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P4 Medicine: Lee Hood's Hopeful Vision of the Future
By John Russell

I spent last week in Seattle attending the Institute for Systems Biology's (ISB) "Intro to Systems Biology" course. It's designed to provide both lecture and hands-on lab experience for experienced researchers and newcomers alike who are seeking a handle on SB approaches. We'll publish an account of the course in a future issue of SBNL and Bio-IT World. In brief, ISB hopes this course will serve several functions, such as planting seeds for new systems biology projects, attracting potential collaborators, and generally promoting the institute's broad view of systems biology. It was a great week.

The institute was founded in 2000 by Leroy (Lee) Hood, Reudi Aebersold, and Alan Aderem. Since that time it has broken a good deal of new ground in systems biology (particularly in technology development), championed the cause of multi-disciplinary teams and approaches to solving biological questions, assembled a faculty of 12, and grown to about 200 staff.

No time spent at ISB would be complete without Lee Hood delivering his wonderfully optimistic and expansive vision of how systems biology will transform medicine. Within 10-20 years, he argues, systems medicine will prevail in a form Hood has dubbed "P4 Medicine," with these attributes:

1. Predictive
2. Personalized
4. Preventative
5. Participatory

He envisions a time when a prick of blood, twice annually, will provide a window into health and disease. Examining the status of 50 or so organ-specific proteins from perhaps 50 major organs and cell types will reveal the interactions of a patient's genome and environment. These 2500 biomarkers will guide patient care, and of course, the treatment regimes they suggest will also be informed by systems biology.

If such ideas were put forward by someone else, one would be tempted to dismiss or substantially discount them. Human health and disease are complex subjects and poorly understood in many cases, while drug discovery and development has proven to be devilishly messy and unpredictable. But Hood is not someone who is easily deterred, and his track record is impressive. While at Caltech, his suggestion to commercialize work on DNA sequencing was roundly discouraged. "I was told commercialization was crass and crude. The way I thought about commercialization was that it was transferring useful things to society," he said.

Of course, he forged ahead (that's a great story in itself), and the eventual result was Applied Biosystems - after 19 existing instrument makers rebuffed his early efforts to solicit funding. He also helped found Amgen.

During his Caltech tenure, he wanted to bring cross-disciplinary expertise - including, banish the thought, engineers - into the biology department. Everyone but the biologists thought was a great idea, he says. Hood, with some money from Bill Gates to support the project, left Caltech for the University of Washington to establish a multi-disciplinary department around molecular biology. Even then, he was discussing plans to eventually add a systems biology department. When he was later deterred from doing so by a new boss, Hood again struck out on his own, forming the Institute for Systems Biology with Aebersold and Aderem.

Along the way, he's made very substantial contributions to many technology development areas - sequencing, proteomics, gene finding - and this year was inducted into the National Inventor's Hall of Fame. Recently he's done interesting work on prion disease in mice, demonstrating the ability to identify brain-specific blood markers despite the (obviously imperfect) blood-brain barrier.

Hood has persistently presented the clearest and boldest vision of systems biology. His timetable may be off. Twenty years to develop 2500 decisive blood-biomarkers and the healthcare infrastructure required to exploit them is, shall we say, aggressive. But big sections of the P4 puzzle may well be sliding into place. The discipline for solving the P4 puzzle, he insists, is systems biology.

Currently, there are lots systems biology definitions floating about, and even ISB researchers agree there is room for nuanced interpretation. Hood, typically, is direct and clear. There are two types of systems biology, he suggests: One sets out to decipher the function of molecular machines (e.g., proteasome) and how they execute biological functions; the second seeks to identify and decipher the function of biological networks and how they "capture, transmit, integrate and disperse biological information."

In this context, Hood argues modern systems biology requires six essential features: 

1. Quantitative measurements for all types of biological information.
2. Global measurements-measure dynamic changes in all genes, mRNAs, proteins, etc., across state changes.
3. Computational and mathematical integration of different data types-DNA, RNA, Protein, Interactions, etc.-to capture distinct types of environmental information.
4. Dynamic measurements-across developmental, physiological disease, or environmental exposure transitions.
5. Utilization of carefully formulated systems perturbations.
6. Integration of discovery-driven and hypothesis-driven (global or focused) measurements. The systems biology cycle: perturbation-measurement-model-hypothesis-perturbation-etc.

