Aging, Disease & Longevity: Recent Discoveries & Future Trends – Pt. I

INTRODUCTION

In the past three years (since 2000), several major advances and discoveries have been made in the Biological Sciences.

The Human Genome Project, a government funded 'mapping' of some 30,000 human genes, is becoming our greatest scientific resource, and will come to be so even more as this century progresses. As geneticists proceed with gene therapy experiments based upon direct expression and inhibition of genes, and also the repair of gene mutations and malfunctions, such work will both depend on, and contribute to, the continuous updating of the Human Genome Project database. This database is the repository of all our genetic knowledge and will carry us well into the 21st century.

New medical technologies are likewise leading the way for 21st century Medicine and the 'new' science of Aging and Longevity. New techniques for engineering more effective, low side-effect pharmaceuticals are revolutionizing Bio-Engineering and Pharmacology Science.

This article begins a two-part feature, with this first installment focusing on three current (within the last three years) discoveries and research trends in the fields of Aging, Disease, and Longevity: Mitochondrial DNA Mutations, Protein Mapping, and MRI Technology.

MITOCHONDRIAL MUTATIONS

The human genome is an ecosystem in which thousands of enzymes continuously interact with, and alter, both each other and the larger RNA and DNA molecules. As RNA and DNA molecules replicate, errors can and do accumulate. Many of these anomalies and mutations in the human genome are eliminated through natural selection (about 20%) but a majority manage to avoid being selected against, and are copied into the next generation DNA. 

Most people with a basic knowledge of cell biology know that DNA--the 'blue print' molecule that governs all living forms--resides in the nucleus of the cell. The nucleus is the 'control center' of every animal cell. However, it was discovered some 30 years ago, that a cell's mitochondria--its 'energy factory'--also possesses a copy of its host's maternal DNA. In both structures, DNA molecules can accumulate errors and mutations. After many years of analysis of mitochondrial DNA (mtDNA) strands, biologist began to realize that mutations accumulate as an animal grows older.

Nature has provided some defense from this. Our DNA encodes enzymes that have the sole function of repairing their own mutations and replication mistakes. DNA polymerase-gamma is one such enzyme. DNA polymerase-gamma normally 'proofreads' mt DNA to ensure correct replication, aiding in DNA repair. 

In order to pin point a more causative role for this enzyme, geneticist Aleksandra Trifunovic and her colleagues of the Karolinska Institute in Sweden, engineered a line of mice to produce a "compromised", i.e., non-functioning, version of this enzyme. Later biopsy analyses of heart, brain, and liver samples revealed up to five times as many errors in their mtDNA as in similar tissue from normal mice. These younger, transgenic mice began to exhibit the typical signs of aging

While this is very exciting news for our understanding of aging, researchers are quick to point out that DNA polymerase-gamma is only one of several molecules that play an important role in cellular aging and longevity. However, while there have been several previous studies that correlate this enzyme with aging symptoms, the Swedish study results are the first strong evidence that mtDNA mutations actually cause aging. 

Correlation studies are helpful to scientist in 'pointing the way' towards future avenues of research. But correlation studies are not experiments, which seek to demonstrate a causative relationship between two (or more) factors. The classic admonition is: just because A correlates with B (is found in the presence of B), doesn't mean that A causes B. 

Geneticists hope to be able to manufacture an enhanced form of this enzyme--or the gene that encodes it--giving the patient extra mtDNA protection.

References: Scientific American, May 27, 2004: Mitochondrial Mutations Blamed for Aging, and, 
Genome by Mitochondrial DNA http://www.plos.org/news/index.html  

_________________________________________________________

PROTEIN MAPPING 

One of the most exciting and important fields in bio-technology today is proteomics--the study of protein structure and function. Its goal is to understand protein expression at the cellular level, and apply this information to scientific and medical problems

Proteins bind to other molecules to orchestrate a myriad of physiological processes. When a malfunction occurs in the protein binding process, the result can be disease. There are about seventy different types of protein binding structures--or domains--within any given somatic cell. The binding loci for each domain are also known as receptors.

