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Personalized medicine is a hot topic in diagnostics today and has attracted major buzz in the popular media. But what, exactly, makes medicine personalized? What role do in vitro diagnostics play? Who are the scientists working right now to make personalized medicine a reality, and what are they up to?

To learn more about the details and potential of personalized medicine, IVD Technology editor Richard Park spoke with Leroy Hood, MD, PhD, cofounder and president of the Institute for Systems Biology (Seattle). In this interview, Hood explains what systems biology means and why he believes it holds great promise for the future of personalized medicine. He defines P4 healthcare and discusses the blood diagnostics that will be a part of it. Hood also talks about the start-up company he is forming, Integrated Diagnostics, and where he plans to take it over the long term.

IVD Technology: Please provide some general information about the Institute for Systems Biology (ISB), including a brief history of ISB and the primary areas in which it is involved.

Leroy Hood: The Institute for Systems Biology is a non-profit research institute created in 2000—the first research center focused on systems approaches to biology and medicine. The Institute believes that a cross-disciplinary environment is essential for systems approaches and believes that the frontier problems of biology should dictate the associated technologies developed and computational and mathematical tools created. The Institute has pioneered the development of genomic and proteomic technologies as well as systems approaches to microbes, yeast, innate immunity, infectious diseases, cancer, and neural degenerative diseases. It has pioneered new blood diagnostic strategies and the necessary technologies needed to discover, validate, and type biomarkers. It has opened new directions in the applications of genomics and proteomics technologies, and it employs model systems of varying complexity—halobacteria, yeast, mice, etc.—to develop new understanding of biological mechanisms as well as push the development of new technologies and computational tools. It currently has about 250 staff and 14 faculty members. It has recently negotiated a $100 million agreement with the state of Luxembourg to attack the most fundamental problem in P4 medicine (predictive, personalized, preventive, and participatory)—the analysis and integration of genome information with molecular and cellular phenotypic information to create predictive models of health and disease.

The big transition that’s occurred over the last eight or nine years is that initially I started the institute to focus on systems approaches to biology, and for the last four or five years many of the faculty have focused almost entirely on a systems approach to disease, or “systems medicine.” As a consequence of this, I began thinking about how to transform diagnostic techniques to deal with disease, and even drug discovery and drug toxicity.

So, we have, for the last four or five years, made some striking conceptual and applied advances in in vitro diagnostics. Our major focus is on the blood because it is an organ that bathes all other organs, and all of these other organs secrete proteins into the blood that can be used as reporter groups for differentiating health from disease states.

Please define systems biology and explain what it means to you.

In essence, systems biology is a holistic rather than atomistic approach to understanding biological function. The last 40 years of biology have focused largely on studying individual genes and proteins in isolation from the systems of which they are a part, but for the first time we can take a global, comprehensive approach to looking at all genes or all proteins and see how they change across the development of physiological responses or the progression of disease.

To give a simple example of what systems biology is, suppose you wanted to figure out how a radio converted radio waves into sound waves. You might first take the radio apart, then catalog the individual components, and perhaps even attempt to understand what the individual components do in isolation. Biology has, for the last 40 years, done just that. We’ve studied individual genes or individual proteins and categorized what they’ve done in isolation. And, of course, the transformational advance that the Human Genome Project gave us was that, for the first time, we had a complete parts list of all the digital information of the genome so that we could assess the responses of all genes or all proteins to experimental perturbations.

The second step in understanding the radio would require that you assemble its component parts into circuits, and then understand what the circuits, both individually and collectively, do in this transformation process of converting radio to sound waves.

In fact, systems biology in living organisms follows exactly the same kind of logic. Living organisms have biological circuits or networks that handle information, and the information is processed and employed to generate phenotypes for development of physiologic responses, or, in cases of disease, for pathologic transformation.

