Genetic Tests

All about interpreting

Stephen M Sammut, Senior Fellow, Wharton Health Care Systems, University of Pennsylvania and Venture Partner Burrill, Company,USA.

\"Profiling can be inherently valuable, but we must keep it in the perspective of the entire picture of a person’s health, lifestyle, environmental factors, and the like.\"

1. Christopher McLeod, President of 454 Life Sciences was quoted as saying, "It's the dawn of a new era when you can look at not just all the genes, but all the genetic information that an individual has. We're just on the cusp of making that economically feasible." Is the hype associated with Genetic-testing justified?

To get started, we really have to define what we mean by “all the genetic information that an individual has.” While it is the case that at some given cost, which is rapidly dropping, individuals will be able to have their genome sequenced in much the same way that James Watson, co-discoverer of the structure of DNA with Francis Crick and Rosalind Franklin, recently did with 454 Life Sciences, a division of Roche. But what is it that Dr. Watson really knows after his profiling? At the age of 78, he did decide to exclude information that might indicate a predisposition to Alzheimers, if present, there was no real meaningful intervention. This, however, is the crux of the matter before us. At the present time we really do not know the full range of genetic markers that might suggest a predisposition to Alzheimers.

What does “predisposition” really means, or what factors will trigger onset of the disease (if it ever presents itself at all), and at what point will the disease, if ever, appear. The implications of most diseases are most grave when they appear in the presence of other diseases. In the United States for example, according to a study prepared by the Bloomberg School of Public Health at Johns Hopkins University, about two-thirds of all healthcare costs are absorbed by people with five or more chronic diseases. Studies in Japan have come up with similar results for their society. This makes for a murky picture and suggests that any genetic profile of a person will require hundreds of statistically verifiable correlations before anyone can draw a definitive conclusion. Moreover, some genetic factors in any given person may mitigate risk suggested by other genetic factors. Each of us is heir to the genetics of our parents, grandparents and so forth, as well as their health and intervention histories.

Profiling can be inherently valuable, of course, but we must keep it in the perspective of the entire picture of a person’s health, lifestyle, environmental factors, and the like. So is it “hype?” I wouldn’t go that far by any means. It is legitimate enthusiasm provided that scientists, clinicians and people bear in mind the real limitations of what we really understand in 2007, and where we will inevitably go as we learn more and integrate the knowledge with preventive care and response to disease.

2. This is a highly knowledge-dependent sector. With each company carrying out its own research, will they be ready to share their valuable knowledge? If not, how will this affect the industry?

You raise a critical issue here. There are companies with proprietary instrumentation that allow for rapid reading, and presumably cheaper reading, of a sequence. These companies can compete based on what is unique to their own equipment platform. There may be cases where they mutually infringe some aspect of the equipment. There may be cross-licensing resolution of these issues, or even down and dirty infringement suits. These are generally engineering problems that can be circumvented by clever scientists and engineers. A good IP attorney doesn’t hurt, either.

The real question with the interdependence of knowledge has more to do with “ownership” of genes, and we have to be clear what “ownership” really means, and the true limitations. This is still an open area of intellectual property in the United States at least, but I suspect that we will converge on international principles related to genomic-related patents. At the end of the day, however, some level of proprietary rights will attach to the discovery and description of the role of the gene, that is to say, the role of proteins expressed (in patent-speak, “utility”). Therein rests the problem. In almost all diseases, there will be multiple genes or mutations implicated in either predisposition to a disease or the disease itself. At the present time, the portfolio of genes apparently related to a disease condition are “owned” by many parties. A company interested in developing the profiles as a business, and then providing interpretation, may have to contend with an enormous patent thicket the resolution of which will take many years and significant layering of royalties. Regardless of the engineering efficiency of given instrumentation, this will impact costs and delay entry thus driving up the required investment capital.

