I recently attended a conference in Boston and wrote up summary for XConomy. That post is here.
Thursday, February 18, 2010
I am just returning from the Tri-Molecular Conference in San Francisco and one strong theme emerged
- There is lots of enthusiasm for molecular diagnostics
- There is lots of disappointment about molecular diagnostics
- The simpler and more actionable the solution the more likely it is that somebody is starting to make money on it
I spent a good part of the first day walking the aisles of the trade show looking for potential collaborators to push molecular data into Electronic Medical Records (EMRs). To my amazement, the majority of people in the trade show were involved in molecular diagnostics on some level but very few (actually none) could point to clinical applications.
I vented some frustration about this during a roundtable discussion later in the day and I was corrected pretty quickly by some very knowledgeable people. The problem was that I tended to define molecular diagnostics through my own lens of pharmacogenetics, but the applications that are gaining adoption on a large scale are much simpler, unambiguous, and actionable. Two key applications were molecular tests for gonorrhea (have you noticed that people always lower their voice when they say gonorrhea?) and H1N1.
This was just the first illustration of the point repeated many times over three days that molecular tests with unambiguous unambiguous and actionable results are rapidly adopted and tests with uncertain results and questionable actions are not yet. This is really an obvious now that everyone has spent so much money trying to do the cool complex stuff first.
Sunday, November 22, 2009
Tim Hunkapiller has always warned me against expecting instant gratification from genetic data. His reasoning is that if Common Diseases were caused by Common genetic Variants they would have been selected out of the population long ago. So while there are some significant heritable diseases, we should not overestimate the clinical utility of common variants.
With this in mind, the insights that you can gain from standard genotyping panels today are limited because they are based upon common variants. Since many of the current personal genomics companies built their business on Genome Wide Association Studies of common variants they have been limited to informational services sometimes derided as “genomic tourism”. The layoffs at 23andMe or the bankruptcy of deCODE are symptoms of the fact that there is a limited market for products that have limited actionability. We are beginning to see Gartner’s technology hype cycle in action with the personal genomics industry rapidly descending into the “Trough of Disillusionment”.
This was highlighted this week at a roundtable discussion Personal Genomes: Promise or Hype? at the University of Washington. Sydney Brenner thoroughly enjoyed his role as curmudgeon in residence by thoroughly ridiculing the nascent personal genomics industry. He compared genomics to astronomy explaining that astronomy had split into astrophysics and astrology. The non-subtle point was that the PG industry was more akin to “genology” than to genetics.
For me his dismissive attitude was somewhat surreal considering that he was sitting next to Mary-Claire King. As he was speaking I recalled the account in James Watson’s DNA that described a woman with a frightening family history of breast cancer who avoided a prophylactic bilateral mastectomy because of insight from Dr. King’s research. In fact later in the week 23andMe and Navigenics responded to a critique in Nature by pointing out that even though the BRCA mutations explain only a small fraction of the population risk for cancer, those people who have dangerous variants have significantly increased individual risk.
I also recalled a pharmacogenetics presentation by Dr. Gualberto Ruaño to physicians at a mental health hospital. The premise of PGx is that a relatively small set of genes metabolize a large number of drugs. Variants that are very common in the population cause either a lack of efficacy for drugs or synthetic disease in the form of adverse drug reactions. Psychoactive drugs are notoriously difficult to prescribe and those doctors were pretty energized about the possibility of reducing failures that could be predicted.
Nobody seriously doubts whether genetics can inform medicine, but the key question is how personal genomics will evolve from novelty to necessity. The limitations of CDCV preclude an all-purpose clinical assay but but there are a few focused scenarios where common variants cause a predictable change in outcome. When you consider pharmacogenetics alone there are an estimated 100,000 deaths in the US per year and a remarkably high number of people have some variation in their genes that effects the way they process medications.
From a technology standpoint, focusing on these scenarios and delivering end-to-end solutions from instrument to iPhone seems like the best way to accelerate the use of personalized medicine.
Sunday, November 8, 2009
“The only hope is true innovation.” – Dr. Zerhouni
One fundamental barrier to progress is the complexity of biological processes. Up to this point we have spent a considerable amount of time and resources on the hardware of biology (DNA) but we are learning that understanding the software (pathways, regulatory networks, response to environmental insults, etc.) is essential to a mechanistic understanding of disease.
