Interdisciplinary Approach
to Endocrinology
‫پنجمین كنگره بین املللي پزشكي‬
‫ سلولي و باليني‬،‫تازه ترين دستاوردهاي پژوهش دردانش پزشكي ازپزشكي ملكولي‬
Bagher Larijani, M.D., F.A.C.E.
Professor of Endocrinology
Director-General, Chief Scientific Officer
Endocrinology and Metabolism Research Institute
Tehran University of Medical Sciences
2
Interdisciplinary Research
Interdisciplinary
Research
Basic
Sciences
Clinical
Medicine
Interdisciplinary research plays a key role in forging a
link between basic medical sciences and clinical
medicine
3
Interdisciplinary Research
Promotion of
Interdisciplinary
Research is priority in
different international
strategic plans
4
Future of Endocrinology:
Interdisciplinary Research
• Many scientists and physicians believe that the future of
medicine lies in interdisciplinary research.
• Attempts has been made to promote interdisciplinary
research in most prestigious medical schools including
Boston University of Medical Sciences
1-Coleman DL, Spira A, Ravid K. Promoting Interdisciplinary Research in Departments of
Medicine: Results from Two Models at Boston University School of Medicine. Trans Am
Clin Climatol Assoc. 2013; 124: 275–282.
5
Interdisciplinary Research in Iran
Ministry of Health and Medical Education can
play a key role in national progress in the fields of
health sciences, technology, and innovation. (1)
1- B. Larijani et al. Iran’s Health Innovation and Science Development Plan by 2025.
Iranian Journal of Public Health 2009; 38: 13-16 (supp)
6
Why Interdisciplinary Research?
• Advances in technology in the past century
began a new era of diagnosis and treatment
• These advances have failed to offer a curative
treatment for many endocrine diseases
including diabetes.
• As a result of the advances, new fields have
emerged such as rejuvinative medicine and
regenerative medicine.
7
New drugs for endocrine disorders
• A specific focus on clinical pharmacology is
crucial if we are to develop new drugs for
endocrine disorders
• Molecular modeling needs to be in priority to
lower the cost of production of new drugs
• A new approach to Iranian traditional
medicine and herbal medicine is necessary to
develop new herbal medication based on the
traditional approaches
8
New treatment modalities
• Regenerative medicine and stem-cell research need to
be in priority if we are to invent new treatment
modalities
• Research on medical ethics is needed need to
overcome ethical, cultural, and religious issues in
regards with barriers to new treatment modalities such
as stem-cell research
• Ethical issues need to address dilemmas such as
rejuvinative medicine which involves use of hormones
in aging normal individuals for restoration of vigor and
youth
• Genetics is needed for gene therapy
9
New diagnostic methods
• In order to invent new diagnostic devices, it is
necessary that analytical chemistry and
biosensor technology
• Genetics and genome mapping is needed for
screening high risk individuals
• Invention of new diagnostic devices similar to
ophthalmoscopes, needs close cooperation
between engineering and physics faculties
and medial faculties
10
An Interdisciplinary Approach to
Cure for
Endocrinology
Diabetes
Approval for
stem-cell
Research
Religion
Medical
Ethics
Molecular
Modeling
Stem-Cell
Research
Future of
Pancreatic βCell
Transplantation
Genetics
Endocrinology
Pharmacology
Traditional
Medicine
New
Drugs
Gene
Therapy
Analytical
Chemistry
Personalized
Medicine
History of
Medicine
Biosensors for
Diagnosis of
Diabetes
11
Diabetes: an example of necessity of
interdisciplinary research
• In the field of diagnosis, advance in analytical
chemistry, optics, and ultrasonography is
necessary
• Genetics can be applied for screening and
identification of high-risk individuals
• Islet-cell transplantation and stem-cell research
needs to make progress for treatment modalities
• Progress in medical ethics is necessary to address
ethical and cultural in order to overcome the
barriers to stem-cell research
12
Timeline of Diabetes-Related Research
From 1923
when
insulin was
discovered,
there has
been little
progress in
treatment
of diabetes
There has been little progress in diabetes-related
research since 1923
Polonsky KS. The Past 200 Years in Diabetes. N Engl J Med 2012;367:1332-40.
13
Milestones in the Treatment of
Diabetes
Discovery of
Insulin
Advances in Stem-cell
research
Progress in
Pancreas
transplantation
Polonsky KS. The Past 200 Years in Diabetes. N Engl J Med
2012;367:1332-40.