Princeton, New Jersey based bio-tech company AxCell Biosciences, a subsidiary of Cytogen Corporation, has mapped all of the ways that proteins with the same type of binding structure interact and connect to one another. In the past three years, aided by new technologies such as protein chips, 2DE Gell Imaging, and capillary electrophoresis, AxCell has been hard at work mapping the protein domains associated with cancer, diabetes, heart disease and several other major killers. Current evidence strongly indicates that these diseases result from defective proteins. Proteomics research seeks to identify normal and altered protein expression in biological systems as they respond to environmental or pathological stresses.

Like mapping the human genome, mapping protein-binding structures generates huge amounts of data. This explosion of new information is feeding another emerging field: bioinformatics, which is about managing this data to yield commercially significant results.

AxCell's protein binding database--an outgrowth of the Human Genome database--has become an invaluable resource for the emerging science of pharmacogenetics, as pharmaceutical companies seek a safer and more cost-effective alternative to 'trial and error' approaches in the development of new drugs. Proteomics also has application in agricultural bio-science, wherein plant diseases are a major concern.

Despite this potential, there remains a high degree of uncertainty, and many more years of experimentation. The work involves manufacturing 'peptide chains' and then combining these with engineered proteins. Analyses of these protein mixtures seek to determine 'the strength of attraction' between each peptide chain and protein. The working theory is that 'strong affinity' shows these two components might interact with each other naturally, and thus drugs made to inhibit those interactions might alleviate some disease symptoms.

Reference: Government Proteomics Site: http://proteomeweb.anl.gov/ , 
AxCell Biosciences Corp.: http://www.axcellbio.com , 
Cytogen Corp.: http://www.cytogen.com , 
National Human Genome Research Institute: http://www.nhgri.nih.gov ,
Assc. Press article: Company Maps Protein Interactions by Linda A. Johnsonap, January 29, 2001	

____________________________________________________________

MRI SCANS SEE AGING BRAINS      

One of the biggest problems facing researchers who seek to understand age-related changes in human brains is identifying (and excluding) patients who already have early-stage Alzheimer's but have not yet been diagnosed. 

In seeking a 'control' population, Scott A. Small of Columbia University and his colleagues resorted to studying rhesus monkeys and rats. Both species experience brain changes as they age but do not develop Alzheimer's-type diseases.

Visualizing blood flow in the body and brain is one of the most valuable functions of Magnetic Resonance Imaging (MRI) technology. Using MRI scans on the monkeys first, the Columbia team was able to view differences in blood flow to the brain. Researchers discovered that older monkeys displayed a "significant decline in blood volume" in a section of the hippocampus (responsible for processing memories) known as the dentate gyrus. 

In studying the smaller rat brain, the research team decided to focus on gene activity in the hippocampus instead of blood flow. A gene in the cells of the dentate gyrus called 'ARC'-- a gene connected with learning -- was closely monitored to determine its activity level, or expression, in different age rats. When scientist speak of gene 'expression' they are referring to the 'switching on' of a gene. Results of these scans showed that the older the rat, the lower the level of ARC expression. This may indicate a cause for cognitive impairment in human, age-related diseases.

The dentate gyrus seems to be the area most sensitive to aging in these species. Scientists have known that Alzheimer's Disease affects the hippocampus, but now they are beginning to see how. By permitting researchers to distinguish normal, age-related brain changes from those created by disease, MRI technology is opening the door for earlier diagnosis, even new therapies.

Ref: National Academy of Sciences report: http://www.beyonddiscovery.org/content/view.article.asp?a=129 ,
also, Scientific American: Scientists ‘See’ Effects of Aging in Brain, April 27, 2004

To the reader: next week's installment will focus on three additional discoveries/trends in this field: RNA Interference, 'SNPs' / The Genome Assembly Archive, and the INDY ("I'm Not Dead Yet") gene.

