A Rahman A Jamal MD, MRCP, PhD, PJN, DPNS, ANS

Director
UKM Medical Molecular Biology Institute

Heart-rending stories:
Stem cells giving hope to patients

The promise of stem cells:

A cure for many diseases

Stem cell research:

Latest advances
Controlling
self-renewal &
differentiation

Programming
somatic cells
into stem cells

Making
embryos from
stem cells

Clinical
applications

1. Controlling stem cells:

A chemical switch for mass production
Hydrogel (rich in alginate)

Proliferation

Differentiation

Cells become collagen-rich

when the population becomes
big enough

Dixon et al, PNAS, 2014

Manipulating the microenvironment:

ECM with autologous proteins

The autologous ECM proteins were then used to culture and expand hESc cells
Khoo et al. (2013) Differentiation.85(3):110-8

Manipulating the microenvironment

to maintain pluripotency

SSEA-4

TRA-1-81

Oct4

Nuclei

Nuclei

SSEA-1

Merged

Merged

Human embryonic stem cells (hESc) grown on extracellular matrix (ECM)

retained its pluripotency after more than 1 year in culture
SSEA-3

Nuclei

Merged

Khoo et al. (2013) Differentiation.85(3):110-8

Breakthrough technique
to culture foregut stem cells
A culture system to isolate
foregut stem cells

Thyroid, upper airways, lungs, liver,

pancreas, stomach and biliary systems

Vast applications to culture cells for

regenerative medicine

Hannan et al, Stem Cell Reports, 2013

2. Reprogramming somatic cells

into stem cells

Improved efficiency of
re-programming cells
Yamanaka method

Rais et al. Nature 2013

Turning skin cells

into iPSCs
4 genes
Low efficiency (<1%
of the cultured cells)

100% efficiency
Removal of Mbd3
protein
Synchronised
conversion into stem
cells
Can produce large
numbers of stem
cells

3. Making embryos
from stem cells

Nodal

Embryonic stem cells

subjected to
growth factor signals

Zebrafish
embryo

BMP
Implications:
Therapeutic cloning

Thisse et al, Science, 2014

4. Clinical application:
Ischaemic Heart Disease
Ischaemic heart
disease
23 RCTs
1200 patients
Reduced deaths and

readmission
Quality of
evidence is low
because of low
numbers

Implications
Need larger clinical

trials
Need better
understanding of
the cells used
Need to study their
mechanism of
action

Beneficial but low quality evidence

Fisher et al, Cochrane Reviews 2014

The regulation of stem cells:

Ethical issues
Embryos

SC for unproven

indications
Mechanism of
action
Stem cell tourism
Ethics of
publications

Regulation of by the
Ministry of Health, Malaysia
National Committee for

Ethics in Stem Cell

Research and Therapy
(2009)
Health Technology
Assessment (HTA)
division
National Pharmaceutical
Control Bureau (NPCB)

Key points: Source of SCs

Allowed
Research on adult
stem cells &
embryonic SC
lines
Use of surplus
embryos

Prohibited
Creation of
embryos for
research
Xenotransplantation

Key points: Labs and facilities

Labs
Research lab
require GLP
Labs producing
cells for trials
must be GMP
compliant

SC Clinics
Regulated under
the Private
Healthcare
Facilities and
Services Act
(1998)

Key points: Indications for therapy

Developmental and
experimental therapies
Hsc for tissue repair, regeneration and
vascularisation
Use of MSCs for various indications
Use of neural stem cells, liver stem cells, etc.
Use of human ESCs

2. Stem cells for

unproven indications
Indications
Stroke
Alzheimers
Parkinson
Kidney failure
Cerebral palsy
Down syndrome
Many others

Challenges
Clinical trials are ongoing but many are
under-powered
Issues of cell dose, route
of administration, use of
controls, etc.

Cell therapy trials for stroke

author

details

outcome

Kondziolka et 12 patients with basal ganglia

al; 2000
infarct transplanted with
neuronal cells

Some improvements in the European

stroke scale but not significant

Kondziolka et RCT for stroke patients (7 per

al; 2005
group)

ESS had no improvement but some

secondary outcome measures such as
Stroke Impact Scale, showed
improvement

Bang et al;
2005

Autologous MSCs given IV 59 wks after onset; 5 patients;

No significant improvement

Yang et al;
2006

Intrathecal injection of ESC

derived NSC; 26 patients and
no control arm

No adverse effects. Improvement in

ESS in 23 patients.

Lee et al; 2010

Autologous MSCs given IV

after onset of ischaemic
stroke; 52 patients;

Safe and effective . But many questions

on the design and results

Keith Muir,
2013

Stem cells injected directly

into damaged brain tissues

Claims that 5 patients are showing

improvement

Japan: Regulation of stem cell

therapy is non-existent

Can we trust the treatment being

marketed and provided
Early trials show promise for some diseases
Unregulated stem cell therapies have arrived
No conclusive evidence on safety and

effectiveness
Generally safe BUT there are reported
complications and failures
Need for clinical trials (for stem cell therapies) be
registered and regulated

3. Mechanism of action:
Differentiation or paracrine?

Paracrine effects: An overused

word but does not explain MoA
THE CLAIM: MSCs act via their trophic, immune

modulating, anti-inflammatory effects

Vague statement
Putative mechanisms are so generic -

meaningless
These claimed mechanisms do not warrant
translation to the clinic at this time and stage
Any putative paracrine factor involved
should be identified and then further
developed

Mechanism of action: Definition

Specific biochemical interaction through
which a drug produces its pharmacological effect

Specific molecular targets to which the drug

binds, such as an enzyme or receptor
E.g. MoA of aspirin involves irreversible inhibition of

the enzyme cyclooxygenase, therefore suppressing the

production of prostaglandins and thromboxanes,
thereby reducing pain and inflammation

NSCs in an Alzheimers disease model:

Identifying key genes and proteins

Jamal et al, submitted 2014

4. Stem cell tourism

Clinics in China, Costa Rica,

Ukraine, Thailand, Mexico

and Russian and perhaps
Malaysia too!
Cell harvested, processed,
cultured from patients in
their countries and
transported
Cost: USD7500 for 100
millions cells (USD5000 for
each additional 100 millions
cells

Stem cells is
now the
magic word

Testimonies from
patients treated in China
Type 2 spinal muscular atrophy:
Patient now able to open his fist and stretch each finger

Optic nerve hypoplasia:

Improved vision

The truth of the matter:

Deaths can occur

Be cautious when assessing

claims of SC therapies
Claims based on
patients
testimonial

Claims that
there is no risk

Multiple
diseases treated
with same cells

No clear
documentation
of source of cells

High cost

Exact
mechanism of
action unknown

5. The ethics of publications and

good research practice

Paper in Nature 2014 describing conversion

of cells into embryonic stem cells by dipping
into acid bath was withdrawn

The disgraced scientist (Hwang):

Paper in Science withdrawn (2006)

Should it be driven
by science or profit?

Summary: Will stem cells change

the transplantation horizon?
The horizon has already beginning to change
More pre-clinical and clinical trials using MSCs and iPCS

data looks promising but more work needs to be done

More companies investing money in cell therapies
Key pre-requisites
Proven safety and efficacy high stringency
Accredited laboratories
Regulated

Funding for research and development

Reimbursement for therapy
Treatment must be based on solid science and trials

Thank you