Seminar at Research integrity event on research integrity, organised by Patricia Murray at University of LIverpool.
Story of deadly regenerative medicine and trachea transplants of Paolo Macchiarini and Martin Birchall
Liverpool, 1.06.2018
2. The trachea transplant scandal of Paolo Macchiarini
• Paolo Macchiarini,
thorax surgeon, stem cell
pioneer, former clinic
head at Careggi and
Karolinska professor
• Transplanted patients
with cadaveric and plastic
tracheas seeded with
bone marrow cells
• Almost all trachea
recipients dead
Photo credit: Staffan Larsson
3. How did it get that bad?
- Was it Macchiarini’s crooked character?
- Or is the system to blame?
4. Both!
- Macchiarini took advantage of hype and greed in biomedical research
- He changed institutions when things got too hot, charmed new university with
fresh promises of fame and money
- Scandal was only uncovered because of Swedish journalists
- Every single university and hospital (including Karolinska!) is still covering up
the Macchiarini affair
5. Macchiarini scandal had it all
- Stem cell /regenerative medicine hype
- Top journal seal of scientific veracity: The Lancet
- Huge funding, political support (especially with Governor of Tuscany)
- Extremely simplistic, evidence-unsupported science and wishful thinking
- Gross misrepresentation of results, clinical outcomes, data manipulation
- Ethics breach at every step
- Institutional threatening of whistleblowers
- Suppression of investigations
- Legal attacks on journalism (myself)
Source: Corriere Fiorentino
7. Figure: courtesy of Pierre Delaere
Everyone wants to transplant a trachea
• Trachea is a living tissue: cartilage rings
on the outside, ciliated epithelium on the
inside, which prevent infection and
clogging
• As a living tissue, it is vascularised and
dependent on blood supply
• Patients with cancer, congenital defects
or accident victims would profit from
trachea transplant
• Tracheas cannot be transplanted due to
technical difficulties to connect the blood
vessels
• Without proper blood supply, any
transplanted tissue will die
8. Regenerative medicine as solution
1. Grow a trachea from patient’s own
stem cells on a dead scaffold,
declare it alive
2. Transplant it into the patient and
stimulate instant vascularisation by
magic
3. Collect funding, awards, fame,
promotions etc
4. Silence the critics and omit the
deaths and suffering of your
patients
5. Go back to 3)
9. Growing trachea tissue from stem cells
• You need a source of patient’s own
stem cells to grow specific
differentiated tissues
• induced pluripotency (iPS) is still
not safe from cancer threat and
was discovered only recently
anyway
• Or, you can ascribe stem cell
qualities or even pluripotency to
whatever cells you happen to be
working with
10. Image posted at
StampComminity.org by
KuoLC5310
Photo by Dan MarshallSource: Alchetron
Ground-breaking paradigm-changing discovery by
Catherine Verfaillie
Bone marrow cells are pluripotent!!!???
Nature 418, 41-49 (4 July 2002)
Nobel Prize almost sure for the head of
KU Leuven Stem Cell Institute…
11. • A mega-correction of Nature 2002
paper and retraction of a related
Blood 2001 paper
• Bone marrow cells then proven to
be NOT pluripotent
• In fact, unclear what non-
hematopoietic bone marrow cells
exactly are or do.
Zombie paper of a zombie scientist
12. Making trachea cartilage from bone marrow cells
Source: University of Liverpool
Source: Azellon, Hollander’s own company
13. The trachea transplanters team of 2008
Paolo Macchiarini
the miracle surgeon, with his Barcelona patient Claudia Castillo
Philipp Jungebluth
Macchiarini’s student and right-hand man
Imagecredit:SVT
Martin Birchall
made the trachea in his veterinary lab in Bristol w/o permit from authorities
Image credit: Wellcome Trust
14. Claudia Castillo’s trachea in its bioreactor.
Source: University of Bristol
The principle of trachea regeneration
Figure: courtesy of Pierre Delaere
Martin Birchall (right), holding a UCL-made plastic trachea.