3. What could prove to be the hurdles to the growth of the industry?

Beyond the IP issues that I’ve just outlined, I suspect that the major challenges to the industry will be a combination of clinical and social issues. On the clinical side, we have many unresolved problems in the interpretation of results. For many years, there has been testing available to counsel aspiring parents as to risk for Tay-Sachs, cystic fibrosis, sickle cell anemia and other diseases. These are specific and testing of the parents is generally a solid indicator of risk for their offspring. In most cases, the would-be parents are working under a “hypothesis of risk” based on family history or related factors. The results of the testing can be interpreted by genetic counselors that can appraise the risk and assist families in making decisions. This long-standing clinical practice is not necessarily analogous to the interpretation of results for most diseases based on genomic profiling, and certainly not in the case of the enormous amount of data that will have to be interpreted. Counselors will be aided by software to be sure, but ultimately advice will have to be rendered. There is, of course, a business implication of interpretation of the genome as a whole and comprehensive counseling based on that. The implication is one of cost. Even supposing that good engineering can get the cost of a profile down to, say US$ 1000, it may require many thousands beyond that to derive an accurate interpretation and set of recommendations. Myriad Genetics, however, has a business model that anticipates these issues and focuses on specific diseases and can provide a comprehensive set of services, interpretations, recommendations and access to reimbursement. Their approach may well be the best interim business model.

The bigger issues, however, will be social and ethical. At the moment, I really would not want a prospective employer or insurer knowing (or thinking that they know) something about my predisposition to a disease (Note “thinking that they know”). As I submitted above, we really are not knowledgeable enough yet to understand the full picture of disease implications. Drawing conclusions that might result in discriminative action is clearly not in the interest of society or people. In times to come when we have a fuller understanding, viable interventions, privacy safeguards, and the clinical care settings for administration, then the testing will make incontrovertible good sense. It is fair to say, however, that for selected risks where we do understand the genetic underpinnings of a disease, that those patients with the emotional and psychological make-up to handle and act upon the information would be better off having it. Again, of course, that their privacy is protected.

One other area worth mentioning is the role of genetic testing as it relates to the testing or use of a particular pharmaceutical agent during clinical trials or general use. It is the case that roughly one-third of all pharmaceuticals have no effect or adverse effects on people. Genetic testing may well identify those people who will benefit and those who will not. The clinical benefits of such technology are obvious. Genentech’s breast cancer products, Herceptin and Her-2, are already a good example of how a drug and diagnostic can marry. This concept is one of the foundations of “personalised medicine” which will become a clinical reality rapidly.

In the interim, we will have to rely on “early adopters” or pioneers to participate in the testing and provide the social framework for going forward.

4. How has been the initial response from the medical community to genetic testing products?

With respect to specific, well established tests for specific diseases, testing has largely been embraced by clinicians, especially when they know that they can provide their patients with viable advice or intervention. Let’s keep in mind that this is a new area of medicine that will demand an enormous amount of learning by physicians as well as quality time with their patients before and after the testing. At least in the US, this is running counter to the trends in care over the last two decades during which physicians have been forced by reimbursement policies to process patients through a gauntlet of allied health professionals prior to spending ten or so minutes with their patients.

5. The industry is yet to come up with a proper business model, are the ones being tried out by companies like Genomic Testing, 23andMe and DeCode likely to survive over the long run?

You’ve actually lumped three companies with entirely different business models together. I’ve already described Myriad Genetics and their well-structured model. DeCode’s primary business is discovery of drug targets and interventions in collaboration with academic health centers, such as Massachusetts General Hospital, and pharmaceutical companies. The model is essentially sound, but the economic rents that can be extracted for any given products or services that result from their data are not clear to me. Nevertheless, when I first learned of DeCode, I was enthusiastic about their mission and approach and that enthusiasm has not waned despite some setbacks.

23andMe hypothetically addresses some of the issues I identified previously. Google, its investor, has other extraordinary initiatives underway in knowledge management and data mining, and genomic interpretation is an interesting manifestation of their activity. The strategy of 23andMe still begs the questions as to sufficiency of data and reliable insight into the relationship of specific genes or sets of genes to disease, but the concept is based on filling the interpretation gap.