By developing an understanding of the biological pathways that allow us to function, we are beginning to understand why multiple genotypes can result in a single disease phenotype. This understanding also creates the possibility of targeting therapies at the junction points of pathways where a single intervention could potentially affect multiple diseases. The tools for this type of analysis are blunt now but they are improving. As they do, markets will begin to form around pathways that include diagnostic assays, medical devices, novel delivery systems, and therapeutics working in concert.
The state of Washington has done extraordinary work and has risen in rank as a grantee of NIH funds. It has the right skills from an academic, legislative, philanthropic, and entrepreneurial perspective to be a major contributor to global health. Given that the state aspires to have a vibrant life sciences sector, we have to recognize that the amount of funding, both public and private must keep pace with the opportunity. Currently the number of identified biomarkers doubles roughly every six months. But the explosion in data has not led to an explosion in knowledge. When you take the existing 1,500 identified biomarkers and assume $30 to $50 million to validate each one it will take up to $75 billion to analyze just the existing inventory.
An important lesson from the NIH is that culture wars are real and researchers ignore them at their peril. You cannot assume that everyone recognizes that what you do is holy (even though you know that it is). The US makes a considerable investment in public health but the results of that in investment are difficult to quantify. When this investment is called into question, researchers have to learn to engage in dialog because a dismissive approach is counterproductive and ultimately politically dangerous.
Dr. Zerhouni spoke at the Washington Biotechnology and Biomedical Association (WBBA) annual meeting on Friday November 6. His role as director of the National Institutes of Health gives him a unique perspective at the intersection of science and public policy. He introduced his talk by paying homage to Ted Kennedy assuring us that the tone and content of the current debate would be far different if Kennedy were alive to influence it.
“Life Sciences will be for the 21st Century what physical sciences were for the 20th” - Senator Ted Kennedy as quoted by Dr. Zerhouni
The worldwide cost of healthcare is rising at rate that is truly frightening. While the bills being debated in Congress now will help to increase coverage, their effect on the rise in costs is likely to be marginal because they are focused on incremental changes and not structural problems. Dr. Zerhouni offered his list of some core issues:
- Progress in acute care has caused a shift in healthcare from acute to chronic care as people live longer. Unfortunately care for chronic conditions is more expensive.
- Aging populations shift the cost structure of medicine and our models for geriatric care have not adjusted quickly enough.
- There are huge disparities in both health status and health care regionally. It is difficult to believe that one top-down system can address them all well. Healthcare in rural Louisiana is radically different in both its goals and outcomes from healthcare in Boston.
- We face both emerging and Re-Emerging diseases. Depression is emerging as one of the largest causes of disability in our country. And the dynamism of the world economy allows diseases that jump species into humans to rapidly become global threats. On the other hand “solved” acute conditions can reemerge because of health practices throughout the world.
- Obesity is a growing problem worldwide and it is insidious because solutions require difficult changes in lifestyle.
The majority of total healthcare costs are for chronic conditions. For those conditions, the cost curve rises dramatically as diseases progress from pre-symptomatic through symptomatic to critical. The opportunity for maximum savings is for early diagnosis and treatment but the current reimbursement system only pays for care after the disease is established. Treating before there is actual biological damage is dramatically cheaper.
4P medicine (Personalized, Predictive, Participatory and Preemptive) is an approach to radically changing the cost basis of healthcare. But the evolution to this paradigm will require social changes as well as technological. In order to make significant progress we need to change focus from health care to health. Imagine a world where elections were influenced by how well a constituency had progressed in key success metrics such as BMI or lifespan.
A major key to 4P medicine is to improve the diagnostic capabilities of clinicians in order to evolve to a world of precision medicine. In recognition of the financial opportunity that this represents, private funding of research has grown considerably faster than public funding. The crossover point was roughly 1991 and now private funding is roughly 2x the NIH budget. Unfortunately the productivity of research has declined for a number of reasons:
- Many of the current needs are met by current therapies
- Given the drugs that are available, new candidates compete against the best in class of existing drugs and not just placebos
- There is a lower tolerance for risk and failures are highly publicized
- Biology has proven to be more complex than expected – there was a time when we thought that simply cataloging the genome would be sufficient to make a large impact on health
- The regulatory burden is higher and our ability to predict toxicology is not very good
In many ways the effort for Translational medicine is walking backwards because of risk aversion and the lack of interdisciplinary approaches.