From Genome to Bedside How Far Have We Come?


 

A wave of excitement swept through medical science in 2003 when the first sequencing of the human genome was completed. News stories were full of enthusiastic predictions of a revolution in health care.

However, good science takes time. In the early years, as researchers laid the foundation for applying the new information, the spotlight shifted to other headlines.

Now, 13 years later, those who haven't been keeping a close watch on the field might be surprised by the scope of genomic applications being used in patient care. Rather than revolution, it was a process of evolution, with advancing technologies and new findings building on each other and gaining momentum until now when we are beginning to see the promise of genomics making a difference in patient care.


Bruce Korf, MD, PhD

"Even before the human genome was sequenced, we were integrating genetics into medical practice to identify inherited disorders like cystic fibrosis. We could counsel couples with a family history of Huntington's Disease so they would have a clearer picture of whether their child would be at risk," Bruce Korf, MD, PhD, chair of the UAB Department of Genetics and director of the Heflin Center for Genomic Sciences, said. "Today, a baby's genome can be sequenced noninvasively through a sample of its mother's blood, and an eight-cell in vitro embryo can be examined to rule out single gene disorders before implantation."

A large and rapidly growing list of disorders has been associated with specific genes, gene combinations and mutations. Researchers around the world are contributing to shared databases to aid in the identification and treatment of hard-to-diagnose diseases.

"We're making progress in prevention," Korf said. "If a patient inherits a gene or if a gene mutates, we may not be able to keep that from happening, but by identifying the gene early--in some cases at birth--we can begin early intervention to influence the course of the disease and perhaps have an effect on morbidity."

Treatment is another area where genomic medicine is beginning to make a difference.

"Cystic fibrosis is a single-gene disease that can occur with different mutations. We have two drugs that can help improve lung function in patients who have one of two mutations. We can examine the gene and identify patients who are likely to benefit," Korf said.

"Cancer is another area where being able to look at the genes involved can be tremendously helpful in predicting which patient is likely to respond to which medication. Under the microscope, two cancers can look alike, but their genes and response patterns can be very different."

This is where genomics is becoming a major factor in drug development for many disorders. The differences in how specific genes respond to various agents is also a cornerstone of research into the causes and potential treatments for a broad spectrum of diseases.

One of the world's foremost researchers in the inherited disease neurofibromatosis, Korf works with the genetic tools and techniques he teaches to medical students at UAB and writes about in textbooks on medical genomics that are being used to educate the next generation of physicians.

There are two questions those in genomics hear often. First, when will medical science be able to repair or replace the genes that are causing so much suffering? And, when will we all have our genome sequenced?

The answer to the first question is that gene editing is happening now in labs in animal studies. And clinical trials using gene therapies for conditions that have no other treatment are underway. However, any therapy that attempts to change the DNA in the cells of a living human's body must be approached carefully. Also, many disorders seem to involve the interaction of multiple genes and epigenetic factors. Those interactions need to be better understood before attempting to untangle them. This is where a great deal of ongoing research is targeted.

To answer the second question, Korf said, "In 2003, sequencing the first human genome cost $100 million. By 2007, the cost was down to $10 million. Today, an exome, the segment of the chromosome where mutations are often found, can be sequenced for around $1,000. An entire genome can be sequenced for about $1500. Adding the time and expertise to analyze the data, counsel the patient and cover associated costs would bring the total into the neighborhood of $6,000. Costs should continue to come down.

"The limiting factor is not so much dollars as it is data storage and having enough people trained to interpret the results," Korf said. "Multiply the number of genes in one body by the entire population, and we would soon be dealing with a volume of information that would grow beyond our current data storage technology. However, data storage technology should continue to advance."

Korf said that, even now, there are some concerns in sequencing that may need to be addressed.

"The first question is what time in life do you sequence the genome? Done at birth, it may pick up potentially serious diseases that occur in childhood that might be avoided with early intervention. But mutations that occur due to exposures later in life would be missed. If sequencing is delayed until adulthood, then some will die from childhood diseases that might have been avoided. Perhaps as costs come down, sequencing can be repeated as needed," Korf said.

"Another concern is what do you tell patients about incidental findings? If you are looking to confirm whether a patient has a treatable disorder and find that they are also at high risk of a currently untreatable dementia or cancer later in life, do you tell them?"

Some will want to know, and some won't, and that can be discussed before testing. If it is a test for a child and the parent doesn't want to tell them about a potential problem, does the child still have a right to know when they reach adulthood?

"The American College of Medical Genetics and Genomics issued guidelines recommending that labs look for pathogenic mutations in 56 genes associated with severe medical disorders for which there are proven interventions prior to onset of symptoms and to return those results to the referring clinician. This is likely to continue being a topic of discussion and the list is likely to change as more diseases become treatable," Korf said.

The science of genomic medicine is evolving at an ever-increasing pace. It has reached a critical mass where genes are becoming more relevant in the everyday practice of medicine and in understanding the causes of disease and the most effective strategies for maintaining health.

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