Source: UCL
Figure: courtesy of Pierre Delaere
15. Science of magic
• Why would bone marrow cells build functional cartilage rings around
dead decellurised trachea? Because magic!
• Why would these “cartilage” and transplanted epithelial cells survive
without blood supply? Because magic (or erythropoietin) lets invisible
blood vessels grow out of nowhere!
• How can plastic become a living tissue and not destroy surrounding
organs instead? Because it’s a magical nanotechnology plastic!
16. Practical considerations
• Bioreactor needs special tricky approvals and a GMP lab
• Macchiarini decided to drop bioreactor, likely because of the Bristol
scare with Birchall’s pig-research lab and misinformed authorities.
Next patients received stem cell and erythropoietin magic straight
into their new grafts
• Cadaveric tracheas need donors, take very long to decellurise and require
GMP labs
• Macchiarini decided to switch to plastic. Officially because the “dying”
patients could not wait
Macchiarini with his first plastic trachea recipient Andemariam
Beyene (who was declared an emergency, though his cancer was
manageable and absolutely not immediately life-threatening)
Image source: SVT
17. Outcome of trachea transplants
• Of 9 Macchiarini’s patients who received a plastic trachea, 8 died. One
survived because the transplant could be removed.
• At least 12 patients received a cadaveric trachea from Macchiarini
and/or Birchall. 2-3 still alive are far from cured, in fact they are likely
alive not thanks, but despite the transplants.
• Almost all patients operated as hospital exemptions/compassionate use
Martin Birchall with his trachea transplant patient Ciaran Lynch. The boy, who lived with a homograft for 10 years,
was likely saved by the modern stent technology, and not by Macchiarini’s stem cell magic. Birchall initially planned
to use a synthetic scaffold, failing that, Macchiarini brought a cadaveric from Italy. Image source: UCL
Claudia Castillo didn’t at all do as great as Macchiarini and Jungebluth portrayed her.
Troubles started right after the operation
18. The Compassionate Use trick of testing technology
• Large animal experiments require
ethics approvals, scientific rationale,
and are very costly
• Need proper controls (untreated or
standard therapies), survival rates
and side effects must be reported to
the peer community
• You cannot report only one barely
surviving pig as success and hide a
dozen dead ones
• Media is barely interested in
successful animal experiments
• Your animal experiments can be
easily disproven by others trying to
reproduce them
Pig vs Patient
• Ethics and regulatory approvals can be
skipped under hospital exemption /
compassionate use, when life of patient is
allegedly in grave danger
• No controls needed. No comparisons
with existing therapies.
• Dead or mutilated patients don’t have to
be ever reported. They cease to have
existed
• Only alleged successes (=survivors) are
announced to peer community and
media
• No one can challenge your claims, only
you have access to patient and medical
history
19. Put your regmed graft where no one can see it
• A patient without a leg cannot be cured, but is not dying.
• But what if a surgeon claims to have grown an artificial leg from stem cells?
Source: New Scientist
Harald Ott made many internal organs, by showing bone marrow cells a
decellurised carcass as a visual cue, and tested those organs in animals . But never
that leg he made. Why? Photo credit: Massachusetts general hospital
20. How to create a hospital exemption
• A patient without a leg or a thumb is suffering and incurable, but is this really a medical emergency?
• Can approvals or animal tests be skipped to “help” such patient with novel regmed technology?
• Same for patients with tracheostomy or slow growing throat cancers:
they are in stable, manageable condition. Do they really need an untested, science-free trachea?
Figure: courtesy of Pierre Delaere
21. Publish quickly before patients die or deteriorate
• A compassionate use transplant must be declared success before it backfires
• Your follow-up reports might become unpresentable or in need of heavy beautification (or lying)
It helps to have an understanding editor. Lancet EiC never
bothers about false data or fake ethics approvals in
regmed papers. Image credit: International Labour Organization on Flickr
22. Blame the patient for the failure
• Cadaveric tracheas always caused death when
transplanted into cancer or very weak patients (plastic
trachea was lethal to all).