Not all the technologies to handle these requirements are currently available, but they are critical to achieving systems biology's goal. Says Hood, "My philosophy is [that] advances in science, irrespective of what the science is, depend on advances in instruments and obtaining new things you can measure and visualize."

Cheaper and faster sequencing technology, for example, will be required not only to make genotyping widely available to physicians and patients, but also to enable researchers to include more patients in their studies to overcome data overfitting problems. Data overfitting currently impedes efforts to find definitive biomarkers because when you sample thousands of features (genes expressed) across relatively few patients, it's pretty easy to find a pattern and convince yourself of its validity. Researchers need larger patient samples. 

"A second need," says Hood, "is going to be the technologies and strategies for doing these blood analyses that I talked about. Being able to interrogate 50 molecular fingerprints that tell us what the organs are all about.

"A third thing is the ability to visualize a living organism at the molecular level. Where this is really critical, is understanding how the nervous system works, because it is utterly clear in the brain you've got 10>12th neurons with 10>15th interconnections and probably enormous heterogeneity. If we take any one of those neurons out and put it in tissue culture it won't remotely behave the way it does in the brain.

"The fourth thing that is utterly mandatory-and these are all interrelated ideas-we're going to have literally billion of data points on patients in the future [and] there's the question of signal to noise; that's really a deep issue. And given the signal, how do we reduce the dimensionality of this enormous amount of data to encode hypotheses? There are really computational and mathematical [advances] we need to think about."

These are just the sorts of technology challenges ISB tackles, usually embedded in an effort to also answer particular biological questions. Hood's belief that science and technology advance together is evident everywhere in the institute. For example, ISB is currently working with a neat micro-fluidic technology that can separate individual cells in channels, pulse a cell with a laser in a way that spurs incorporation of material in the surrounding media, but doesn't lyse the cell.

Development of new instruments proceeds through five distinct stages, says Hood: conceptualization; proof of principle; developing robustness; increasing speed (and economy); and then start all over. "We see this today in DNA sequencing, where there are techniques today that are three, four or five thousand times faster than what we developed back in 1986. Academics are great at steps 1, 2 and 5, terrible at 3 and 4," he says.

No surprise, ISB is busily collaborating with technology developers and contributing to the open source community. One effort is its Accelerator - "not an incubator" says Hood - begun in 2003 with a few partners, designed to fund early-stage ideas for one-to-two years, and provide space (not at ISB) and access to ISB computational and experimental facilities. ISB faculty may play consulting or scientific advisory board roles.

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Hood laments, "VCs are very conservative. They want phase 2 or later drugs. We read 300-plus plans, and funded six companies. Of the six, two have gone to second-stage funding and only one has failed. ISB gets an equity position and we see that as our endowment. We own founder's stock. What we'd really like is one of these companies to be as successful as Amgen." Who wouldn't?

Here's Hood's list of "technologies that will transform our understanding of digital and environmental information":

  • High-throughput DNA sequencing
  • Nanotechnology-miniaturization, parallelization, integration and automation of measurements
  • In vivo molecular imaging
  • Global proteomics analyses: concentrations, interactions, processing, modifications, localization and structure
  • Computational tools for capturing storing, analyzing, integrating, visualizing and modeling data (and information)
  • Synthetic biology-synthesizing biological networks, new materials, synthesizing genomes
  • Convergence of technologies-information technology, nanotechnology, material sciences, imaging, etc.-focusing on biology

Perhaps more vexing than the technology hurdles-which, characteristically, Hood believes will be surmounted-are organizational, educational, and societal challenges. Systems biology emphasizes many disciplines working closely together. Hood says strategic partnerships with academia, industry, government laboratories, and international groups will be essential, he says.

"We're thinking about setting up a P4 industrial consortium where we will search out from each of those major sectors of healthcare industries, the industry leader, or at least the industry's most venturesome companies, to, with us, take on one or more milestone and create a consortium where the knowledge can be shared among all members and we can really push the agenda forward," Hood says.

