Nephrology Grand Rounds Presentation at the University of Alberta discussing the big picture issues surrounding xenotransplantation and its relation to stem cell generated organs and bioengineered organs in the future

1. KIM SOLEZ, MD

2. Disclosures
Financial, none. Politically, a biggie:
As Chair of Banff Foundation for Allograft Pathology, I pushed Tissue
Engineering Pathology as the logical future of Transplant Pathology starting
in 2011, ignoring the possibility of Xenotransplantation Pathology. I knew
the joke that Xenotransplantation is “always right around the corner” and
assumed it was not actually happening for a long time.
Now it looks like I backed the wrong horse for eleven years with the recent
success of Xenotransplantation! But maybe not, when considered long term.

3. Plan of
Presentation
Plan of Presentation
Need for Something Beyond Allotransplantation
Pig Organs as Interim Step. New Banff Xenotransplant Classification Needed.
Stem Cell Generated Organs When Ready. Another Banff Classification!
Too Complex for Human Brain, Need AI Help. Have Research Team for That.
Xenotransplantation Part of Larger Plan for How AI Can Save Humanity
Effort Cannot be Science Alone, Needs Humanities, Part of University’s AI4Society
Signature Initiative
You Can Help! Every One of You!

4. Eleven Years Makes Big Difference! In 2017-19
Regenerative Medicine was in Ascendancy! Then
declined again.
Nearly everyone went sightseeing to avoid
regenerative medicine and xenotransplant
sessions at 2015 AST CEOT. About 5 people
attended with me. Sessions were great!
In 2017 CTRMS was a full partner with CST in
Halifax meeting. Tissue Engineering Pathology
added to Banff organ chair mandates at Banff
2017.
Pre-meeting for Banff 2019 in
Pittsburgh was devoted to
Regenerative Medicine/Tissue
Engineering Pathology. No
escape!

5. Stem Cell Technologies on Google Trends –
News Headlines and Forecast

6. Current
transplant
protocols
reach fewer
than 5-10%
of those in
need.

7. Current transplant protocols reach fewer
than 5-10% of those in need.

8. Worldwide 1.4 million people are
in need of transplantation for end
stage organ failure.
Current transplant protocols
reach fewer than 5-10% of this
number.
Regenerative medicine and/or
xenotransplantation can save the
remaining 90-95%, over one
million people annually!

9. Regenerative Medicine Already Here! Working for
Tubular Organs, Bladder, Trachea, Esophagus, Vagina.
o Tissue engineered
bladder.

10. Double Think:
Stem Cells are Greatest Hope
and Greatest Hype, Stem Cell
Tourism Estimated to be $3
Billion a Year Industry and
Growing, with More than 700
Clinics Worldwide
o Mason C et al. Regen Med. 2011 May;6(3):265-72. doi:
10.2217/rme.11.28. Cell therapy industry: billion
dollar global business with unlimited potential.
o Timothy Caulfield - Stem Cell Tourism June 2015
o https://www.youtube.com/watch?v=B0r89nMtg10

11. The Positive Aspects of Stem Cell Therapies and
Xenotransplantation, The True Hope, Has Potential
to Reverse Three Looming Problems in Medicine:
1. The loss of “luster” in transplantation.
2. Workforce problems in nephrology
due to lack of appeal to young
people/potential trainees worldwide.
3. Technological unemployment in
medicine due to replacement of human
workers by machines.

12. “They will never be able to reverse those trends.” Together we can
do those things, reverse those trends, make life good again!
1. The loss of “luster” in
transplantation.
2. Workforce problems in nephrology
due to lack of appeal to young
people/potential trainees worldwide.
3. Technological unemployment in
medicine due to replacement of
human workers by machines.

13. Nephrologists & Renal Pathologists May Be Only
People Still Employed in 2045!

14. Banff Classification of
Kidney Transplant
Pathology
Histologic criteria for the
diagnosis of rejection and
other conditions in the
transplanted kidney,
began 1991, updated and
expanded every two
years in consensus
meetings.

15. Banff Lesion Scoring :
Imprimatur of An Educated
Tx Pathologist
imprimatur 1. The formula (=‘let it be
printed’), signed by an official
authorizing printing of a book; hence
as sb. an official license to print.
The Oxford English Dictionary (2nd. ed.)
Banff lesion scoring: g cg i ci t ct v cv
ah mm ptc C4d

16. o 1991 First Conference
o 1993 First Kidney International publication
o 1995 Integration with CADI
o 1997 Integration with CCTT classification
o 1999 Second KI paper. Clinical practice
guidelines. Implantation biopsies.
o 2001 Classification of antibody-mediated rejection:
Regulatory agencies participating
o 2003 Genomics focus, ptc cell accumulation
scoring
o 2005 Gene chip analysis. Elimination of CAN,
identification of chronic antibody-mediated
rejection.
o 2007 First meeting far from a town called “Banff” –
La Coruna, Spain.
o 2009 Working groups. Meeting in Banff, Alberta,
Canada
o 2013 Establishment of Banff Foundation for
Allograft Pathology

17. Significance of ‘Banff papers’
o More than 5,000 citations
of the 14 Banff meeting
reports
o 977 Banff /
Transplantation papers in
PubMed
o Banff 2003 meeting
report (ABMR criteria) =
most cited AJT paper
o 3 Banff meeting reports
are among the top 4 cited
AJT articles