Aging, Disease & Longevity: Recent Discoveries & Future Trends – Pt. I  by Michael Ricciardi
 
INTRODUCTION
 
In the past three years (since 2000), several major advances and discoveries have been made in the Biological Sciences.
 
The Human Genome Project, a government funded 'mapping' of some 30,000 human genes, is becoming our greatest scientific resource, and will come to be even more so as this century progresses. As geneticists proceed with gene therapy experiments based upon direct expression and inhibition of genes, and also the repair of gene mutations and malfunctions, such work will both depend on, and contribute to, the continuous updating of the Human Genome Project database. This database is the repository of all our genetic knowledge and will carry us well into the 21st century.
 
New medical technologies are likewise leading the way for 21st century Medicine and the 'new' science of Aging and Longevity. New techniques for engineering more effective, low side-effect pharmaceuticals are revolutionizing Bio-Engineering and Pharmacology Science.
 
This article begins a two-part feature, with this first installment focusing on three current (within the last three years) discoveries and research trends in the fields of Aging, Disease, and Longevity: Mitochondrial DNA Mutations, Protein Mapping, and MRI Technology.
 
MITOCHONDRIAL MUTATIONS
 
The human genome is a complex ecosystem in which thousands of enzymes continuously interact with, and alter, both each other and the larger RNA and DNA molecules. As RNA and DNA molecules replicate, errors can and do accumulate. Many of these anomalies and mutations in the human genome are eliminated through natural selection (about 20%) but a majority manage to avoid being selected against, and are copied into the next generation DNA. 
 
Most people with a basic knowledge of cell biology know that DNA--the 'blue print' molecule that governs all living forms--resides in the nucleus of the cell. The nucleus is the 'control center' of every animal cell. However, it was discovered some 30 years ago, that a cell's mitochondria--its 'energy factory'--also possesses a copy of its host's maternal DNA. In both structures, DNA molecules can accumulate errors and mutations. After many years of analysis of mitochondrial DNA (mtDNA) strands, biologist began to realize that mutations accumulate as an animal grows older.
 
Nature has provided some defense from this. Our DNA encodes enzymes that have the sole function of repairing their own mutations and replication mistakes. DNA polymerase-gamma is one such enzyme. DNA polymerase-gamma normally 'proofreads' mt DNA to ensure correct replication, aiding in DNA repair. 
 
In order to pin point a more causative role for this enzyme, geneticist Aleksandra Trifunovic and her colleagues of the Karolinska Institute in Sweden, engineered a line of mice to produce a "compromised", i.e., non-functioning, version of this enzyme. Later biopsy analysis of heart, brain, and liver samples revealed up to five times as many errors in their mtDNA as in similar tissue from normal mice. These younger, transgenic mice began to exhibit the typical signs of aging
 
While this is very exciting news for our understanding of aging, researchers are quick to point out that DNA polymerase-gamma is only one of several molecules that play an important role in cellular aging and longevity. However, while there have been several previous studies that correlate this enzyme with aging symptoms, the Swedish study results are the first strong evidence that mtDNA mutations actually cause aging. 
 
Correlation studies are helpful to scientist in 'pointing the way' towards future avenues of research. But correlation studies are not experiments, which seek to demonstrate a causative relationship between two (or more) factors. The classic admonition is: just because A correlates with B (is found in the presence of B), doesn't mean that A causes B. 
 
Geneticists hope to be able to manufacture an enhanced form of this enzyme--or the gene that encodes it--giving the patient extra mtDNA protection.
 
References: Scientific American, May 27, 2004: Mitochondrial Mutations Blamed for Aging, and, Genome by Mitochondrial DNA http://www.plos.org/news/index.html  
 
_________________________________________________________
  
PROTEIN MAPPING 
 
One of the most exciting and important fields in bio-technology today is proteomics--the study of protein structure and function. Its goal is to understand protein expression at the cellular level, and apply this information to scientific and medical problems
 
Proteins bind to other molecules to orchestrate a myriad of physiological processes. When a malfunction occurs in the protein binding process, the result can be disease. There are about seventy different types of protein binding structures--or domains--within any given somatic cell. The binding loci for each domain are also known as receptors.
 
