Genomics 101

According to the latest American Cancer Society statistics, about 40% of the population of the United States will develop cancer some time during their lifetime. In 2007, one in four deaths in the U.S.(559,650) is estimated to be due to cancer, the second most common cause of death in the U.S., exceeded only by heart disease. These numbers are rather daunting unless you consider that at least half are preventable by lifestyle adjustments. Cancer is caused by two factors - your genetics (nature) and your environment (nurture).

To understand your nature, you need to understand the relationship between DNA, genes, proteins and disease. The easiest way to begin your education is to view an excellent short video, courtesy of the National Human Genome Research Institute, called Exploring Our Molecular Selves. The more you understand, the better equipped you will be to ask questions of your health care providers. Educating yourself will ensure that you will be making an informed decision and working collaboratively with your medical specialist to select the best treatment available.

What are genes? The genetic instructions for the development and function of living organisms are contained in a large molecule called DNA. This molecule is divided up into 46 chromosomes, 23 inherited from your mother and 23 from your father. It makes it easier if you think of the chromosomes as books or better yet two 23 volume sets of encyclopedias. Each book can be broken down into genes or chapters. It’s those genes that direct the cell to assemble small molecules called amino acids into larger protein molecules.

This ladder-like DNA molecule that contains our personal instruction book is made up of four smaller molecules that create nature’s language: adenine (A), guanine (G), thymine (T), and cytosine (C). The rungs of the ladder, called bases, are our letters, and they pair to each other in a very specific way. The A always pairs to T and the G always pairs to C. No other arrangement is possible. These four letters can be arranged into sixty-four different three-letter "words". These words are molecular codes that represent the twenty amino acids we just talked about, as well as some very important directions like start or stop making a protein.

This 64 word code directs another part of the cell to assemble those amino acids into a huge number of proteins that differ in sequence, shape and function. Strings of amino acids in funny shapes are the building materials and enzymes that are you and if something goes wrong with how they are assembled you may have a problem.

Genetically any two human beings differ by only 0.1%; we are 99.9% the same! That 0.1% is responsible for the physical differences that we see, our disease susceptibilities, and the metabolic differences we experience when taking medications. Patients diagnosed with the same disease respond differently to the same medication. Some are cured; some end up in the hospital and the rest experience something in between. Personalized medicine is about matching the right drug with the right person, but without an accurate tool to measure those genetic differences prescribing pharmaceutical treatment is nothing more than an educated guess.

Understanding gene environment interactions is particularly important because the chronic diseases that face us today are recent developments, occurring over only a few generations. These diseases are complex and multifactorial, that is, they are caused by a complex interplay of multiple genes and environmental factors. These factors are in the physical environment as well as in the behavioral and social environments. Genomes can’t change over such a short period of time but our environments have, leading to adverse effects on individuals who are genetically predisposed to respond poorly to these new challenges.

Advances in personalized medicine will be possible if it is known how these variations differ between healthy and sick people, and how individuals with particular variants of DNA are affected by environmental factors. For more information on personalized medicine please refer to the following website. http://www.ageofpersonalizedmedicine.org/

How do our genes cause cancer? At the moment of conception, all the information needed to build you is stored in the nucleus of that single cell. Some of the genes are variants that predispose you to any number of diseases, cancer being one of the most important. Most humans have half a dozen to a dozen of these variations which may lead to single gene diseases like cystic fibrosis, Tay Sacs and sickle cell anemia. These are only three examples of the thousands of rare inherited single gene mutations found throughout the world.

Cancer may have an inherited component but it is a multi-gene disease, which means that mutations in a particular cell start to accumulate during your lifetime. These are called somatic mutations and are not inherited. When a cell goes from one cell to two cells, it has to reproduce the over six billion bases that make up the code as well as the cell structure. Does the cell make mistakes? Yes, but there is a very elaborate correction system in place to limit the number of mistakes, as well as other genes that maintain a proper growth rate. This system is not perfect, though, and mistakes are not corrected leading to those somatic mutations.

These accumulated random mutations differ not only in the different types of cancer but also in different individuals. Other factors, epigenetic, are also involved in changing the activity of genes that do not involve the genes sequence being altered. Since the genes behavior does not involve a change in the DNA code it is not considered a mutation. Most cancers are now considered to be a mixture of genetic and epigenetic changes.

