The Forever Fix gang: Corey Haas with book, surrounded by mom Nancy and dad Ethan Haas, Ricki Lewis on left next to Lori and Hannah Sames. At book signing 3/24/12, Barnes + Noble, Albany NY.


Tags

Glenn Nichols, surrounded by his hospice team. The author is in yellow.

Genetic Linkage

Personal Genome Sequencing: Too Much Information?

October 18, 2011

Tags: whole exome sequencing, human genome, DNA, Michael Hayden, James Watson, Han G. Brunner, International Congress of Human Genetics, Complete Genomics, Radoje Drmanac, Segolene Ayme, Joris Veltman, Luanne Hudgins, OrphanNet, rare diseases, Huntington's disease, BRCA1, Lynch syndrome, incidentaloma, Leslie Biesecker, National Human Genome Research Institute, Personal Genome Sequencing: Too Much Information?, ICHG2011

October 11-15, 6,200 researchers and clinicians met in Montreal for the 12th International Congress of Human Genetics. After my brain recovered from the long days of meetings, one panel discussion emerged as my favorite: what I thought was going to be a dull comparison of DNA sequencing technologies turned out to be a spirited look at how genome (or exome, the protein-encoding part of the genome) sequencing will impact medicine.

Moderator Han G. Brunner, of University Hospital St Radboud in Nijmegen, the Netherlands, opened the discussion by asserting that diagnostics for single gene conditions will remain the norm for the near future, “because whole exome and genome sequencing will yield an excess of information that is useless, uninterpretable, and possibly damaging to the patient.”

Each panelist had five minutes, and then the sparks flew as opposite opinions pinged back and forth.

First up was Radoje Drmanac, co-founder and CSO of Complete Genomics, which, he claimed, would soon be cranking out a million genomes a year. “We should have our genomes sequenced as early as possible. In my mind, this is not a question.” (Disclosure: I ate mozzarella sticks from Complete Genomics when I wandered into a cocktail party while hunting and gathering the evening before.)

Next Michael Hayden, of the University of British Columbia, countered with a list of hyped headlines from the ‘90s predicting how the human genome project would transform lives. “We mustn’t oversell the importance of whole genome sequencing. Results should come with a disclaimer: ‘you should not change health behavior because of this information. This does not determine your chances for getting a disease or indicate anything on disease outcome,’” he said to loud applause.

Segolene Ayme, from Stanford University, looked farther into the future of medical practice. “Instead of recognizing phenotypes and obtaining genotypes to support a differential diagnosis, it will become the standard of care to order a sequence and then predict what phenotypes might be.” But she wonders and worries about how physicians will morph into genetic specialists. “I get calls from primary care providers who don’t know the difference between a chromosome and a gene. They do not understand the concept of a sequence variant of unknown significance. How will they communicate concepts of single gene inheritance, let alone predisposition to complex disorders?”

Joris Veltman of Radboud University supported whole exome sequencing to solve diagnostic mysteries by comparing DNA between parents and their sick child. “It’s important that we look at everything and don’t think we already know what causes a condition such as blindness. It’s sometimes easier to interpret an exome than to interpret a single gene.”

The conversation looped back to caution when it was Louanne Hudgins turn. She represented Orphanet, a platform that links the genetics community to rare disease organizations. “Patients’ needs haven’t changed just because technology has evolved. They want to know the diagnosis, if family members should be warned, and if there are ways to decrease suffering and meet basic needs. I’ve never heard of a patient wanting to know about diseases they don’t have.” We’ve spent 20 years trying to figure out how to deliver the news that a person has BRCA1 or Huntington’s disease mutations, she added, “and now we’re discussing releasing information on genes we don’t know the functions of.”

After the five-minute intros, Hayden picked up from Hudgins. “I’m against providing whole genome sequencing data to patients. I’m not against doing it for research. What is clinically valid and useful? A finding that is actionable.” He ticked off examples: Lynch syndrome, familial hypercholesterolemia, and Marfan syndrome. He then introduced the elephant in the room, the unexpected findings, or “incidentalomas,” that will turn up in sequenced exomes. In the 500 exomes that Veltman’s team is sequencing to study intellectual disability, for example, one or two Huntington’s disease cases might be detected, and if the owners of those two genomes are young, they might not yet have symptoms. Should they be told? Informed consent protocols must include exactly what patients want to and do not want to know, Veltman added.

Drmanac listened attentively to the discussion of which parts of a sequence to report to a patient and which to shield. “We should sequence a patient’s genome first to find what is actionable. Just because we know what only 10 to 15% of the genome does shouldn’t stop us from having our genomes ready and available. The human genome belongs to the computer, not to a patient.”

As the audience collectively gasped, the moderator broke in: “For those of you who didn’t hear, he said ‘the genome belongs to the computer not the patient’. I think very few people will agree with that.” But Drmanac countered, “We can’t carry our sequence in our minds. It has to be in a place like a computer.“ And he wasn’t alone in his views. A few attendees saw value in genetic information not necessarily linked to a treatment. Sometimes families feel better knowing more about their disease, said a pediatrician. A clinical geneticist pointed out that researchers shouldn’t worry about incidentalomas when anyone can have a genome sequenced from a direct-to-consumer company.

Another luminary in the audience, Leslie Biesecker of the National Human Genome Research Institute, turned the conversation around yet again. “I came in an optimist about the technology, an absolute believer that it will work, but also with a keen appreciation for the fact that medical history has had many great ideas that were slam dunk gotta work, but that went down in flames. That can happen because it was fundamentally a bad idea, or just not done correctly. What everyone said on this panel is correct in one way or another. The challenge is to figure out how to reconcile these competing issues. Let’s please get some data from patients who aren’t celebrities about what worked for them, what they want and what they don’t want, so we can have a rational basis for how we care for our patients.”

The most memorable part of the symposium was when Michael Hayden challenged DNA co-discoverer James Watson’s use of the phrase “genetic losers” two days earlier, when he was on a panel of people who’ve had their genomes sequenced. Watson was referring to people with inherited disease. “The beauty of having the human genome sequence is that we recognize our own uniqueness, our links to everybody, and that we all have mutations,” said Hayden, again to applause.

Selected Works

instruction
Project to engage students in helping families with rare genetic diseases
Book Club Reader's Guide
Many challenging questions to stimulate thought and discussion.
Instructor's Guide
38 discussion questions to get students thinking and talking about gene therapy, including the science, ethical issues, and the drug approval process.
Narrative science
The Forever Fix is the uplifting true story of 8-year-old Corey Haas, who was cured of hereditary blindness just 4 days after gene therapy.
College Textbooks
A spectacularly-illustrated, clearly written human anatomy and physiology textbook, used in pre-health profession programs throughout the U.S.
A highly engaging, clearly written, beautifully illustrated introduction to the science of human genetics for the non-scientist. Now in its 10th edition.
Nonfiction
DNA reflects who we are -- but it isn’t the whole story.

Quick Links