The Latest Evolution of the -Omes: The Diseasome Comes to Life

In 1988 if you had told most scientists that the human genome would be sequenced within 20 years, and that the resulting genome would turn out to be the least complicated of the –omes, most of them (including this one) would have said that you had been reading too much science fiction.

I distinctly remember discussions in graduate school about how the human genome probably contained around 150,000 genes. As the years progressed, techniques improved and research continued ... and the size of the human genome began to collapse quickly. At one point I remember hearing a colleague comment on how humans appeared to be "de-evolving" at a record pace! By the year 2000 the human genome had shrunk to around 50,000 genes, and over the next eight years it continued to contract. Recent estimates place the number of genes at around 24,000–30,000.

What had happened was not some major evolutionary genomic constriction event; rather, it was a greater understanding of how genes interacted and were processed by the metabolic machinery of the cell. Scientists began to think that it was not the genes themselves that were important; it might be the gene products that truly mattered.

For many molecular biologists, and probably most of the biotechnology community, the genome turned out to be somewhat of a bust. A disease is a phenotype, an outward portrayal of a trait, which in the case of most diseases has an underlying cause in the genome, but not in all cases. Creutzfeldt-Jakob disease is a nice example of a condition that is caused not by a defect in a gene (although there is some suggestion of genetic susceptibility), but rather by a malfunctioning protein called a prion. In fact, most diseases are caused by protein-related problems. Thus, in order to understand human disease it was necessary to take a good look at the proteome, or the sum of the proteins within a cell.

The size of the proteome appears to be even more elusive than the size of the genome. Estimates range from between 90,000 to more than 400,000 proteins in the human proteome. Of course this number is dependent on a number of items, including cell type, influence of external stimuli, cell age, nutritional state, etc. The proteome is the cell's response to its environment, and therefore it is expected that it will fluctuate depending on the needs of the cell.

So while some still work to identify the entire proteome, attention has shifted to what the proteome can tell us about the health of a cell. To do that, it was necessary to understand interactions within the proteome. This is called the interactome and it encompasses the study of all interactions at the molecular level within cells. The interactome is based primarily on protein-protein interactions. This led to amazing breakthroughs in systems biology, which integrated biochemistry, molecular genetics and cell biology to more fully understand how cells work.

Something very interesting occurred at this point. When studying protein interactions it is often useful to go back and identify the genes that code for each protein. Advances in biotech have made this a relatively easy process, and it was only a matter of time before scientists began to uncover some intriguing connections. In a New York Times article by Andrew Pollack, the author interviews scientists who have used studies of the proteome and interactome to reveal genes common to both heart attacks and muscular dystrophy — two seemingly unrelated conditions.

In other words, molecular science has come full circle. An understanding of the genome is once again important, but so is an understanding of the interactome and proteome. Together, these items are sometimes called the diseasome. The diseasome represents the latest evolution of the -ome; it fully integrates all information to understand factors that may cause a disease.

If you are having a hard time visualizing the diseasome, then a quick visit to an interactive graphic on a portion of the diseasome prepared by The New York Times will help immensely. If you notice, there are connections in this diagram that seem to be impossible if you think only about the disease, such as genes linking myocardial infarctions and Alzheimer's disease. But if you step back from the disease for a second, and integrate the information, it starts to make sense. At the cellular level, metabolic activities are directed by genes and proteins interacting in complex manners. Since there are a limited number of genes and proteins, but a seemingly unlimited number of diseases, then there must be common factors that we have previously missed.

So what does all of this mean? The ability to visualize these interactions may allow medical researchers to develop innovative methods of detecting and treating disease states. Some, such as Dr. Albert-László Barabási at The New England Journal of Medicine and Northeastern University, have called this network medicine.

In the very near future, as more of these interactions are mapped out, doctors may begin to prescribe unique combinations of drugs that would have not even been considered 10, or even five, years ago.

Diseases that previously were thought to be too complex to cure, such as muscular dystrophy and diabetes, may very soon be things of the past.

Note: this article first appeared in the June 5, 2008 issue of BioWorld Perspectives, and is reproduced here by permission of AHC Media, LLC

It May Not Pay to be Smart...If You Are a Fly

It pays be to smart.....doesn't it? Many of us struggled through years of undergraduate and graduate school just to get an upper-hand in the great game of life. But now, a new research article in the journal Evolution suggests that, at least for flies, being smart is going to cost you... in lifespan.