With respect to the company Genomic Testing, I would rather address the model of companies doing genomic testing (the lower case “g” and “t”) generally as opposed to this company specifically, Several companies have entered or will enter the service area of running genomes, especially as laboratory costs drop. These are the companies that may have the biggest challenge operationally, especially in marketing their services, assuring people of confidentiality, and figuring out where they want to be along the spectrum of interpretation. There is enormous liability risk for these laboratories, not because they will get the genome wrong, but they will inevitably get the interpretation wrong more often that getting it right. Clearly, they will have to figure out where they can safely play in the value chain.

6. How can the industry address issues related to Ethics and data security in the future? Is it too early to start worrying?

It is not too early to start worrying, in fact the debate started even before the Human Genome Project was approved and underway. As I commented earlier, data security will be a major hurdle for acceptance of this technology. If insurance companies pay for the testing, they will likely want the results. To what extent can I trust a lab or an organisation that does the interpretation? Any company can establish a sound protocol for patient protection, but mistakes happen even under the most diligent of circumstances, witness the recent enormous breech of patient data in the Japanese health care system.

7. How much longer is it likely to be before it becomes economically feasible to provide genetic-tests?

Allow me to summarise a few of the points that I’ve already made. The actual laboratory costs of testing are not the issue. They will inevitably drop, even to the point where the cost is trivial relative to other costs in the healthcare system.

The fundamental economic issues are the costs associated with interpretation, the massive time-shifts that are likely to result from how this data is communicated to patients, and the paradigm shift that will have to occur in changing medical care philosophy from one of reacting to disease to preventing disease. For many decades people have cavalierly said that the medical community does not promote preventive medicine because there is no money in it for anyone, except perhaps the nutritional supplement companies and the manufacturers of exercise equipment. I am deliberately cynical here in order to make a point. Genomic testing performed to identify disease predisposition for the purpose of early intervention will not be cheap. Yes, sometimes it will be merely a matter of exercise and better diets, but in most cases the options will be expensive intervention with life-long medicines, gene-therapy (yet another set of issues), or frequent monitoring, e.g., annual colonoscopy. Most of these preventive measures will essentially shift the cost from treating disease to preventing it. It is not simply a matter of “pay me now or pay me later.” Unless our predictive skills are near-perfect, we will spend scarce money preventing diseases that might never have occurred, and possibly doing so over a life time. I have said elsewhere that if a woman has a predisposition for breast cancer, do you start intervention at puberty, in her twenties, or after childbirth. We will eventually know the answer. Personally, we are unanimously in favour of prevention, but let’s not delude ourselves to the economic implications. This will be a new world of medicine and a new world of healthcare costs.

8. What does the industry need to do to ensure that this happens?

Frankly, this goes beyond the capacity of the industry to address directly. The companies and their advocates—and the advocates, including myself, are many and include influential politicians, business leaders and celebrities, many of whom are “putting their money where their mouths are”—have the challenge of convincing the political and medical communities that despite the sea-change that will follow in the costs and practice of medicine that there is the potential of revolutionary advance in the progress of humankind. We all have the moral obligation to assure that this new care will not be an option for only the “haves” to the exclusion of the “have nots.” This worries me because most of humanity is still awaiting access to essential medicines, vaccines and basic care.

9. Amidst all this, where do the patients/consumers stand currently and what does the future hold for them?

If consumers think the way I do, they are also in a state of shock and awe. My comments probably suggest that I might be over-thinking the issues. I would say in response, so are a lot of people inside and outside of medicine.

The direct benefits to consumers, i.e., an intervention for a specific predisposition, are not on the immediate horizon. That is so reason not to move ahead with alacrity. The potential mass of data—if we solve the privacy issues—will be of enormous benefit in the discovery of drugs and other interventions to address the very same predispositions that will be found with a basis of confidence. And the discoveries may come as fast as the visionaries suggest.

Society and those of us in the business of healthcare will, for the foreseeable future, be in a period of vast experimentation seeking optimal modes of the technology, the most productive and sustainable business models, and sensible approaches to integrating this unprecedented knowledge into healthcare and our lifestyles. It is an interesting time to be alive, and the younger among us may live longer than ever imagined.

Author Bio

Stephen M Sammut