14
The Global Burden of Diabetes
The majority of Iranian Population is
forecast to be in this range in 2025
(IDF Official Report)
• 366 million people have diabetes in
2011; by 2030 this will have risen to
552 million
• 80% of people with diabetes live in
low- and middle-income countries
• The greatest number of people with
diabetes are between 40 to 59 years
of age
15
Why Diabetes is a Future Concern in
Iran?
Iran Population Estimate, 2025
Iran Population Estimate, 2005
70-74
70-74
Male
Female
60-64
60-64
50-54
50-54
40-44
40-44
Age
Age
Male
30-34
30-34
20-24
20-24
10-14
10-14
0-4
0-4
15
10
5
0
% of Population
5
10
15
15
10
Female
5
0
5
10
15
% of Population
The population of Iran is projected to
grow older in 2025.
B. Larijani et al. Iran’s Health Innivation and Science Development Plan by 2025. Iranina Journal of Public Health 2009; 38: 13-16 (supp)
16
Burden of Diabetes in Iran
Level 3 Tree Map of All Causes of DALYs In 2010
DALYs =
Disability
Adjusted Life
Years
Diabetes is
a major
cause of
DALYs in
Iran
(The sum of
years of
potential life
lost due to
premature
mortality and
the years of
productive life
lost due to
disability.)
17
The change in the leading causes of
DALYs from 1990 to 2010 in Iran
In the past
two decades,
the burden of
diabetes has
significantly
increased in
Iran
http://www.healthmetricsandevaluation.org/gbd/country-profiles
18
Ranking of leading age-standardized rates of disabilityadjusted life years (DALYs)
(relative to comparator countries in 2010)
Diabetes ranked 9th in Iran in
ranking of DALYs in 2010
http://www.healthmetricsandevaluation.org/gbd/country-profiles
19
Interdisciplinary Approach to
Endocrinology
( Diagnosis and Treatment)
• Technological advances in the field of screening and
diagnosis of Diabetes
– Application of Analytical Chemistry (Biosensors) .
– Employment of genetics to spot high risk individuals
• New treatment options:
–
–
–
–
–
–
–
Whole pancreas transplantation
Pancreatic islet transplantation
Regenerative medicine (Stem-cell therapy)
Gene therapy
Personalized medicine
New drugs developed with the use of molecular modeling
Traditional medicine
20
Biosensors in Endocrinology
Advantages of
biosensors for clinical
use:
• Detect small amounts
• Fast response
• Cost-effective
• Online monitoring
• Portable
Biosensors can effectively
detect very small amounts of
biologically active substances
21
Detection of Glucose in Saliva
• Glucose measurement in saliva and tears
with the use of biosensors
Jonathan C. Claussen, Anurag Kumar, David B. Jaroch, M. Haseeb Khawaja, Allison B. Hibbard, D.
Marshall Porterfield, Timothy S. Fisher. Nanostructuring Platinum Nanoparticles on
Multilayered Graphene Petal Nanosheets for Electrochemical Biosensing. Advanced Functional
Materials, 2012; DOI: 10.1002/adfm.201200551
22
Invention of a Biosensor-Based Device for
Measurement of Glucose in Saliva by EMRI
Scientists
• Glucose measurement in saliva can
provide a pain-free alternative for
estimation of the blood sugar
• As glucose concentrations are
extremely low in saliva, a very
sensitive technique is required
• Researchers of the EMRI have
invented a portable device for
measurement of glucose
concentrations in saliva in a joint
project.
The device invented by
EMRI scientists (joint
project).
23
Diagnosis, Screening and Monitoring
Diabetes
1776: Saccharometers for detection
of glucose in urine
Future: Smartphone screens will detect
glucose in saliva (Spit-on-Phone)
Currently: Glucometers for detection of
glucose in blood
Near future: EMRI Developed device for
detection of glucose in saliva will be
commercially available
24
EMRI Joint Invention was Broadcasted
via MedGadget
25
Biosensor-Based Device for Detection
of Sulfonylurea in the Urine
• Patients with hypoglycemia can be brought to the
emergency ward in coma: the cause?
• EMRI sciences have invented a biosensor-based
device which is capable of detecting sulfonylurea
in the urine
EMRI invented biosensor-based device for
detection of sulfonylurea in the urine
26
News of the EMRI Invention
MegGadget broadcasted the news of the invention
27
Curative treatment for Diabetes:
Whole Pancreas Transplantation
• Pancreas transplantation
was first used for the
treatment of diabetes in
humans in 1966.