Researchers at the University of Lausanne bred flies that were "smarter" in responding to specific scents than other flies. When they took at look at the lifespan of these flies they realized that the "smart" flies lived about 15% less time than the , well, "not as smart" flies.

Drosophila are often used as model organisms for a variety of genetic studies. This study is important in that it may help shed some light on the "costs" of intelligence. By costs I mean what the organism has to give up in order to develop intelligence, and this is something that we really need to know if we are going to ever figure out how complex intelligence evolved on this planet. However, lets make something clear... these were not smart flies. Flies really aren't very bright, I know, I breed them. They are like fish in a tank... pretty to look at, but not much going on upstairs. So although we can use fruit flies for a variety of purposes, let us not give them credit for being smart.

What I worry about is what will happen when a sound-bite of this information gets out. We already have a problem keeping kids in school - telling them that straight A's will cost them 10 years of their life... well, that would be a mistake. Someone, somewhere, is going to use this information to justify dropping out of school and smoking 2 packs a day.... just watch.

My Friend, E. coli

While as a geneticist my vote would go to Drosophila melanogaster as the greatest organism of all time, I do recognize that Escherichia coli is probably one of the most beloved organisms of the biomedical research community. This versatile little microbe can be found in teaching and research labs from high schools to research institutions and large biomedical facilities. We probably know more about E. coli than almost any other organism on the planet, including ourselves. Many of the advances in medicine and drug development would probably not be possible if it were not for this wonderfully versatile little bacteria. But, as we are all aware, E. coli has a dark side.

The March 24 issue of New Scientist features an article ("Mystery Food Poisoning Traced to Salads") which presents statistics on the increase in the rate of food poisoning associated with salad greens. While the article does not specifically mention E. coli, if you asked the common person on the street what was causing the food poisoning in spinach and lettuce, most would guess this bacterium. In fact, E. coli is probably the only microbe, or any other organism for that matter, that most people know by its scientific name! Unfortunately, that recognition is not a good one. From baby diapers and water parks in the 1990s to ground beef and salad greens in this decade, E. coli has earned a reputation as a menace.

I have found that most students are surprised to find out that their intestines contain more bacterial cells than there are human cells in their bodies. Most are disgusted by the thought, and some actually pale when I mention that one of the leading organisms is E. coli. I have even had a few ask if they can get antibiotics from the campus health clinic to rid them of these "parasites."

After a brief discussion of why these little creatures are present in our system, and the benefits that they provide us by protecting us from harmful bacteria, synthesizing necessary vitamins, and stabilizing our blood glucose levels, most of the students develop a real appreciation for E. coli. From that point we can proceed to discussions on how important it is to keep your intestinal bacteria content by reducing unnecessary use of antibiotics and consuming plenty of fiber. It is then relatively easy to understand why probiotics, such as yogurt and Acidophilus pills, work as supplements. With a little public relations work, E. coli is transformed from the villain to a misunderstood hero.

Why is any of this important? In the March 1 edition of Science News, science writer Janet Raloff ("Nurturing Our Microbes") presents an intriguing possibility that someday it may be possible to reprogram our natural flora of microbes to combat disease. She first discusses how probiotic supplements may be used to increase the efficiency of intestinal bacteria in enhancing our immune system, by increasing the absorption of nutrients such as calcium and by regulating weight. Raloff then presents comments by Jeremy Nicholson of the Imperial College in London, who said that future drug therapies might one day be directed at the bacterial inhabitants of the intestinal system.

As a researcher, I think that is an important advance for medicine. We all know of the problems that have plagued large-scale implementation of gene therapy. Given the number of bacteria in the lumen of the gut, it should be possible to achieve a higher rate of transformation than is experienced in in vivo eukaryotic cells. Furthermore, by having the bacteria produce the drug of interest, it may be easier to get the drug directly into the bloodstream than traditional oral routes that need to navigate the hostile environment of the stomach.

And since this is an election year, and at least some of the focus appears to be on health care, the use of genetically modified E. coli may reduce the cost of certain medicines, since once transformed the individual would have a constant, renewable source of the drug.