The fundamental idea in systems medicine is the simple hypothesis that disease arises as a consequence of the perturbation of one or more biological networks. In the diseased organ, that perturbation changes the envelope of information that’s expressed by these biological networks; this altered information changes dynamically during the progression of the disease. This changed envelope of information actually encodes the pathophysiology of disease. But as well it allows us for the first time to start taking systems approaches to diagnosis, to therapy, and even eventually to prevention. That is the essence of the strategy that we’re developing for P4 medicine.

How has ISB been involved in doing research for and developing in vitro diagnostics? What are ISB’s strategies in terms of looking at blood diagnostics?

About five years ago we started experiments with prion disease in mice. This is a degenerative neurological disease. We experimentally initiated this disease through prion infection of the brain, then followed the change in RNA level information expressed in the brain. We compared at multiple time points across the onset of disease the messenger RNA levels between normal and diseased brains. This subtractive analysis let us look only at the mRNs changed during disease progression. We developed a variety of biological and computational techniques to reduce the enormous amount of noise that was present in these data. We generated about 50 million data points in this analysis. From these date we identified a core of 300-some genes that seemed to be the essence of the prion pathologic disease response. We were able to show in terms of network behavior that this core set of genes explained virtually everything we knew about the pathophysiology of prion disease. But even more, it told us about aspects of the disease that never before had been discovered.

One of the really interesting points it raised was the demonstration that the change in patterns of gene expression in these animals occurs much earlier than the onset of clinical signs. So one of the first questions we asked is, “Do some of these transcripts that have changed before the onset of clinical signs encode proteins that get secreted in the blood, and can we see altered levels of these proteins in the blood so as to be able to do preclinical or presymptomatic diagnostics?” The answer was yes.

Now, where this obviously would be very exciting is if we could do it for cancer, where early detection could result in more-effective early treatment. From a systems point of view, something was still missing in the strategy for blood diagnostics because most of the proteins that enabled pre-symptomatic diagnosis were synthesized in multiple organs, so if they changed in the blood, one couldn’t be sure that the change came from one organ like the brain, which is the major organ in which the pathology of prion disease was focused.

So, the next step we took in a systems view of diagnostics was to ask, “Can we identify organ-specific transcripts through a comparative analysis of the messenger RNA populations of 40 major organs in humans and in mice? Does each of these 40 organs have transcripts that are uniquely expressed in that organ?” The answer was that there are 50 or more organ-specific transcripts for most organs. We went on to demonstrate that a reasonable fraction of these organ-specific transcripts then encoded proteins that were secreted in the blood. So, what was exciting, then, is we had a brain-specific blood “fingerprint,” which contained about 30 proteins. The level of each of those proteins reflects the operation of the cognate biological network in the brain that encodes each protein; hence, in a normal brain, these brain-specific proteins will be expressed at one level, and if one or more of the brain networks are disease-perturbed—say, by Alzheimer’s—the levels of the corresponding blood protein would change to constitute an Alzheimer’s-specific blood fingerprint.

This suggests that our collection of 30 brain proteins would generate unique concentration patterns that would allow us to uniquely distinguish health from disease, and, given disease, the fingerprint changes would be unique for each disease because each disease perturbs differing combinations of biological networks.

So here, for the first time, we can do blood diagnostics where we’re certain that we know the locus of origin of the change in going from health to disease, and secondly, we actually can begin to make predictions about the biological implications of altering the corresponding cognate biological networks. This is a powerful new approach to blood diagnostics that we’ve been pioneering over the last four to five years.

In the future I see us developing organ-specific blood fingerprints with 50 or more proteins for each of, say, the major 50 human organs, and actually having routine biannual tests that would allow us to measure these 2500 proteins and distinguish health from disease. I can see that as a major part of the transition over the next 10 years, where we’ll go from a focus on health versus disease to a focus on wellness.

From a diagnostic point of view, these fingerprints let us do four really interesting things. First is presymptomatic diagnosis. Second, if given a disease, we can stratify the disease. That is, there are different types of prostate cancer; they need different kinds of therapy. The diagnostics that I’m talking about will be able to stratify those diseases and determine which will be the most effective therapeutic agents for each. Third, if given a particular type of, say, cancer, we can actually follow its progression, and in the future I would argue that treatment will be a function of the stage of progression as well as the type of cancer. And four, these diagnostics will be useful for following therapy and assessing the effectiveness of treatment. I would guess that over the next five years, this new type of organ-specific blood diagnostic will really come to encompass many different aspects of medicine.