Princeton, New Jersey based bio-tech company AxCell Biosciences, a subsidiary of Cytogen Corporation, has mapped all of the ways that proteins with the same type of binding structure interact and connect to one another. In the past three years, aided by new technologies such as protein chips, 2DE Gell Imaging, and capillary electrophoresis, AxCell has been hard at work mapping the protein domains associated with cancer, diabetes, heart disease and several other major killers. Current evidence strongly indicates that these diseases result from defective proteins. Proteomics research seeks to identify normal and altered protein expression in biological systems as they respond to environmental or pathological stresses.
 
Like mapping the human genome, mapping protein-binding structures generates huge amounts of data. This explosion of new information is feeding another emerging field: bioinformatics, which is about managing this data to yield commercially significant results.
 
AxCell's protein binding database--an outgrowth of the Human Genome database--has become an invaluable resource for the emerging science of pharmacogenetics, as pharmaceutical companies seek a safer and more cost-effective alternative to 'trial and error' approaches in the development of new drugs. Proteomics also has application in agricultural bio-science, wherein plant diseases are a major concern.
 
Despite this potential, there remains a high degree of uncertainty, and many more years of experimentation. The work involves manufacturing 'peptide chains' and then combining these with engineered proteins. Analysis of these protein mixtures seek to determine 'the strength of attraction' between each peptide chain and protein. The working theory is that 'strong affinity' shows these two components might interact with each other naturally, and thus drugs made to inhibit those interactions might alleviate some disease symptoms.
 
References: Government Proteomics Site: http://proteomeweb.anl.gov/ , 
AxCell Biosciences Corp.: http://www.axcellbio.com , 
Cytogen Corp.: http://www.cytogen.com , 
National Human Genome Research Institute: http://www.nhgri.nih.gov ,
Assc. Press article: Company Maps Protein Interactions by Linda A. Johnsonap, January 29, 2001          

_________________________________________________________________
 
MRI SCANS SEE AGING BRAINS      
 
One of the biggest problems facing researchers who seek to understand age-related changes in human brains is identifying (and excluding) patients who already have early-stage Alzheimer's but have not yet been diagnosed. 
 
In seeking a 'control' population, Scott A. Small of Columbia University and his colleagues resorted to studying rhesus monkeys and rats. Both species experience brain changes as they age but do not develop Alzheimer's-type diseases.
 
Visualizing blood flow in the body and brain is one of the most valuable functions of Magnetic Resonance Imaging (MRI) technology. Using MRI scans on the monkeys first, the Columbia team was able to view differences in blood flow to the brain. Researchers discovered that older monkeys displayed a "significant decline in blood volume" in a section of the hippocampus (responsible for processing memories) known as the dentate gyrus. 
 
In studying the smaller rat brain, the research team decided to focus on gene activity in the hippocampus instead of blood flow. A gene in the cells of the dentate gyrus called 'ARC'-- a gene connected with learning -- was closely monitored to determine its activity level, or expression, in different age rats. When scientist speak of gene 'expression' they are referring to the 'switching on' of a gene. Results of these scans showed that the older the rat, the lower the level of ARC expression. This may indicate a cause for cognitive impairment in human, age-related diseases.
 
The dentate gyrus seems to be the area most sensitive to aging in these species. Scientists have known that Alzheimer's Disease affects the hippocampus, but now they are beginning to see how. By permitting researchers to distinguish normal, age-related brain changes from those created by disease, MRI technology is opening the door for earlier diagnosis, even new therapies.
 
References: National Academy of Sciences report: http://www.beyonddiscovery.org/conten/view.article.asp?a=129 , also, Scientific American: Scientists ‘See’ Effects of Aging in Brain, April 27, 2004
 
To the reader: next week's installment will focus on four additional discoveries/trends in this field: RNA Interference & 'SNPs' / The Genome Assembly Archive, and the INDY ("I'm Not Dead Yet") gene.