• Macchiarini blamed patients for being too weak for his
technology to succeed and sought to recruit “healthy”
young patients, e.g. victims of accidents
Macchiarini’s patient Yulia Tuulik (victim of traffic accident) being talked into
agreeing to a plastic trachea by Harvard Bioscience CEO David Green (right).
Image source: SVT
Macchiarini transplanted Yesim Cetir (victim of a
botched surgery) with a plastic trachea. Multiple organ
transplants could not save her life in the end.
Image source: Hayrulla Cetir
23. Pathological liar?
• Macchiarini insists all his patients were in fact very, very sick and that he in fact extended their
lives. And everything is a big conspiracy of jealous ex-colleagues against his success.
• 8 of 9 plastic trachea patients dead, circumstances of several utterly unknown. Macchiarini
operated at least 10 patients with cadaveric trachea, we only know of them only because he
(mostly) admitted to those; only 2-3 survivors are known.
Macchiarini with colleague Parshin and patient Zhadyra Iglikova (victim of traffic
accident, who received a cadaveric trachea). Image source: journal NakedScience
24. Control the facts to control the future
Birchall (and his surgeon partner Martin Elliott) say:
• everything was Macchiarini’s fault. Suddenly, they both were always against the use of plastic tracheas
• Macchiarini’s science of cadaveric trachea regeneration is otherwise solid, as sufficiently evidenced by
the fact that Ciaran Lynch is alive. Their other patients had lives saved or at least extended and
improved. Clinical trials desperately needed to help others.
Keziah Shorten received a cadaveric
trachea from Macchiarini (and UCL
doctors), then a plastic trachea from
Birchall. Image source: Kent Live
The forgotten patient Shauna Davison. She
received a cadaveric trachea from Birchall.
Image source: Gazette Live
The Ciaran Lynch trachea transplanters team, from left: Birchall, Mark
Lowdell (maker of the graft), Macchiarini, Elliott. Image source: Daily Mail
According to this publication, Keziah Shorten
and Shauna Davison had good quality of life
and lived longer than expected, thanks to
cadaveric trachea transplants.
25. A scapegoating non-investigation at UCL
In 2017, UCL engaged an external commission to investigate their trachea
transplants. The investigation proved to be a whitewashing exercise to protect
English trachea transplanting doctors and finger Alexander Seifalian, a Persian
physicist as culprit for patient abuse, who was previously sacked on corruption
allegations.
Seifalian (right), with his and Birchall’s PhD student Claire Crawley in 2011.
Photo: UCL
26. A scapegoating non-investigation at UCL
• Birchall and other trachea transplanters (Elliott, De
Coppi) were carefully protected from any negative
associations
• Investigators chose not to publish certain information
on patient abuse available to them, because it would
have damaged Birchall. Especially his plans to use a
synthetic trachea on Ciaran.
• Seifalian alone was found guilty of manufacturing
plastic tracheas and vascular grafts for export in a non-
GMP certified lab. That despite UCLH having used a
POSS-PCU nose in own patient!
• Seifalian was denied a right to appeal before the report
was released
• Investigators called for more human patients to be
treated with cadaveric trachea
27. Your money is already in!
Birchall was preparing three public-funded clinical trials with cadaveric tracheas and larynxes:
• INSPIRE (funded by Innovate UK with £1.9 Million) on 4 young cancer-free stenosis patients. Patients
not to be told of past trachea transplant outcomes, method presented to them as utterly novel.
• TETRA (funded by EU with €6.8 Million) on young cancer-free stenosis patients
• RegenVox (with Hollander/U of Liverpool), funded by MRC with £2.8 Million to use cadaveric larynxes
regenerated with bone marrow cells on 10 patients
How Videregen imagines trachea replacement. What happens to
patients afterwards is apparently irrelevant. Image source: Videregen
Both trachea transplant trials are managed by Liverpool-based company Videregen. Birchall
is their paid advisor. Image source: TETRA Consortium
Steve Bloor,
Videregen CEO.
