Bridge between Transplantation and

Regenerative Medicine Kim Solez, MD

I first spoke about the inevitable transition from transplant pathology to tissue engineering pathology at Banff 2011 in Paris, and Banff 2013 in Brazil, and then at length at the New Orleans Pathology 2015 meeting in July 2015.

A paper in press in Critical Care Medicine references those previous presentations and notes that many different modalities of examination may be used to detect tissue engineering pathology in the future including detection of soluble biomarkers. Solez K; Multibiomarker Article Gives a Taste of What the Era of Regenerative Medicine/Tissue

Engineering Pathology Will Be Like, Crit Care Med. (in press)

This presentation is the first definitive platform presentation before a transplantation audience.

1. Technology and Future of Medicine Course LABMP 590

Starts Sept 1st Tuesday and Thursdays 2-3:20 CCIS L1-140 Special 6 pm sessions in eHub, Hub Mall 9007 on Sept 3rd, 8th, and 10th http://www.singularitycourse.com

Stem Cell Technologies on Google Trends – News Headlines and Forecast

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

Worldwide 1.2 million people are in need of transplantation for end stage organ failure. Current transplant protocols reach fewer than 10% of this number. Regenerative medicine can save the remaining 90%, over one million people annuallly!

ViaCyte Announces Highly Anticipated Encapsulation Clinical

Trial Site Expansion into Canada JDRF-funded researcher, Dr. James Shapiro

will be the lead investigator at the Canadian site. TORONTO, July 29, 2015 -- ViaCyte, Inc. announced the opening of a second site in its Phase 1/2 trial for Type I Diabetes which utilizes PEC-01™ pancreatic progenitor cells and the proprietary Encaptra® drug delivery system which is designed to protect the transplanted cells from a patient’s immune system.

Regenerative Medicine Already Here! Viacyte Trial for Diabetes Therapy.

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

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.

Timothy Caulfield - Stem Cell Tourism June 2015https://www.youtube.com/watch?v=B0r89nMtg10

University of Alberta Health Law Institutehttp://www.hli.ualberta.ca/en/Publications.aspx Stem cell Publications

Stem cell hype: Media portrayal of therapy translationMARCH 30, 2015 Policy Options: Athletes and unproven stem cell therapiesJANUARY 01, 2015

Research ethics and stem cells Is it time to re‐think current approaches to oversight?DECEMBER 04, 2014

University of Alberta Health Law Institutehttp://www.hli.ualberta.ca/en/Publications.aspx Stem cell publications continued

Representations of Stem Cell Clinics on TwitterDECEMBER 01, 2014 Unproven stem cell-based interventions & physicians' professional obligations; a qualitative study with medical regulatory authorities in Canada.OCTOBER 14, 2014 Professional Regulation: A Potentially Valuable Tool in Responding to "Stem Cell Tourism"SEPTEMBER 09, 2014

University of Alberta Health Law Institutehttp://www.hli.ualberta.ca/en/Publications.aspx Stem cell publications continued

Stem Cell Tourism and Public Education: The Missing ElementsSEPTEMBER 04, 2014 Policy recommendations for addressing privacy challenges associated with cell-based research and interventionsFEBRUARY 03, 2014 Commercialization and Stem Cell Research: A Review of Emerging IssuesDECEMBER 20, 2013A Role for Patient Advocacy Groups in Countering the Premature Commercialization of Stem Cell InterventionsOCTOBER 01, 2013

The Positive Aspects of Stem Cell Therapies,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.

“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.

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

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 meeting.

1991 First Conference 1993 First Kidney International publication 1995 Integration with CADI 1997 Integration with CCTT classification 1999 Second KI paper. Clinical practice guidelines. Implantation biopsies. 2001 Classification of antibody-mediated rejection: Regulatory agencies

participating 2003 Genomics focus, ptc cell accumulation scoring 2005 Gene chip analysis. Elimination of CAN, identification of chronic

antibody-mediated rejection. 2007 First meeting far from a town called “Banff” – La Coruna, Spain. 2009 Working groups. Meeting in Banff, Alberta, Canada 2013 Establishment of Banff Foundation for Allograft Pathology

BANFF Classification - Milestones

Significance of ‘Banff papers’• More than 5,000 citations of the 14 Banff meeting reports• 915 Banff / Transplantation papers in PubMed• Banff 2003 meeting report (ABMR criteria) = most cited AJT

paper• 3 Banff meeting reports are among the top 4 cited AJT articles

Tissue Engineering Pathology Added Soon!•

The Banff ProcessConsensus communication in renal transplantation

a

The Banff lesions

g, i, t, v - score

The Banff communityPathologistsNephrologistsTx-SurgeonsLab-Medicine

established by

consensus in 1991

The Banff classificationCurrent consensus for diagnostics

moderatedBanff meetings

thesis-antithesis-synthesis

tentative

thresholds

participate

refinementBanff Working Groups

Feedback concerning weaknesses and strengths by results from independent research

New membersBiostaticiansMolecular Biologists“Omics”-specialists

Off-springsLiverPancreasLung, HeartCTA

Organizational structure of the Banff Foundation For Allograft Pathology

Board of Trustees: K. Solez (Chair), L. Racusen, D. Glotz, J. Demetris, M. Mengel, M. Mihatsch, D. Seron

2015 Local Conference chair: Michael Mengel

Organ Steering committee Chairs: Composite tissues: Linda CendalesHeart : Patrick BrunevalKidney: Mark HaasLiver: Jake DemetrisLung: William Wallace and Carol FarverPancreas: Cinthia Drachenberg

