Future of medicine in diagnosis of disease

FUTURE OF MEDICINE IN

DIAGNOSIS OF DISEASE

Contents

Pharmacogenomics

Regenerative medicine

Molecular medicine

Robotic surgery

Nano technology

Pharmacogenomics

Pharmacogenomics

Pharmacogenetics : The study of genetically

controlled variations in drug response

Pharmacogenomics: The science that allows us

to predict a response to drugs based on an

individuals genetic makeup.

Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, et al. (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism

and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106: 2329–2333. doi:

10.1182/blood-2005-03-1108

Genetic Variability Can Affect:

Pharmacokinetics - Plasma Clearance, Delivery

of Drug or Metabolite to Target Cells,

Pharmacodynamics - The Relationship Between

the Drug Concentration & Its Therapeutic Effect.

The Likelihood of an Adverse Reaction



10.1182/blood-2005-03-1108

ORIGIN OF

PHARMACOGENETICS

Three Discoveries in the 1950s Gave Rise to

the Discipline of Pharmacogenetics:

Primquine Sensitivity (G-6-PD Deficiency)

The Slow Metabolism of Isoniazid (Acetylation

Polymorphism & Tuberculosis

Atypical Plasma Cholinesterase Giving Rise to

Prolonged Effects of Succinylcholine (Respiratory

Apnea)

BENEFITS OF

PHARMACOGENETICS

Improve Drug Choices:

Each Year, ~100,000 Americans Die of Adverse

Reactions to Medicine & ~2 Million Are Hospitalized

Pharmacogenomics Will Predict Who's Likely to

Have a Negative or Positive Reaction to a Drug

Safer Dosing Options:

Testing of Genomic Variation Improve

Determination of Correct Dose for Each Individual



10.1182/blood-2005-03-1108

Improvement in Drug Development:

Permit Pharmaceutical Companies to Determine in

Which Populations New Drugs Will Be Effective

Decrease Health Care Costs:

Reduce Number of Deaths & Hospitalizations Due

to Adverse Drug Reactions

Reduce Purchase of Drugs Which Are Ineffective in

Certain Individuals Due to Genetic Variations

Speed Up Clinical Trials for New Drugs



10.1182/blood-2005-03-1108

Metabolism of 6-MP

Pharmacogenetics: A Case Study

Borgiani P, Ciccacci C, Forte V, Romano S, Federici G, et al. (2007) Allelic variants in the CYP2C9 and VKORC1 loci and interindividual

variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics 8: 1545–1550. doi: 10.2217/14622416.8.11.1545





Genetic Analysis Permits

More rapid determination of stable therapeutic

dose.

Better prediction of dose than clinical methods

alone.

Applicable to the 70-75% of patients not in

controled anticoagulation centers.

Reduces between 4,500 and 22,000 serious

bleeding events annually.

Genetic testing now required by FDA



REGENERATIVE MEDICINE

DEFINING REGENERATIVE

MEDICINE

Regenerative medicine is a heterogeneous

domain, incorporating multiple technological

avenues of investigation.

United by a shared goal of stimulating, directing

or augmenting the body’s capacity for self-repair

and regeneration.

Our approach concentrates on technologies

using novel biomaterials – living cells, genes

and bio scaffolds.

M. Adamczak and A. Wiecek, “The adipose tissue as an endocrine organ,” Seminars in Nephrology, vol. 33, no. 1, pp. 2–13, 2013.

DEFINING REGENERATIVE

MEDICINE

Excludes small molecules and biologicals (e.g.

antibodies) that aim to stimulate in vivo

regenerative action.

Basic cell culture tools/media suppliers not

included unless have specialist focus.

Adult Stem Cell

Undifferentiated Cells

Found throughout the body after embryonic development

Multiply by cell division to replenish dying cells

Regenerate Damaged Tissues.


Types of Adult Stem Cells

Hematopoietic

Mammary

Mesenchymal

Neural

Endothelial

Olfactory

Neural crest

Testicular


Properties

Defining properties- self-renewal & potency

Lineage

Signaling pathways

Multidrug resistance

Plasticity / Transdifferentiation


THERAPEUTIC FOCUS OF CELL

THERAPY FIRMS

Stem cells

Cell therapy

0

1

2

3

4

5

6

7

8

9

10

Stem cells

Cell therapy

STEM CELL USE IN

REGENRATIVE MEDICINE

Adult (tissue) stem cells are useful in tissue and organ regeneration:

Blood-forming stem cells to regenerate blood and immune systems

Brain-forming stem cells to regenerate neuroprotective potential in brain.

Skin-forming stem cells/burns.

Skeletal muscle stem cells for muscular dystrophies.

Mesenchymal cell cultures make scar, fat, bone and cartilage; not any other tissues.


Benefits of Adult Stem Cell

Research

Easy to obtain

Potentially limitless in supply

Patients can use their own stem cells for

treatment and therapy

Adult stem cells are politically neutral

Not offensive to any major interest group nor do

they generate controversy.