Parenthetically, you can use the organ-specific fingerprints from the liver, the kidney, the heart, and the muscles to assess drug toxicities. These are all organs where major drug toxicities occur; we can use them to assess an early clinical trial—whether side effects or toxicities are occurring on these sites that are off the main target of the drug—or we can use them in personalized medicine to assess the individual’s response to a given drug. A systems view of diagnostics opens up a realm of really exciting new possibilities.

What sort of partnerships and alliances has ISB formed with IVD manufacturers and companies in the IVD industry, and what sort of diagnostic technologies has ISB developed as a result of its partnerships?

We are in the process of negotiating a series of company-strategic partnerships right now. We have not finalized any of them. The strategic partnerships tend to be more in the realm of companies that have uniquely powerful technologies rather than those that do in vitro diagnostics.

What we are in the process of doing is creating a platform company for personalized medicine called Integrated Diagnostics. It will use this strategy of organ-specific markers to execute the various aspects of disease diagnostics that I discussed earlier. This company will also make use of some powerful new technologies that we’re developing that will create protein-capture agents that are more effective, more stable, less expensive, and easier to use than, say, antibodies.

We are also developing microfluidic protein chips that, in time, will easily allow us to take a fraction of a droplet of blood and make 2000 organ-specific protein measurements, so that we can carry out the more global blood-protein organ-specific analyses. We have made, however, a series of strategic partnerships with individuals at academic institutions, and in one case with a company. One of our major strategic partnerships is with Jim Heath, a brilliant chemist at Caltech, with whom we’re working on these new protein-capture agents and on the microfluidic chips.

Relatively recently, we’ve consummated a strategic partnership with the state of Luxembourg that involves three objectives. The fiirst is setting up a center for systems biology mimicking our institute in Seattle. The second is pioneering two major research projects that lie at the heart of P4 medicine—analyzing genomic information and analyzing phenotypic information and integrating the two so as to create predictive models about future health history and consequences of disease. Finally, we’re working together on the creation of Integrated Diagnostics. For the two research projects, we will receive about $100 million over the next five years. We hope this will be a major new transformational effort in bringing P4 medicine to fruition much sooner.

Could you provide some information about the current state of Integrated Diagnostics and where you hope to take this company in the long term?

We hope to make it the definitive diagnostics company for personalized, or P4, medicine. We hope to use the organ-specific fingerprint strategy to identify a few proteins that permit us to diagnose particular diseases—Alzheimer’s, for instance—and include in this panel those that can carry out presymptomatic diagnosis—that is, diagnose disease very early before there are any clinical signs whatsoever. That, obviously, will be important for cancer, too, because it will allow the initiation of early and hence more effective treatment.

We also hope to stratify individual diseases. For example, in prostate cancer, perhaps 80% of the cancers are relatively benign and really aren’t going to hurt the individual, whereas the other 20% can be very malignant. What happens with many of the 80% of the patients that have benign prostate cancer is that they get treated with radical surgery, radiation, or chemotherapy. A substantial fraction of these exhibit morbidity such as incontinence or impotence—and this costs the medical system many billions of dollars per year. So if we could just stratify prostate cancer into those you should treat and those you shouldn’t treat, we could save the American healthcare system tens of billions of dollars a year.

These diagnostic markers can, given a particular disease type (stratification) of, say, a tumor, assess how far that tumor has progressed. That will be important in the future, because treatments will change with increasing progression of the disease.

Finally, these markers will be absolutely terrific for following response to therapy and assessing whether the diseased organ is returning back to a normal behavior. We think these panels of blood markers will be very powerful in catalyzing the transformation from our current reactive medicine to P4 medicine.

What is the impact of the complete sequencing of the human genome on the development of IVDs?