However, before we proceed with the development of drug-producing recombinant bacteria, I would like to make a suggestion. If the drug companies state that they are ready to produce a genetically altered bacterium, especially one named E. coli, the general public is going to have a revolt.

Movies such as I Am Legend have not presented a pretty picture of genetically engineered organisms. Recent public responses to cloned meat, and once again to certain forms of immunizations, reveal that the general public is not convinced that we know what we are doing.

So my suggestion is this — start a public relations campaign on behalf of E. coli. Get E. coli, or its agent, on The Daily Show and Good Morning America. Start thinking about how to spin the benefits of E. coli to an increasingly research-phobic public. Work the media, begin ad campaigns, and most importantly, get the message out to the science teachers to incorporate it into their curriculum. For if we don't, this promising medical advance may be a tremendous waste of money.

Note: this article first appeared in the April 10, 2008 issue of BioWorld Perspectives, and is reproduced here by permission of AHC Media, LLC

Autism in the News

Autism is once again in the news. In the past several weeks news agencies, such as CNN, have brought autism back into public thinking through coverage both on TV and the web. While the news network has done an adequate job of presenting the concerns of parents and the opinions of the scientists, they have done very little to present the basic scientific information about autism. From my perspective, most people are completely confused about autism. In the past, an autistic child was sometimes viewed as the fault of the parents, and in the current round of coverage the disease is sometimes being presented as a result of a medical community which prefers not to face the facts regarding vaccinations. Neither of which is really true. Instead, we need to recognize that autism is a very complicated disorder – and that complicated disorders can take some time to sort out.

First of all, and probably most importantly, autism is most likely not a single disease. Like Alzheimer’s disease and cancer, autism is a term that we have adapted to explain a related group of symptoms, in this case severe communication disorders. Alzheimer’s researchers now distinguish their disease using terms such as “late-onset” and “early-onset”. We need the same approach for autism. We need to develop a common set of classifications for the disease so that we all know what type of autism we are talking about. And these classifications need to be easily understood by the news organizations and general public. No scientific techno-babble please! For those who are trying to understand autism, we need to be able to distinguish the various forms so that we know if the news and the scientific community is talking about a common form or a rare form. Also, since autism is not a single disease, we can’t expect that the disease is caused by the same factors in each case. Which leads me to the second important point – genetics.

Autism is probably what geneticists call a multifactorial, or complex, disorder. What this means is not only is genetics involved, but also environmental factors. Those environmental factors are without doubt chemicals. While the news has been focusing on thimerosal, a chemical additive that was used in many vaccines, the truth is that we live in an increasingly chemical world. Some scientists estimate that we come in contact with over 70,000 man-made chemicals over the course of our lives. We have no idea how many of these chemicals interact with each other. In other words, our cells, and especially the easily influenced cells of a developing child’s nervous system, are being bombarded with a potentially hostile array of chemical compounds. Now, back to the genetics. Many of our genes have minor variations that go unnoticed until the cell is placed in a certain environmental condition. So say for gene X there are 2 variants, lets call them X-1 and X-2. When X-1 is exposed to a certain chemical cocktail, the gene continues to function normally. But when X-2 is exposed to the same group of chemicals, the environment alters the way the gene works, called gene expression by scientists, producing slight changes in the cells. In a complex trait it may be necessary to have many of these gene variants, say X-1, Y-4 and Z-2 acting at the same time to produce a disorder. Sorting out multifactorial complex traits takes time and patience by the scientific community.

So what can we do? As parents and concerned individuals we need to aggressively lobby our elected officials to increase funding to not only study this disease, but to make life better for the increasing number of kids who are being diagnosed with autism. In addition to long-term studies of people with autism, we need to start enrolling pregnant mothers in prenatal studies that examine everything from the genetics of the parents to the types of chemicals that the mother comes into contact with during her pregnancy. Only then will we be able to provide some real answers on what is causing autism, and maybe develop a means of reducing its impact on future generations.

New Hope for Short People???

"Tall people have tall children, and short people have short children." For many this statement summarizes all that needs to be known regarding the relationship between a person’s height and heredity. For geneticists, however, these types of general observations represent an open intellectual challenge, since a more careful observation of the human population reveals that there is considerable variation with regards to height, and that it is possible for tall people to have short children, and vice versa.