TARGETED DISEASE WITH

RM

Systemic lupus erythematosus

Multiple Sclerosis

Rheumatoid Arthritis

Ulcerative Colitis

Vasculitides

Polyarteritis

Wegener’s granulomatosis

Autoimmune Hemolytic Anaemia

Type 1 Diabetes Mellitus


Limitations of adult stem cell

The isolation of some types of ASC, for example theisolation of neural cells from a patient's brain, would beimpractical

Where a person suffers from a genetic disorder or sometypes of cancers, ASC isolated from that individual willretain the damaging genetic alterations underlying thedisease and so be of little therapeutic value

Unambiguous identification is difficult

Maintenance in culture is difficult


MOLECULAR

TECHNOLOGY

MOLECULAR MEDICINE

Molecular medicine helps in

improved diagnosis of disease

earlier detection of genetic predisposition to disease

Rational drug design

Gene therapy and control systems for drugs

Pharmacogenomics "custom drugs"

Morris TA, Marsh JJ, Konopka R, Pedersen CA and Chiles PG. Improved imaging of deep venous thrombi during anticoagulation

using radiolabelled anti-D-dimer antibodies. Nucl Med Commun 2004; 25: 917-922.

Definitions

DNA polymorphism: A DNA sequence that occurs in two or more variant

forms

DNA marker: polymorphic locus useful for mapping studies

RFLP Variation in the length of a restriction fragment detected by a

particular probe due to nucleotide changes at a restriction site

SNP: two different nucleotides appear at the same position in genomic

DNA from different individuals

DNA fingerprinting: Detection of genotype at a number of unlinked highly

polymorphic loci using one probe

Genetic testing: Testing for a pathogenic mutation in a certain gene in an

individual that indicate a person’s risk of developing or transmitting a

disease



RFLPs

Fig. 11.7 – genetics/ Hartwell

Amplify fragment

Expose to restriction

enzyme

Gel electrophoresis

e.g : sickle-cell

genotyping with a

PCR based protocol

SSLPs

Similar principles

used in detection of

RFLPs

However, no change

in restriction sites

Changes in length of

repeats



SNPs (single nucleotide

polymorphisms)

Sites resulting from a single change in individual bp

SNP detection using allele-specific oligonucleotide

(ASOs)

Very short probes (<21 bp) specific which hybridize to one allele or other

Such probes are called ASOs



How to identify disease

genes Identify pathology

Find families in which the disease is

segregating

Find ‘candidate gene’

Screen for mutations in segregating families

How to map candidate

genes2 broad strategies have been used

A. Position independent approach (based on

knowledge of gene function)

1) biochemical approach

2) animal model approach

B. Position dependent approach (based on

mapped position)



Position independent

approach1) Biochemical approach: when the disease protein

is known E.g. Factor VIII haemophilia

Blood-clotting cascade

in which vessel

damage causes a

cascade of inactive

factors to be converted

to active factors



2) Animal model approach

compares animal mutant models in a phenotypically similar human

disease.

E.g. Identification of the SOX10 gene in human Waardenburg syndrome4

(WS4)Dom (dominant megacolon)

mutant mice shared phenotypic

traits similar to human patient

with WS4 (Hirschsprung disease,

hearing loss, pigment

abnormalities)

WS4 patients screened for

SOX10 mutations

confirmed the role of this gene in

WS4.

Dom mouse Hirschsprung



B) Positional dependent approach

Positional cloning

identifies a disease gene

based on only

approximate

chromosomal location. It

is used when nature of

gene product / candidate

genes is unknown.

Candidate genes can be

identified by a

combination of their map

position and expression,

function or homology

Robotic surgery

What is robots?

The term robots was introduced and coined in a 1921 play Rossoms Universal Robots by Karel Capek of Czech.

from the Czech ”robota” meaning forced labor, Meaning evolved into dumb machines that perform

menial repetitive tasks to the highly intelligent robots of popular culture.

Today robots are used to perform highly specific, highly precise, and dangerous tasks in industry and research previously not possible with a human work force.

Robotics, however, has been slow to enter the field of medicine and surgery

Blanco FJ. Robotic radical prostatectomy: present and future. Arch Esp Urol 2011;64(8):839-46.

Robotic surgery started in 2000 with adult

surgery – mainly urology

The surgeon does the surgery - not the robot

No robot (yet) to clean the instruments


History of robotics

The first documented use of a robot-assisted surgical procedure occurred in 1985.

PUMA 560 robotic surgical arm was used successfully in a delicate neurosurgical biopsy, a non-laparoscopic surgery.

The robotic system allowed the potential for greater precision when used in minimally invasive surgeries, such as laparoscopies which typically utilize flexible fiber optic cameras.

The 1985 procedure lead to the first laparoscopic procedure involving a robotic system, a cholecystectomy, in 1987.

The following year the same PUMA system was used to perform a transurethral resection.

In 1990 the AESOP system produced by Computer Motion became the first system approved by the Food and Drug Administration (FDA) for its endoscopic surgical procedure.


