI's management reviewed by independent investigation]. Dagens Medicin (in Swedish). Retrieved February 12, 2016. 
  45. ^ "Decision about Paolo Macchiarini's employment at Karolinska Institutet". 
  46. ^ Philip Oltermann (March 24, 2016). "'Superstar doctor' fired from Swedish institute over research 'lies'". The Guardian. Retrieved March 24, 2016. 
  47. ^ "Experimenten: Stjärnkirurgen" [The Experiments: The Star Surgeon]. Dokument inifrån (in Swedish). Sveriges Television. January 7, 2016. Retrieved January 28, 2016. 
  48. ^ Alpman, Marie (January 28, 2016). "KI-kirurgen utreds på nytt" [KI surgeon investigated again]. Ny Teknik (in Swedish). Retrieved January 28, 2016. 
  49. ^ "BBC Two - Trust Me, I'm a Doctor, Series 2, Episode 2 - Can organs be purpose-grown using stem cells?". BBC. 

External links[edit]