All opinions are my own and do not necessarily reflect those of Novo Nordisk.
Last night I had the great opportunity to hear Maynard Olson give a public lecture on Genomic Medicine. As one of the founders of the Human Genome Project, he’s been around in a pivotal role for much of the revolution in our understanding of the genome. A revolution, as he himself points out, that we are still just beginning.
He gave his speech as part of the UW Genome Sciences Department’s summer lecture series, and spoke to a packed auditorium about how the information we are learning about the genome has implications for diagnostics, therapeutics, and public policy. I’ve heard Maynard speak before, and he’s always refreshingly down-to-earth, candid and measured in his descriptions and comments. Not for him are flights of speculation or hyperbole, and he actually ended his talk with a call to stop the hype. As he said, “The product is solid. It doesn’t need hype.” Maynard, who is slim, with a fringe of red hair that’s silvering at the sides (kind of like Reed Richards), does not look at all near his age of about seventy years.
His talk was broadly broken into four sections. The first part, a nod to a broad audience which included a fair number of high school kids and even some kids who looked younger (although maybe it’s just my eyes that are getting older), was a general overview of genetics including the central dogma. Maynard included an invitation to any high school students who might want to form a study group to look at and learn more about DNA sequences and how they function. He encouraged those students to find his email address on the web and get in touch. Which led to the one of the first jokes of the evening when he paused and added, “And if you can’t find my email address, in this age of search, you might want to brush up your skills because searching things online is most of what genomicists do these days.” Funny, and also true. He ended this section with a commentary on how even with our vast knowledge, so much more knowledge remains uncovered, with no real prospect that we’ll get a handle on the minute details any time soon. In his opinion, in a hundred years, understanding all the molecular parts will still be an unsolved problem.
As he said, “The weak link…is our primitive understanding of human biology, particularly at the molecular level.” He drew a contrast to surgery, which has made phenomenal strides over the past several decades and which relies on an understanding of physiology and endocrinology and pathology at the level of the whole organism, and not the molecules underlying it all.
The next three parts of his lecture covered the specific topics of diagnostics, therapeutics and policy. He noted that the early advances in application of genomic information to health are almost all on the level of diagnostics, which unfortunately widens, at least for now, the gap between information and actionable findings. Still, as he pointed out in describing the case of the Beery twins, whose genetic disease was recently solved, for many parents the desire to know, to put a name on what is afflicting their children, is in itself a relief and positive outcome, whether treatment exists or not. One of the interesting things that has come out of the initial exome and whole genome diagnosis projects has been the finding that the most challenging part is for clinicians to figure out how to use the data–what to communicate back to the families and what to do about incidental findings.
Here Maynard pointed out the real problem of how variants of unknown significance (VUS’s, kind of an echo in my mind to ROUS’s) are just that: unknowns. Even for many known pathogenic variants, it’s still unclear precisely how they cause disease. Here he pointed out examples like the cystic fibrosis gene mutations and BRCA1 breast cancer-causing mutations in a nod to Mary-Claire King, who was in the audience. How should clinicians and families deal with variants that might, maybe, possibly have some kind of effect on health?
Still, use of genomics is entering the clinic, and not just for orphan diseases. Maynard spent some time describing how oncology (as so often happens) is a the forefront of using this kind of information to help treatments be tailored to specific individuals. In some types of cancer, such as acute myeloid leukemia (AML), certain mutations are associated with better long term survival rates than other mutations, giving doctors and patients information on decisions like whether to undergo a bone marrow transplant or not once a patient is in remission.
The trickier question, addressed in part 3, was about new treatments. In drug development there’s often a sense if the cause can be identified, that helps lead to a cure. That’s sort of true, but it vastly oversimplifies the complexity of drug development. Would I, as a drug development researcher, want to know what causes disease X? Sure. Will that suggest an immediate small molecule or protein target or approach for a cure? Frankly, often it does not.
When talking about therapeutics, Maynard brought out a lance he’s been using for years to tilt at the windmill of established process. Why are we going for single targets, he asked, when we know from examples like cancer that we want to hit multiple targets at once to have the best chance of success? He illustrated this with an example from the Journal of Oncology, in which a clinical trial for a BRAF inhibitor in a melanoma patient resulted in remission at 15 weeks, but recurrence at 23 weeks. Strikingly, the new tumors appeared at the same sites as the initial ones. This suggests that cells resistant to the treatment were already in the initial tumors, and so hitting just one pathway (BRAF) was not enough. Instead, hitting tumors with more than one drug is almost necessary to achieve full remission. He also drew upon the example of HIV therapy which relies on a cocktail of drugs to combat the mutable nature of HIV. However, Maynard had to acknowledge the barriers of intellectual property that keep these kinds of combinatorial therapies from happening more often.
Maynard ended this part of his lecture with a discussion of how we could be taking an approach toward variant analysis which refreshingly did not have a cute acronym: Candidate Exploitation of Conditional Beneficial Loss of Function Mutations (CBLOFMs). In this category he put variants such as the LDL-receptor related protein 5 mutation that leads to greater bone density, and the myostatin mutation that leads to greater muscle mass, and the PCSK9 mutation the greatly reduces Low Density Lipoprotein (LDL) levels, all of which can be construed as having potentially beneficial effects if put in the right context. For example, Amgen is close to launching a drug targeting PCSK9 to reduce LDLs in patients with high cholesterol.
The last part of his lecture concerned policy and the use of genomic information for precision medicine, and he discussed a National Academy of Sciences report for which he was a co-author, and in which is discussed the need for a different approach to medicine that relies on building an information commons And in that commons, “the patient should be the nexus around which information if organized.” Maynard also speculated on the role of patient advocacy groups, and how they could be fundamental in helping make this new orientation happen. As he described this vision, he commented that the actual immediate need is to accumulate enough information and not get bogged down in individual genome storytelling: “taxonomy, not narrative.” Maybe it doesn’t sound so sexy, but it is a necessary step.
At the end, Maynard stepped back from the podium and mopped his brow (it was hot), leaving us all more enlightened about how genomics will inform our future health.