A Quantitative And Multifactorial Trait

For years scientists have known that height is a quantitative trait, meaning that the population does not fall into distinct phenotypic classes. Anyone who purchases clothes knows that people are not "tall," "short" or "medium." Instead, height in humans is distributed around a mean value. This form of distribution, or bell-shaped curve, is characteristic of a trait that is under the influence of multiple genes, each one having an additive effect on the phenotype. The more of the
alleles that a person has, the further along the distribution the phenotype is located.

Geneticists also recognize that height is a multifactorial trait. Multifactorial does not mean simply that multiple genes are involved. The term multifactorial indicates that there are both genetic and environmental factors that are contributing to the observed phenotype.

A wonderful illustration of the multifactorial basis of human height is provided by Ricki Lewis in her textbook, Human Genetics, Seventh Edition. Lewis presents two photos of the graduating class of Connecticut Agricultural College, one taken circa 1920, the other in 1997. In both photos, the students were placed into phenotypic classes by height (to the nearest inch). The distribution of both classes follows a distinctive bell-shaped curve characteristic of a quantitative trait. The difference is that the mean height of the 1997 class was much greater than that of the 1920 class. Whereas the tallest individual in 1920 was 5’9", the tallest individual in 1997 was 6’5".

Since it is unlikely that a "tall" mutation has infiltrated the entire graduating class, and therefore the genetic basis of the two populations should be roughly the same, then there must be some other factor involved. Human geneticists and medical professionals say that the overall change in height over the past several decades is primarily due to improvements in human nutrition – an environmental factor. Building on this, geneticists have suggested that human height may be the
result of the interaction of environmental factors with several major genetic mechanisms and a host of minor genes.


Use Of Genome-Wide Association Studies

As a geneticist who has studied quantitative traits in Drosophila, I can testify that one of the hardest problems facing quantitative geneticists is the ability to tease out the influence of major and minor genes on a phenotype. Many methods exist to investigate the contributions of a single gene to a phenotype, but searching for all of the minor contributing genes has remained a relatively difficult task. Recently, a research group led by Timothy Frayling at Peninsula Medical School in Exeter, UK, reported the use of the genome-wide association studies (GWAs)
to identify genes responsible for variations in the height of humans (Nature Genetics, October 2007). The use of association studies in human genetic analysis is nothing new as they have been used with a variety of genetic markers for several decades. However, the use of GWAs in this manner is something significant as it allowed the researchers to look at contributing alleles across the genome, and not simply in the vicinity of candidate genes. This technique should give researchers the ability to identity a greater number of minor genes, or those that make smaller contributions to the phenotype in question. This could prove to be very useful for complex diseases and traits that are under the control of multiple genes.


Breakthroughs In HMGA2

The gene that Frayling’s group identified, HMGA2, is not a new discovery. As the researchers report, it has been known for some time that severe disruptions of this gene can cause drastic changes in the height phenotype (dwarfism and gigantism) of mice. What Frayling was able to show is that certain alleles of this gene are associated with height at specific times during development. Interestingly, the associations indicated that certain alleles are associated with an
increase in height between the ages of 7 and 11 years and persisting into adulthood. This identification of this temporal importance suggests that other genes remain to be identified that play a role earlier in life. But there is also a catch – the gene that is responsible for the added height is also associated with an increased risk of certain types of cancer. The gene product of HMGA2 belongs to a family of proteins that act as DNA-binding proteins, meaning that HMGA2 most likely has a role in the regulation of gene expression. Although HMGA2 is not an oncogene, it has been observed to be overexpressed in certain types of tumors, meaning that while a gene might be a minor gene in one quantitative trait, it may be a major gene for another trait.
With the developing promise of gene therapy might it be someday possible to prevent individuals from being vertically challenged? In today’s world there is always someone who will want to capitalize on a discovery such as this by promising increased height to short people. Though some might see it as an opportunity to change or select the phenotype of an individual, in reality this paper has a far greater significance. The identification of HMGA2’s role in height
is an important breakthrough in the study of complex quantitative traits, and it demonstrates the power of new genome analysis techniques that are coming online. As Frayling and his colleagues suggest, the true power of this technique will be when it is applied to the study of complex diseases.

This article was originally published in BioWorld Perspectives (vol 1 # 46) in November 2007 and is reprinted here by permission from AHC Media LLC.