• In 2006, approximately
1400 procedures were
recorded.
• This method is proved to be
effective in controlling
diabetes, especially
unstable diabetes.
www.ustransplant.org (Accessed 7/6/09)
28
Islet Transplantation VS
Pancreas Transplantation
Islet Transplantation
Whole Pancreas
Transplantation
Simple procedure
Major surgery
Abundant sources
Limited sources
Mortality <1% in the first
year
Mortality increases 10%
each year
Various alternatives
(encapsulation)
Need for lifelong
immune suppression
Indicated before DM
complications
Is more suitable after
complications
29
Pancreatic Islet-cell Transplantation
30
Islet Transplantation Timeline in Iran
• 2002: A scientific visit to University of Alberta Clinical Islet
Transplant Program
• 2005: EMRC-TUMS established a fund to build GMP facility
for pancreatic islet processing
• 2007:
– Joint collaboration with IKE Barber human Islet
transplantation laboratory- UBC, Vancouver, Canada
was formed
– Drawing up SOPs and work instructions for each step
was designed
– Capital equipment and instruments were purchased
– First islet isolation was performed in the facility
Cont’
Larijani B et al. Establishing a cGMP pancreatic islet processing facility: the first
experience in Iran. Cell Tissue Bank 2012; 13(4):569-75
31
News of the Foundation of the Facility
Larijani B et al. Establishing a cGMP pancreatic islet processing
facility: the first experience in Iran. Cell Tissue Bank 2012; 13(4):56975
32
In 2010:
– - GMP facility was set up
and experimental isolation
of human pancreatic islets
(process validation) was
carried out
– - Clinical islet
transplantation was
preformed in 2 patients
Larijani B et al. Establishing a cGMP pancreatic islet processing facility: the first
experience in Iran. Cell Tissue Bank 2012; 13(4):569-75
33
Published Successful Examples of
stem-cell therapy in type 1 diabetes
34
EMRI Experience:
Studies Methods And Protocols
• Intervention
– Human fetal liver-derived Hematopoietic stem cells
– Cells certificates are prepared for each patient IV
injected within 20-30 min.
• Follow-up
– Patient were visited followed up (1w-2w-4w-8w12w…)after cell therapy.
– Laboratory test (CBC, HbA1C, FBS, LFT, TG,
cholesterol, U/A, C-peptide, surface markers,
immunoglobulins.
Ghodsi M, Heshmat R, Amoli M, Keshtkar A, Arjmand B, Aghayan H, Hosseini P, Sharifi A M, Larijani B. The Effect of
Fetal Liver-Derived Cell Suspension Allotransplantation on Patients with Diabetes: First Year of Follow-up. Acta
Medica Iranica 2012; 50(8): 541-546
35
Fetal Stem Cell Transplantation
(The First Study)
EMRI Double blind RCT 2007
56 patients
type 1 (n=31)
type 2 (n=25)
Method
Fetal hepatic-drived hematopoietic stem
cells
Systemic IV injection
Results
No significant difference was found between cell therapy and placebo groups .
