BY GABRIELLE EISENBERG
In the 1800s, a simple monk named Gregor Mendel performed experiments on pea plants in his garden and spurred the beginnings of modern genetic research. Since Mendel, the structure and function of genes and DNA have been subject to insatiable human fascination and continuous experimentation. Among the many scientists throughout history who explored this subject, there exists a few notable figures that one can almost be certain will pop up in any introductory biology lecture. Erwin Chargaff developed base-pair ratios, and Alfred Hershey and Martha Chase confirmed DNA to be the genetic material. James Watson and Frances Crick (using photos produced by Rosalind Franklin) determined the double-helix structure of DNA, and Matthew Meselson and Franklin Stahl identified the semi-conservative nature of DNA replication. Each of these discoveries revolutionized our understanding of genetics, and by 2003, researchers were able to sequence the human genome. This amazing advancement in science and technology opens the doors to previously unimaginable medical opportunities; however, it also brings new ethical dilemmas that need to be addressed.
You may be wondering how the process of mapping the human genome works. Dr. Liyong Wang, a molecular biologist at the Hussman Institute for Human Genomics at the Miller School of Medicine, whose research focuses on the genetics of complex diseases, described the different ways this can be done. The first, more traditional method is family-linkage analysis, where samples are collected from families in which the target gene is present. Dr. Wang states, “There are 23 chromosomes and within them are microcell markers. These are used to identify DNA in an individual or related individuals, and you can genotype about 400 of these microcell markers across 23 chromosomes. Some chromosomes are longer, so there are more markers there, and some chromosomes are shorter so there are fewer markers. Since they’re across the genome, you can use the microcell markers to do a linkage analysis in families.”
However, simply using these markers is not enough, for they do not provide a clear enough picture. Because the human genome has 3 billion base pairs, using a 300 base microcell marker only shows results at every 10 megabases. Dr. Wang explains, “That’s a long sequence, so even if one marker is travelling with a disease, you still have a 10 to 20 megabase region that has hundreds of genes in it. You just know that this is a region with the disease, but you don’t know where the disease is.” Luckily, there is a solution. Dr. Wang continues, “You use single-nucleotide polymorphisms (SNPs). There are over 10 million of them across the whole genome; therefore, 10 million compared to 300 makes the resolution much higher. You do that and then use family base association to narrow down the region.”
Another method commonly used in genome mapping is the case-control method. Dr. Wang explains, “There is no linkage because there is no segregation between generations, so for a case-control design you always just do association. Right away, you use the SNP marker and do association to see which SNP is more represented in a case compared to a control and vice versa. You can do about one million markers through the genome, and then you can use a computer to predict your genotype at the next marker, where there is a reference panel that has the sequences of approximately one hundred individuals. This resolution is getting higher and higher for associated study.”
Finally, although now the whole genome can be sequenced in just a few days, researchers commonly use exon sequencing, which maps only the small percent of genes that code for proteins. According to Dr. Wang, “We focus on those exons first because if there’s a variation in the exons, it is likely to change the protein sequence and may have a stronger function impact. Although, we know from our experiments that a lot of variations in the intragenic regions are also very important for regulating gene expression. They do not directly affect a protein product, but they can affect how much a gene is expressed or where a gene is expressed, which is more relevant to the complex disease.”
Once the genome is mapped, what happens next? That’s where things get tricky. Because genetic information reveals so much about our bodies’ functions, it is very different from other health information and therefore presents challenges to medicine that have not been dealt with previously. For example, DNA is the genetic material, so what is found in your genes was passed to you from your parents, and it is what you will pass to your children. Therefore, genetic testing differs from other medical testing, for the results give information about other family members’ health. Susan Hahn, a genetic counselor at the Hussman Institute for Human Genomics, explains, “If you have an identical twin, and you wind up testing for a gene your twin didn’t want to be tested for, I’m basically testing you both because you have identical genes. It’s the same thing with testing a child for a disorder the parent doesn’t want to know about… if the child has it, you know that the parent has it. That’s an ethical issue, trying to protect people’s autonomy.”
Additionally, the knowledge you gain from these tests is permanent. Hahn elaborates, “Once you know something about yourself – once you know that you have a gene that causes some sort of health effect – you can’t undo that information. And until we can actually do something about that, and you have power from that information, it leaves you in this awkward limbo land where you might know something about yourself and what your future may hold without having any avenue to fix that issue.”
Genomics is further complicated by the fear of discrimination. In order to address some of these fears, the federal government passed a piece of legislation called the Genetic Information Nondiscrimination Act, or GINA. However, GINA has its limitations. According to Hahn, “It only protects a person in the presymptomatic state, so for example, if you have a mutation that puts you at risk for breast and ovarian cancer, prior to having cancer, GINA would protect you from discrimination. But once you get cancer, or whatever disease based on the genetic information, it doesn’t apply anymore.” Furthermore, Hahn says, “GINA does not protect against life insurance, long-term care insurance, disability insurance or any other type of coverage; it only pertains to health insurance. It also protects against employment discrimination, so an employer can’t require the information and can’t use the information if they happen upon it to make any decisions regarding hiring, firing, promoting, or paying their employees. Basically, they’re not allowed to touch the genetic information or use it in any way. And this only pertains to employers who have 50 or more employees, so small companies are immune from the legislation.”
These are just a few of the potential obstacles genetic mapping presents. However, the prospect of genomic medicine outweighs these issues. In reference to this promising medical future, Hahn states, “Genomic medicine is probably going to be the next big disruptor in medicine. It’s going to hopefully revolutionize the way we practice. Currently, medicine is focused more on a reactive than proactive approach. And what I mean by that is currently, we don’t treat people until they get sick, so there’s a lot of effort and energy that is focused on treating diseases after they occur rather than preventing them from happening. And part of that, in the health care system’s defense, is that we don’t actually have a lot in the arsenal right now to put towards prevention. And so genomic medicine is hoping to remedy that.”
Also, genomic medicine will help immensely with prescribing medications. According to Hahn, “How people respond to a medication is largely driven by their genetics… whether or not a drug works for us and what dose we should take is largely driven by our genes. At some point in the future, we’ll have genetic testing and have a profile on hand, and a physician will look at that to decide what drug and dose they’re going for that person just so that prescribing is a little more precise, you can minimize side effects, and you can increase the chance that the drug is going to work the first time.”
Finally, genetic mapping and genomic medicine will change the way we look at diseases in general. Hahn says, “By understanding the genes that put us at risk for disease and understanding how those genes are causing the disease or contributing to that disease occurring, not only does it help us identify through genetic counseling who is at risk for disease, but it also gives us avenues for new therapies. If you understand the biology behind a disorder through our genetic understanding of the disorder, then that is going to help us figure out what is going on in the body and will give us different ways to intervene so that you never get that disease to begin with. This way, you can identify people at risk and hopefully prevent them from developing the disease later on.”
It is clear that genomics easily lends itself to ethical conundrums; however, this is only because it is so novel. As genomic medicine becomes more realistic and common, more legislation will likely be passed to protect the rights of the consumer. Genomic medicine will be revolutionary, and it is only possible due to the technological advancements in the study of genetics, advancements that researchers like Mendel and Watson and Crick could not begin to imagine. And because of this progress, genomics can shape the future, creating a map to better medicine.