Types of Robots

Passive

Retractor system

Position the tool and then hold

Active

Robot would actively move the tool upon the

surgeons command


Surgical Robots in 2007

AESOP (Automated Endoscopic System for Optimal Positioning)

Voice activated mechanical arm

Steadier than human, never tires

daVinci

FDA approval in 2002

Laparoscopic instrumentation controlled by the surgeon positioned remotely at a console


Development of daVinci

Defense Advanced Research Projects Agency (DARPA) for military research of remote battlefield surgery

Cholecystectomy performed remotely via telesurgery from 300 miles away

Intuitive Surgical created in 1999 after acquiring patent rights from military

First robotic prostatectomy performed in 2001Blanco FJ. Robotic radical prostatectomy: present and future. Arch Esp Urol 2011;64(8):839-46.

Remote Transatlantic

Telesurgery

Advantages of daVinci Robot

Magnified (12x), stereoscopic 3-D vision

Robotic wrist with 6 degrees of freedom

Movements are scaled, filtered, translated


daVinci Robotic System

Disadvantages of daVinci Robot

Expensive

- $1.4 million cost for machine

- $120,000 annual maintenance contract

- Disposable instruments $2000/case

- Hospital reimbursement same DRG

Steep surgical learning curve

Increased staff training/competance

Increased OR set-up/turnover time


Future of...(20+ Years)

Socrates - allows surgeons at remote sites to connect to an operating room and share video and audio, to use a “telestrator” to highlight anatomy, and to control the AESOP endoscopic camera. expanding the use of preoperative (computed tomography or magnetic resonance) and intraoperative video image fusion to better guide the surgeon in dissection and identifying pathology

NANOROBOTS (less than 1000 nanometers) are in development in the medical field to be inserted into our bodies and perform surgeries on a molecular level within our bodies and repair us as a mechanic would a vehicle. (VIDEOS) reference to possibilities.


Nano technology

Nanomedicine may be defined as the monitoring, repair,

construction and control of human biological systems at

the molecular level, using engineered nanodevices and

nanostructures.

Nanotechnology Thorough, inexpensive control of the

structure of matter based on molecule-by-molecule

control of products and by products; the products and

processes of molecular manufacturing, including

molecular machinery.

Betzig,E.,Patterso,G.H.,Sougrat,R.,Lindwasser,Q.W.,Olenych,S.,Bonifacino, J.S.,etal.(2006).Imaging intra cellular fluorescent

proteins at nanometer resolution. Science 313, 1642–1645doi:10.1126/science.1127344

Nanosurgery A generic term including molecular repair

and cell surgery.

Nanodentistry The maintenance of comprehensive oral

health by employing nanomaterials, biotechnology

including tissue engineering and dental nanorobotics.

Bio-nanomaterial science Materials which are in direct

contact with biological fluids or living tissue, with minimal

adverse reaction or rejection by the body.

Nanomachine An artificial molecular machine of the sort

made by molecular manufacturing.

Betzig,E.,Patterso,G.H.,Sougrat,R.,Lindwasser,Q.W.,Olenych,S.,Bonifacino, J.S.,etal.(2006).Imaging intra cellular fluorescent


Nano technology can be used

for

Biomaterials

Bone

Teeth

Cells

Cartilage

Immune system

Viral and bacterial attack

Drug delivery

DiagnosticsBetzig,E.,Patterso,G.H.,Sougrat,R.,Lindwasser,Q.W.,Olenych,S.,Bonifacino, J.S.,etal.(2006).Imaging intra cellular fluorescent


Nano materials

Orthopedic prostheses such as total knee and hip joint

replacements, spinal implants, bone ixators, and tendon

and ligament prostheses;

Cardiovascular implants such as artificial heart valves,

vascular grafts and stents, pacemakers, and implantable

defibrillators;

Neural implants (e.g., cochlear implants) and

cerebrospinal fluid drainage systems (e.g.,

hydrocephalus shunts);

Plastic and reconstructive implants such as breast

augmentation or reconstruction, maxillofacial

reconstruction, artificial larynx, penile implants, and

injectable collagen for soft tissue augmentation;

Bartko,A.P.,andDickson,R.M.(1999b).Three-dimension al orientations of polymer-bound single molecules. J. Phys. Chem.B 103, 3053–

3056.doi: 10.1021/jp9846330

Dental implants to replace teeth/root systems and bony tissue in the oral cavity;

Ophthalmic systems including contact and intraocular lenses;

Catheters and bladder stimulators;

Drug-dispensing implants such as insulin pumps;

General surgical systems such as sutures, staples, adhesives, and blood substitutes.Bartko,A.P.,andDickson,R.M.(1999b).Three-dimension al orientations of polymer-bound single molecules. J. Phys. Chem.B 103, 3053–

3056.doi: 10.1021/jp9846330

Nanotechnology will contribute to a wide range

of diagnostic applications through the

development of:

Implantable Diagnostic Devices

Internal Diagnostics

Intracellular Diagnostics

Pathogen Detection


3056.doi: 10.1021/jp9846330

New Applications of

Biosensors Stent Monitor

Restenosis

Pressure gradients

Plaque build-up

Artery thickening

Smart Catheter

Fibrillation Detection

Post-operative Patient Monitoring

Drug Delivery


3056.doi: 10.1021/jp9846330

Future of medicine in diagnosis of disease

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