Ghodsi M, Heshmat R, Amoli M, Keshtkar A, Arjmand B, Aghayan H, Hosseini P, Sharifi A M, Larijani B. The Effect of Fetal
Liver-Derived Cell Suspension Allotransplantation on Patients with Diabetes: First Year of Follow-up. Acta Medica Iranica
2012; 50(8): 541-546
36
Safety Study
3 Years After Cell Transplant
2007
• Fetal stem cell
transplantation
:Double blind
RCT
2010
• Safety
evaluation of
fetal stem cell
transplantation
Purpose
Results
Evaluation for
complications of
diabetes or any
other lifethreatening
complication
• No lifethreatening
complications or
malignancy
• No significant
difference between
case and control in
micro and macro
vascular
complications
Evaluation of Fetal Cell Transplantation Safety in Treatment of Diabetes : a three-year follow-up
Current Status : Submitted at “ Stem Cell Research and Therapy “
37
Fetal Stem Cell Therapy
The Second Study
Open-label, Single-arm Clinical Trial , 2008
84 type 1 diabetes patient s
Age: 50-60
Intervention
Fetal stem cell transplant
Hepatic-derived suspension
Results
Insulin independence:
4 patient ,6 months
Insulin independence :
Insulin independence:
3 patient ,12 months
2 patient ,18 months
Significant decrease in insulin
dosage ,70% of patients
Ghodsi M, Heshmat R, Amoli M, Keshtkar A, Arjmand B, Aghayan H, Hosseini P, Sharifi A M, Larijani B. The Effect of Fetal Liver-Derived Cell
Suspension Allotransplantation on Patients with Diabetes: First Year of Follow-up. Acta Medica Iranica 2012; 50(8): 541-546
38
Mesenchymal Stem-Cell Therapy
(EMRI Experience)
Open-label, single-arm clinical trial
23 patients
Positive anti-GAD
antibody
Diagnosis: less than 6
months
Method
Autologus Mesenchymal stem cells
prepared from bone marrow (BMA)
Systemic IV injection
Results
Insulin independence:
Insulin independence:
3 patient ,10months
1 patient 24months
39
Molecular Modeling in Endocrinology
• Models are :
– Representations containing the essential
structure or some object in the real world
– Built after simplification of the object or event
– Models are not “real” and have their limitations
but could be “useful”
• Advantages of application of molecular Modeling in
Medicine
– Reducing the cost of production of new
medication
– Minimizing the need for clinical trials
– Obviating the need for animal studies in some cases
40
Molecular Modeling
Molecular modeling:
Modeling or mimicking
the behavior of
molecules. It includes
three branches:
• Mathematical
modeling
• Molecular Modeling
• Cells/organs/animal
s as disease models
41
Clinical Genetics:
Follow up of a family with insulinoma and
hyperparathyroidism
Patients present with insulinoma and hyperparathyroidism
pancreatic mass and liver metastasis in abdominal CT and
parathyroid multifocal adenoma or hyperplasia in MIBI scan
42
Clinical Genetics:
(Follow up a whole family with MEN1 Syndrome)
43
Traditional Iranian Medicine
• Iranian Traditional Medicine can
be defined as knowledge and
practices used in diagnosis,
prevention and elimination of
diseases in Persia from ancient
times to present (1).
• Iranian Traditional Medicine (TIM) is entirely based
on practical experience and observations passed
down from generation to generation.
H Rezaeizadeh1, M Alizadeh1, M Naseri2, MR Shams Ardakani. The Traditional Iranian
Medicine Point of View on Health and Disease. Iranian J Publ Health 2009; 38(1):169-172
44
45
Origin of Traditional Iranian Medicine
• Roots back to 8000 B.C. (1)
• Is a branch if not the root of the so called
Arabic-Unani Medicine as quoted by Cyril
Elgood, the English medical historian. (1)
• It is even claimed that Persians taught the
Greeks the elements of that system of
medicine, which has been known ever since
as Greek medicine (2,3)
1- H Rezaeizadeh1, M Alizadeh1, M Naseri2, MR Shams Ardakani. The Traditional Iranian Medicine Point of
View on Health and
Disease. Iranian J Publ Health 2009; 38(1):169-172
2- Elgood C (1992). Iran Medical History and the Regions of Eastern Caliphate, translated by Baher F. Amir
Kabir Publications,
Tehran, pp.: 22, 37.
3- Elgood C (1979). A Medical History of Persia and the Eastern Caliphate from the Earliest Times to the Year
A.D. APAPhilo Press, Amsterdam.
46
Avicenna and Diabetes
• Avicenna (980–1037) provided a detailed account on diabetes
mellitus in The Canon of Medicine: (1,2)
–
–
–
–
–
–
Abnormal appetite
Collapse of sexual functions
Sweet taste of diabetic urine
Primary and secondary diabetes
Diabetic gangrene
Treatment of diabetes using a mixture of lupine, trigonella
(fenugreek), and zedoary seed, which produces a considerable
reduction in the excretion of sugar, a treatment which is still
prescribed in modern times.
• Avicenna also described diabetes insipidus very precisely for
the first time, though it was much later that Thomas Willis
differentiated it from diabetes mellitus in a chapter of his
book Pharmaceutice rationalis (1674). (1,2)
1- History of Diabetes. (n.d.). In Wikipedia. Retrieved October 21, 2013 from
http://en.wikipedia.org/wiki/ History_of_diabetes
2- Siva L, Mythili , Kumar PS, Rani J. Diabetes and Iron Metabolism.