Cancers are generally classified by the organ they originate in only because physicians have lacked the ability to classify them genomically. Our cancers differ because our mutations and epigenetic conditions differ. The most pressing issue is what causes the genetic and epigenetic changes? Are they caused by substances in our environment, our lifestyle, a genome that isn't perfect or a combination of all of the above? One thing is for sure, your genes are involved, and without the proper genomic information medical intervention is often a trial and error process leading to unnecessary or inappropriate treatment. This is about to change in a very big way leading to truly personalized medical care.

What do we mean by "gene expression" and how do we measure it? A little journey back to your roots, when you were only one cell, should help. A fertilized egg is unbelievably complex. Think of the city you live in with all its houses and streets, doors and windows, power lines, sewage system etc and it isn't as complex as you were at the one cell stage.

Now, think what it would take to make an exact copy of your city. An exact copy! Just considering time alone it would probably take decades but "you" did it in hours when you became two cells. Obviously all the raw materials were available for this construction project but what about the communication and coordination. "Gene expression" is about communication and coordination and the ability to very accurately listen to that dialogue is one of the foundation blocks of modern genomic medicine.

When all your genes, your genome, are in sync you are disease free. Over time factors that may or may not be under your control alter the dialogue among hundreds of genes. Some "over express", talk too loudly, others "under express", talk too softly and some shut down and don't talk at all. It doesn't take a rocket scientist to realize that when communication breaks down the end result is something less than perfect - a disease. Think about any activity in which you participate that requires quick and accurate communication and you are just beginning to appreciate what goes on in your trillions of cells.

How do we record that conversation? A gene is nothing more than a code that directs how a protein gets assembled. Proteins can be enzymes, regulators, supporters, defenders, communicators and transporters. Proteins R Us! To make these proteins genes send out coded messages that can be captured. The more a particular gene's protein is needed by the cell the more messages it sends. The key to capturing this information is accuracy and sensitivity. What this means is that you capture only and all the messages you are interested in.

Think of a crowded room with hundreds of people talking all at once and you only want to key in on one person's words. It has its difficulties. Now think of that same room and capture at least 100 conversations simultaneously with an accuracy of 99%. The ability to capture all those messages at close to 100% accuracy is at the heart of personalized medicine. The genes we are listening to (100 or more conversations) have been identified by researchers as those that are at the heart of a particular disease. It is probably pretty apparent to you that different diseases involve different genes but it might not be so obvious that the same disease may involve different gene expression patterns in different people.

What are nano-biochips? Iris BioTechnologies is in the business of putting genetic information on silicon chips to be used as diagnostic probes. Our biochips measure the expression patterns of genes that researchers have implicated in cancer or other diseases. The information you have just waded through is essential to best understand how our probes work and how they will benefit you. We only need to add two more words to your working vocabulary - complementarity and hybridization.

With a little bit of chemical manipulation, DNA can be cut up into thousands of pieces using biological scissors called restriction enzymes. Add the right amount of heat and these pieces will come apart at the ladder rungs, where the bases connect, to create millions of molecular half ladders. If we cool things down a bit each half will hook up to its complement, the other half of the ladder. That’s complementarity and it is very specific, only allowing opposites to connect.

We use this principle when we build our Nano-BioChips. We want to capture the mRNA molecules that are coming from the genes of a cancerous tumor. We put specific half ladders that represent all the known genes that researchers have determined are involved in cancer. The tumor mRNA is tagged with fluorescent dyes and pumped into our chip system. When a compliment is found, the two connect (hybridize) according to the A-T G-C rule.

These reactions will occur in the presence of millions of molecules that are similar but not identical to the target genes mRNA. In other words, we can find particular pieces of hay in a haystack. This hybridization process is illuminated by a strong light to excite the fluorescent molecules, photographed and analyzed by a computer. The gene profile test sample is then compared to our reference database with regard to the natural history and treatment response of a group of very similar patients. This will enable healthcare practitioners to more accurately determine the presence and classification of a particular disease and provide an accurate early assessment of risk.

With this information, physicians will be able to monitor the progression of the disease state and help identify the most appropriate treatment. In essence, the information provided by Iris BioTechnologies will help improve medical decision making in a way that will revolutionize the way in which medicine is practiced.