Image source: Catapult Cell Therapy
28. A huge money grave, but patients (almost) safe
All three of Birchall’s clinical trials derailed, without any patient being harmed:
• INSPIRE: suspended before recruiting without much hope of restart
• TETRA: cannot go anywhere without results from Inspire
• RegenVox: suspended before recruiting without much hope of restart
Meanwhile, Videregen seeks new partners in Asia and US!
UCL & GOSH however transplanted a child with cadaveric trachea in May 2017, under
compassionate use. Her current status is unknown
29. Opposition from Liverpool
Patricia Murray and Raphael Levy wrote in November 2017
to Parliament's Science and Technology Committee, calling
for
• proper investigation of UK-made trachea transplants by
Birchall et al
• halt of all clinical trials and compassionate use trachea
transplants
• need for solid preclinical evidence before human
experimenting
• reform of UK research integrity oversight.
UCL and other parties involved
(not Videregen though) replied
and clinical trials were officially
listed as suspended
30. Academic and journalistic responsibility?
Spain: no investigation so far, nobody knows how many deadly trachea transplants and
where exactly they took place
Italy: no investigation at Careggi in Italy,
Macchiarini enjoys political protection, but
some very critical reporting by Corriere Fiorentino
Sweden: The only country where media did a good job of
exposing the scandal, which also led to personnel
consequences at KI. Prosecutors relied on
evidence of other misconduct-tainted trachea
transplanters to drop manslaughter
charges against Macchiarini
Russia: Krasnodar hospital announced to use cadaveric
decell trachea technology without any mention of Macchiarini
Germany: Macchiarini remains adjunct professor at MHH.
Almost all German reporting about him and
Jungebluth is positive and hails past successes.
I lost two ruinous court cases on the grounds of
judges trusting the medical irreproachability of
Jungebluth and Macchiarini, while declaring
mine and even Swedish media reporting as libel.
32. Suchitra Sumitran-Holgersson
• Caught manipulating data at Karolinska
Institute, acquitted for bizarre formality
issues
• At University of Gothenburg, teamed up
with surgeon Michael Olausson for
regmed vein transplants
• Transplanted an elderly patient with
cadaveric stem-cell-magic treated
trachea, patient died
• Briefly collaborated with Macchiarini
regarding Yesim Cetir transplant
• Found guilty of research misconduct and
unethical human experimenting by two
investigations in Sweden
• Her company Verigraft got €2.2 mn EU
funding based on misconduct-tainted
human research
Olauson and Sumitran-Holgersson, showing veins made by stem cell magic. Never bothered
obtaining ethics permits. Image source: University of Gotenburg
33. Charles Vacanti
Harvard Anesthesiologist,
famous (or notorious) for :
• The ear-mouse
• STAP hoax (stimulus-triggered acquisition
of pluripotency)
Less known:
• Attempt to transplant a plastic trachea into
a juvenile patient in 2010. Stopped short
by the surgeon in charge
Source:BWHBulletin,May2010
Vacanti (right) with lab member Ken Kojima. These man developed both STAP
and plastic trachea. Image source: Boston Globe
Vacanti-mouse. Image source: Wikipedia
34. Heike and Thorsten Walles
• Thorsten Walles was former trainee of
Macchiarini
• Walles perfromed 3 tracheal transplants with
“regenerated” decell pig-intestine: in 2003,
2007, 2009
• First published in 3 papers with Macchiarini as
corresponding author
• No ethics votes
• No preclinical animal testing
• No preclinical endotoxin testing
• No proper informed consent
• Evidence of data manipulation in Walles
papers
• Ongoing investigation by University Würzburg
Thorsten and Heike Walles (formerly Mertsching) Image source: University of Würzburg
36. Emmanuel Martinod
• Frozen non-donor-matched aorta turned
into living trachea
• Almost all patients survived
• Stents were removed
• Miracle at last?