International Journal of Science Innovations and Discoveries 2012; 2 (2): 62-73
47
EMRI Traditional Medicine Research
Group
• This research group was established in 2008
• The main objectives of this group are to:
– Expand the existing knowledge on Traditional Iranian
Medicine (specifically herbal medicine) through systematic
reviews
– Integrate applicable elements of Traditional Iranian Medicine
into current practice of Endocrinology
– Discouraging harmful and ineffective practices of Traditional
Iranian Medicine
• The TIM group of EMRI has so far published:
–
–
–
–
–
44 Articles on diabetes
15 Articles on hyperlipidemia
12 Articles on obesity
2 Article on hyperprolactinemia
15 Articles on antioxidants
48
Angipars: a milestone in
Interdisciplinary Research at EMRI
• One of the most important
objectives of the traditional
medicine research group of
the EMRI is to evaluate
efficacy and safety of different
and introduce novel drugs to
the market.
• Invention of Angipars ™ which is a new herbal-based
treatment option for treatment of diabetic food by EMRI
in 2007 can be considered as a perfect example of the
result of research on the efficacy and safety of a herbal
medicine and introducing it to the pharmaceutical market
49
Scholarly articles published on
Angipars
50
Citations to EMRI published articles in the
field of Traditional and Herbal Medicine
51
An Interdisciplinary Approach to
Cure for
Endocrinology
Diabetes
Approval for
stem-cell
Research
Religion
Medical
Ethics
Molecular
Modeling
Stem-Cell
Research
Future of
Pancreatic βCell
Transplantation
Genetics
Endocrinology
Pharmacology
Traditional
Medicine
New
Drugs
Gene
Therapy
Analytical
Chemistry
Personalized
Medicine
History of
Medicine
Biosensors for
Diagnosis of
Diabetes
52
EMRI Research Organizational Chart
53
EMRI Research Groups
Currently, apart form 9 EMRI Research Centers, 8 Affiliated
Research Groups actively involved in research activities of the
Institute, some of them are to be promoted to Research Center
status. These Research Groups are:
–
–
–
–
–
–
–
–
54
Islamic Fasting Research Group
Evidence-based Medicine Research Groups
Immunogenetics Research Group
Bionanotechnology Research Group
Traditional Medicine Research Group
Medical Ethics Research Group
Molecular Modeling Research Group
Innovation Research Group
EMRI research activities
EMRI publications has significantly increased
since its establishment and citations to the
articles show a remarkable rise
55
Source:
Ranking of Iran in endocrinology scienceproduction
During the past decade, Iran ranked 23rd with
1.62% of the scientific production in
endocrinology
56
Source:
Ranking of world endocrinology
authors
During the past decade, Director of the EMRI
ranked 3rd amongst the world endocrinology
authors
57
Source:
TUMS position in endocrinology scienceproduction
During the past decade, TUMS ranked
23rd amongst world universities in
terms of endocrinology scienceproduction
58
Source:
Ranking of universities of Iran in
endocrinology science-production
During the past decade, TUMS ranked
1st amongst universities of Iran in
endocrinology science production
59
Source:
EMRI Supplement Issue for IJPH
Published in 2014
Advances in Interdisciplinary
Endocrinology: A Supplementary Issue
60
Interdisciplinary Advances in Endocrinology
• Advances in
Interdisciplinary
Endocrinology: A
supplementary issue
of the Iranian Journal
of Public Health
• A comprehensive
textbook project in
Interdisciplinary
Endocrinology
published as a
Supplement Issue
Future plans for the Textbook
61
Future of Interdisciplinary
Endocrinology (Special Issue)
EMRI has successfully initiated a special issue in collaboration with
International Journal of Endocrinology: Future of Interdisciplinary
Endocrinology (impact factor: 1.515)
62
New horizons in Diabetology
(Special Issue)
EMRI has successfully initiated a collaborative publication with Journal of
Diabetes Research: New Horizons in Diabetology (impact factor: 3.536)
63
Conclusions
• Significant advances has been made in Iran
during the past decade:
– In 1392 (AH) Iran ranked 17th in the world in terms of
total number of published scholarly articles
– 38% of the articles were in the field of medicine
– 25% of highly cited articles were on medicine
• However, we are lagging behind in terms of
production of health-related technologies, new
drugs, and applied medical sciences
64
Conclusions, cont’
• If we are to overcome this gap in knowledge
production in Iran, we need to promote
interdisciplinary research in all branches of
medicine.
• We used endocrinology as an example of how
interdisciplinary research can result in production
of applied knowledge and national scientific
achievements.
• We believe that other branches of medicine
should take a similar approach if we are to
overcome the gap.
65
66