Banff Working Group (BWG) Leads: Molecular transplantation pathology: Michael Mengel, Banu SisIsolated v-lesions: Banu Sis, Ed KrausQuality assurance in transplantation diagnostics: Michael Mengel and Parmjeet RandhawaC4d-negative ABMR: Mark Haas, Banu Sis, Alexandre LoupyFibrosis scoring: Robert Colvin, Brad Farris, Michael MengelDigital Pathology in Transplantation: Jake Demetris

2015 Scientific program committee: Alex Loupy (Chair)Mark Haas, Banu Sis, Kathryn Tinkham, Candice Rofousse, Chris Bellamy, Lynn Cornell, Carmen LeFaucheurComposite tissues: Linda CendalesHeart : Patrick BrunevalLiver: Jake DemetrisLung: William Wallace and Carol FarverPancreas/Islets: Cinthia Drachenberg and John Papadimitriou

Secretary/Treasurer: Michael Mengel

funding

collaboration

reports to

reports to

collaboration

collaboration

reports to

collaborationprogress reports to Budged

proposal and accountability for meeting costs

support

BANFF Conferences On Allograft Pathology 1991-Forever?

The World is Changing Rapidly!

The World is Changing Rapidly!

The World is Changing Rapidly!

The World is Changing Rapidly!

Perfused 7 days without oxygen or nutrients! Of course no nuclei seen!

Canadian Data on Public Interest in Regenerative Medicine

The Technological Singularity

Podocytes go wandering into the interstitium! Song et al.

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

Many problems with stem cell generate organs not being discussed. Need to get those conversations to happen.

The recellularized organ clots like crazy, impossible to regenerate more than 80% of endothelial surface. Artificial heparinized surface not fenestrated. Cell traffic abnormal.

Hard to get right types of cells to right places. Podocytes seems to be terminally differentiated cells,

when attempt to culture them they turn into different type of cell.

Kidney progenitor stem cell difficult to identify, kidney work has lagged behind.

Easy to make stem cell generated kidneys that lack loop of Henle. Could produce lethal polyuria. What is “function”?

Many old fashioned questions of physiology about how the stem cell generated organ works, not just true for kidney, true for every organ. Logo still works for future!

Banff Foundation for Allograft Pathology and Banff Meetings Must Adapt to Future Changes in Field of Transplantation

Transplant pathologists will also become tissue engineering pathologists, pathologists who analyze 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.

It is OK to Allow the Natural Resistance to Change and Nostalgia for the Past to Motivate You!

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.

Beginning at the Very Beginning! “We are at the very beginning of time for the

human race. It is not unreasonable that we grapple with problems. But there are tens of thousands of years in the future. Our responsibility is to do what we can, learn what we can, improve the solutions, and pass them on.” - Richard P. Feynman, (1918-1988) Physicist, Nobel Prize Winner

"The sense of the future is behind all good policies. Unless we have it, we can give nothing either wise or decent to the world." - Snow CP, (1905-1980) Novelist and Philosopher.

"To a large extent, the future lies before us like a vast wilderness of unexplored reality. The God who created and sustained the evolving universe through eons of progress and development has not placed our generation at the tag end of the creative process. God has placed us at a new beginning. We are here for the future." - Sir John Templeton (1912-2008 ), Financial Analyst

Beginning at the Very Beginning!

Like 1851 when the first International Classification of Diseases was presented in the Grand Exhibition of Technology at London’s Crystal Palace

Emphasis was on cause of death

Classification focus is on sustaining life. Native and transplanted organ diseases can also

occur in tissue engineered organs. The classification focus of the new pathology

discipline of Regenerative Medicine/Tissue Engineering Pathology is exactly the opposite of traditional classification of disease which starts with causes of death. In Regenerative Medicine/Tissue Engineering Pathology the emphasis is on the degree of normality necessary to sustain life: 

Normal,  Abnormalities of unknown functional significance,  Abnormalities which will impair the main functions

of the organ,  Abnormalities leading to severe organ dysfunction

where function may not be great enough to sustain life. 

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!)

Song et al. In addition to missing cells and disordered structures,you have cells in the wrong places. Podocytes in the interstitium.

Focus of Tissue Engineering Pathology The specific questions become: 1. Are too many

cells missing, 2. Are too many cells in in the wrong places? 3. Are too many structures missing (long loops of Henle)? 4. Is there too much endothelial disruption for the organ to be properly perfused? 5. What are the risks of neoplastic transformation?

Classification categories should be not one-off, but reproducible, generalizable.

Tissue engineering pathology has been up to now really dull (articles since 1967), since most reports were of scaffolds with no inflammatory reaction "Move along, nothing to see here" pathology, but from today becomes really exciting with novel morphological changes and lives hanging in the balance, clinical trials starting!

Banff Classification of Tissue Engineering Pathology major focus 2017 meeting in Spain and 2019 in Turkey.

In our original location we had mule deer poking their heads into the meeting rooms! We’ve come a

long way! Please help us transition to the future!

We are grateful to the Roche Organ Transplantation Research

Foundation for funding the establishment of the Banff

Foundation for Allograft Pathology2013-2016

Dr. Doris Taylor was unable to attend this meeting due to illness. I will be presenting her talk, but you may also enjoy these recent

videos of hers:https://www.youtube.com/watch?v=C4EQybkb6Qk (33 min.)

https://www.youtube.com/watch?v=prl9XjgtfM0 (2.5 min)

https://www.youtube.com/watch?v=wuuxIKCCMA0 (10 minutes)