I think the major effect that the complete sequence analysis of the human genome had on medicine is that it gave us a complete parts list of all human genes, and from that complete parts list we have easy access to essentially any gene product through PCR analysis. This makes it easy for us to use biology to identify candidates as diagnostic markers, and then obtain and test the genes in a relatively quick and straightforward fashion.

Why hasn’t molecular diagnostics reached the growth levels that many had expected, and what are your impressions of future prospects for molecular diagnostics?

I think many people really misunderstood the implications of the Human Genome Project. It was nothing more than the creation of a parts list. Yet it became touted as a list of many different potential drug targets and many different potential diagnostic markers.

What people are just beginning to realize is that if you are to do diagnosis or therapy, it isn’t just a matter of knowing all the genes; rather, it’s a matter of creating biological strategies and chemical approaches to the delineation of the right kinds of products for therapy or diagnosis.

So the Human Genome Project really had little to do with diagnostics, and virtually nothing to do with designing drugs. It just gives us the complete parts list of human genes. To think that the Human Genome Project would magically transform medical diagnosis or therapy is extremely naïve.

What both diagnostics and therapeutics will require are deep, thoughtful, powerful new strategies for the selection of appropriate candidates. I’ve outlined one here: the organ-specific blood fingerprint, which I think is really going to be transformational. You can ask why, in spite of the fact that we’ve spent billions of dollars on biomarkers over the last three or four years, has almost nothing come of it? The answer is that we haven’t had the right strategies for diagnostics. I think the organ-specific blood strategy is a powerful approach that will catalyze the initiation of the first two P’s in P4 medicine—predictive and personalized. Ultimately, organ-specific blood diagnostics are going to move us toward a focus on wellness of the individual rather than disease of the individual. This is, of course, the third P—preventive.

What role will genomics and proteomics continue to play in developing IVDs, especially molecular diagnostics?

There are two parts to the identification of blood diagnostic markers of disease. One is the discovery and preliminary validation of these markers and the preliminary demonstration that they will be useful to medicine. This requires the typing of perhaps hundreds of controls and individuals with disease. Two, if we’re going to use these markers on tens of thousands of indivduals and eventually on hundreds of millions of people, we must ask, “What are the typing technologies that will let us do this on a very large scale?”

With regard to discovery and validation, I think both classic genomics and proteomics are going to play very important roles in the discovery and prevalidation processes. I think proteomics will play an essential role because the basis for our organ-specific blood-fingerprint strategy is the quantification of proteins. We have developed microfluidic chips that will in time be capable of analyzing thousands of proteins quickly, cheaply, and quantitatively, and this can potentially be done in a doctor’s office. We will need this type of methodology if wellness tests will require biannual analyses of the organ-specific fingerprints from the blood of each individual.

What are your views on personalized medicine?

I think personalized medicine is a major opportunity for medicine over the next five to 10 years. The reason I have cited P4 medicine is that I think personalized medicine has many more dimensions that are usually considered (predictive, preventive, and participatory)—and I think it is important to emphasize the full dimensions of this revolution in medicine. The revolution in medicine is going to transform it from its currently reactive state to the four Ps: predictive, personalized, preventive, and participatory. The essence of personalized medicine is the acknowledgment that humans are genetically diverse. Your genome and mine differ on average by 6 million letters of the DNA language, so our bodies carry out their common functions in distinct ways.

You simply cannot take a population of humans and have averages of various important medical parameters. Rather, each person is going to be the control for his or her own transition from health into disease. That means we’re going to have to gather, for each individual, really detailed molecular information in a longitudinal sense so we can determine what’s normal for the individual and then identify transitions into disease states.

In your opinion, are the companion diagnostics that are currently available for personalized medicine appropriate and acceptable, or do IVD manufacturers and IVD companies need to do more to contribute to personalized medicine?