18. Odd Spike in 2005

19. New Analysis of Google Scholar Citations per
Year Shows Steady Growth Without Outliers

20. Best network analysis
comes from analyzing
top 250 authors

21. The Banff Process
Consensus communication in renal transplantation
a
The Banff
lesions
g, i, t, v - score
The Banff
community
Pathologists
Nephrologists
Tx-Surgeons
Lab-Medicine
established by
consensus in 1991
The Banff
classification
Current consensus for
diagnostics
moderated
Banff meetings
thesis-antithesis-synthesis
tentative
thresholds
participate
refinement
Banff Working
Groups
Feedback concerning weaknesses and strengths by results
from independent research
New members
Biostaticians
Molecular Biologists
“Omics”-specialists
Off-springs
Liver
Pancreas
Lung, Heart
CTA

23. The Next Banff Meeting will be Sept. 19-
23, 2022. Sept 17-18 “Poetry, Pigs, & AI
Will Save Humanity By and By.”

24. Sept. 17-18 Gathering Features Shima
Aisha Robinson, Edmonton Poetry Festival
Director&Alice Sanctuary Pigs

25. Sept. 17-18 Gathering Features Shima
Aisha Robinson, Edmonton Poetry Festival
Director&Alice Sanctuary Pigs

26. The Technological Singularity

27. Podocytes go wandering into the interstitium! Song et
al. 2013

28. o Song et al. Interstitium,
vessels, and glomeruli
with missing cells.
Disordered tubule
formation with multiple
interconnecting
lumina of differing sizes.
“Can you really call this a
kidney?” (Yes!)

29. o Song et al. (2013) In
addition to missing
cells and disordered
structures, you have
cells in the wrong
places. Podocytes in
the interstitium. Nine
years later we still do
not have a solution to
this.

30.  Seize the Day! Use the
disquiet that using pig organs
brings to energize finding
solutions to the remaining
challenges of stem cell
generated organs, getting
right cells in right places.

31.  Res Ipsa
Loquitur, the
thing speaks for
itself. No one
wants to be
using pig organs
for any longer
than we have to.
They are just an
interim bridge
technology
while we wait for
stem cell
generated
organs to be
perfected.

32. There is no slippery slope. Right now, 124,061,094
pigs a year are consumed in US, enough for 1 pig for every three humans.
Transplanting pig organs is a better use of pigs, will probably increase
respect for pigs and decrease number consumed for food. Everyone
benefits, even the pigs. Still, it does not seem a satisfactory long-term
solution, so best to regard it as an interim measure.

33. How Many Pig Lifetimes Will It Take Before
Stem Cell Generated Organs Are Perfected?

34. Is it just a matter of throwing money at the
problem? Global warming is a problem like that.
We know how to solve global warming with a
planetary sunshade. It is just a matter of spending
the resources.

35. This is the new James Webb Telescope deployed
at Sun-Earth LaGrange Point 2. Deploying a
planetary sunshade at Lagrange Point 1 would
solve global warming, if we spent the money to do
that. Stem cell generated organs are not as easy as
that. We also need conceptual breakthroughs.

36. Many problems with stem cell generate
organs not being discussed. Do not exclude
yourself from the action in this area!

37. Many
problems with
stem cell
generate
organs not
being
discussed.
Need to get
those
conversations
to happen.
o The recellularized organ clots like crazy,
impossible to regenerate more than 80% of
endothelial surface. Artificial heparized
surface not fenestrated. Cell traffic abnormal.
o Hard to get right types of cells to right places.
o Podocytes seems to be terminally
differentiated cells, when attempt to culture
them they turn into different type of cell.
o Kidney progenitor stem cell difficult to
identify, kidney work has lagged behind.
o Easy to make stem cell generated kidneys that
lack loops of Henle. Could produce lethal
polyuria. What is “function”?
o Many old-fashioned questions of physiology
about how the stem cell generated organ
works, not just true for kidney, true for every
organ.

38. o Transplant pathologists will also
become tissue engineering
pathologists, pathologists who
analyse organs grown from stem
cells. This is not something beyond
us, we can adapt to a work life that
includes stem cells. Someone
needs to cross the disciplines. But
before then we will become
Xenotransplant Pathologists. Alex
Loupy, who will lead Banff
classification of Xenotransplants,
has suggested a Precision
Medicine approach.

40. o Many of the questions that
need to be posed about
stem cell generated organs
are old fashioned questions,
intact nephron hypothesis,
cell regeneration, stunned
myocardium, contraction
band necrosis etc.
Use your nostalgia!
Stimulate conversations
between stem cell
researchers and transplant
physicians.
o Meanwhile immerse
yourself in the ethics of
Xenotransplants.
o Help us think this through.

41. AI Can Assist
Because the
Number of
Possible
Approaches to
Xenotransplant
and Stem Cell
Generated
Organs
Exceeds
Human
Cognitive
Capacity
It is like protein folding which AI solved in
Fall 2020 but the human brain cannot
understand.

42. AI Can Assist
Because the
Number of
Possible
Approaches to
Xenotransplant
and Stem Cell
Generated
Organs
Exceeds
Human
Cognitive
Capacity
We have proposed that AI approaches be
employed to assist with the big thirteen
challenges of humanity. Here are the first 6.

43. AI Can Assist
Because the
Number of
Possible
Approaches to
Xenotransplant
and Stem Cell
Generated
Organs
Exceeds
Human
Cognitive
Capacity
We have proposed that AI approaches be
employed to assist with the big thirteen
challenges of humanity. Here are the second
6.

44. AI Can Assist
Because the
Number of
Possible
Approaches to
Xenotransplant
and Stem Cell
Generated
Organs
Exceeds
Human
Cognitive
Capacity
We have proposed Xenotransplantation and
and Stem Cell Generated Organs as the 13th
big challenge of humanity that AI can assist
with. We look forward to your thoughts on
that! We have assembled an awesome
research team of faculty and students from
around the world for the task!