I think the revolution in P4 medicine is going to be led by powerful new diagnostic strategies. I would argue that we’re just at the very beginning of creating powerful new diagnostic strategies and tools. And I would say those tools really ought to have several important features. First, they ought to be measurements you can take from the blood, because the blood bathes all organs, and all organs secrete or shed proteins into the blood; hence, you can use the blood to assess the status of all organs. I also think it is very important to have strategies for identifying the markers that will allow us to address where changes or problems are occurring.

Using organ-specific blood proteins as markers and indicators of where pathology is occurring is really a systems approach to diagnostics. The idea is a simple one: organs operate by virtue of many biological networks, and the individual proteins that are organ-specific represent one or more networks that are responsible for their synthesis. These protein levels change when you move that network from being normal to being diseased. Those changes then get reflected by the blood when they are secreted into it.

So in a sense, organ-specific fingerprints for a given organ—the brain, say—give us a means for distinguishing health from disease in the brain, and, if disease, the fingerprints would then be unique for each type of disease. Alzheimer’s, other neural degenerative diseases, and glioblastoma, a tumor of the brain—each of those would perturb different networks or different combinations of networks; and hence, there would be different levels of these organ-specific proteins represented in the blood.

A very, very important part of personalized medicine is the pharmaceutical side. So in order for these powerful new diagnostic strategies to emerge and to come to fruition, doesn’t there have to be a very strong and essential pharma side?

Yes; however, big pharma is extremely conservative and quite skeptical of new strategies for doing anything, whether it’s diagnostics or approaches to therapy. The question of whether you need to persuade big pharma of new approaches in order to have them be realized, or whether in fact you demonstrate success without them is an interesting question. I am sure there will be a few pharma companies that will realize the power of these new systems-diagnostics opportunities; most will be very skeptical. The real issue is whether big pharma produce drugs in a cost-effective way and in a reasonable timeframe. They will have to do this in the context of smaller drug markets than the blockbusters, because of the heterogeneity of a given disease. Systems diagnostics will allow us to stratify these diseases into the various types. This stratification can then be used to identify the drugs that will work for a given disease type. Hence, drugs will need to be discovered for much smaller markets than big pharma has sought in the past.

It is worth noting that big pharma is spending significantly more money now than they have in the past, yet they are producing far fewer drugs. And, frankly, the drugs they are producing, for the most part, are not very effective.

My view is that the systems approach to medicine will provide transformational ways of identifying drug targets—and do so rapidly and effectively. I believe that systems diagnostics will really provide the companion drugs that are now represented by herceptin diagnostics and a few other examples.

Now, are big pharma companies going to buy into this? Most big pharma will not buy into systems strategies. I suspect that smaller drug companies and biotech will come to understand the opportunities. And then big pharma will buy them when the results are successful. Thus, I think success will be the driver of systems approaches rather than a total dependence on big pharma.

In addition to whatever issues exist with the pharmaceutical companies, what would you say are the primary challenges to personalized medicine eventually becoming a regular part of routine clinical practice? And when do you envision all of this potentially happening?

I think some of the major barriers and challenges of P4 medicine are going to be not in dealing with the technical barriers, but in dealing with societal barriers; that is, questions of intellectual property, security of information, ethics, of who will have access to the enormously increased amounts of information we’ll have on individual patients, and, most particularly, questions of payers and providers and the extent to which they’ll accept these new strategies and new ideas. Because, in the end, if payments are not forthcoming, P4 medicine will not become a part of the practice of medicine.

The companies that do personalized genomics—Navigenics, for instance—are representative examples of catalyzing society’s concerns about social and ethical issues. Is it appropriate to know that you have the ApoA4 gene and hence an increased susceptibility to Alzheimer’s when you can do nothing about it? Those are all important issues to discuss.

Leroy Hood, MD, PhD, is cofounder and president of the Institute for Systems Biology (ISB, Seattle). His research has focused on the study of molecular immunology, biotechnology, and genomics. He has published more than 600 peer-reviewed papers, received 14 patents, and coauthored textbooks in his areas of expertise. He can be reached via Todd Langton, ISB’s associate director of PR and communications, at tlangton@systemsbiology.org.