"We're also thinking about establishing one or a limited number of ISBs in other countries. The reason is systems biology is really a hot commodity and everybody wants to understand how to do it right. Creating institutions in foreign countries gives you access to new talent and opens up new fund-raising strategies. A big reason for [doing this] is funding at NIH is going to be disastrous over the next three or four years. To do big things like P4 medicine, you're going to have to go outside the traditional funding arena."

Hood is less sanguine about Big Pharma's ability to adopt systems biology and P4 medicine. He reports having talks with "one forward-looking company" but concedes he may not succeed in convincing them this is the way to go.

"What will convince [pharma] are examples of drugs that came out of these approaches that were produced rapidly and economically. The only question is whether or not, after you get those examples, it's too late for them to get in the ball game. I think what's going to happen is there are going to be a lot of younger companies who see that this is the way to do things, and they'll be getting set up to do these kind of things.

"In the past, what pharma has tended to do is merge with these companies, and it was easy in most cases because they merged to take the product and threw the company away. Whether they can merge with a company and retain its unique individuality is a question. I know of only one example (Roche/Genentech) when that's been done and that was done superbly."

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Transforming the way we train researchers and doctors is another challenge. "Today, you're lucky if the physician takes 25 measurements. That's a pebble in the ocean," he says. P4 will require many more multi-parameter measurements. One payoff will be less expensive medicine, and here's Hood's list of why that will be the case:

  • Stratification of patients into treatment groups
  • Inexpensive digitalization of measurement technologies
  • Powerful assays to follow treatment response
  • Powerful methods to identify early drug toxicities
  • Systems approach to drug discovery
  • Early diagnostics-better treatment control
  • Prevention is less expensive than treatment.

"I'm really convinced P4 is going to be here in the next 10 to 20 years and the way where we're training physicians today is completely wrong for what they need to know in this P4 medicine," says Hood. "We're trying very hard to persuade one daring medical school to take a risk and move ahead aggressively to initiate the fundamental scientific changes and educational changes that will fuel this new approach. It's not a trivial thing to do because medical schools are conservative."

Hood has met with a few "very good" medical schools. One issue he's encountered is that administrators, perhaps naturally, have their own agenda, and they see attempting anything new as part of a zero sum game. They fear the establishment of a systems medicine institute - which is hardly cheap - will steal dollars from their favorite programs, he says.

Such foot-dragging is inevitable and-to some extent-even healthy, in the sense that the stakes are high (medical care). Yet sometimes, dramatic change is needed. While the analogy is far from perfect, one is reminded of Intel's decision to abandon the DRAM business, which was increasingly cutthroat, unprofitable, and besieged by foreign competitors, and instead pursue microprocessors.

Intel transferred its top talent almost immediately away from making memory chips to creating a microprocessor business. On the one hand it was a huge gamble; on the other hand, there would always be companies willing to churn out memory chips. Intel gambled on assuming a leadership position in a new knowledge-driven technology.

Hood says he generally believes new technologies and approaches require new organizational structures: "If any of those 19 instrument companies had said yes, I don't think we (Applied Biosystems) would have done as well. And if the University of Washington had agreed to setting up a systems biology department, I probably would still be there, and I don't think we would have accomplished as much as we have at ISB."

Of course, there's more to do, and Hood has high expectations. He prodicts that innovations over the next 20 years in biology and medicine will include the following:

  • Systems approaches to biology and medicine will dominate biological sciences in the 21st century-global science networks and strategic partnerships.
  • Systems approaches will pioneer new opportunities in agriculture, bio-energy, biology, bio-remediation, health, nutrition, an understanding of human development, neurobiology and better educational strategies.
  • Systems approaches will move medicine from its current reactive mode to predictive, preventive, personalized and participatory (P4 medicine) modes-with a focus on wellness.
  • The digitalization of biology and medicine will constitute a far greater revolution than the digitalization of information technologies.
  • P4 medicine and the digitalization of medicine will enable healthcare to become cheap and easily executed, and therefore exportable throughout the globe-including to the developing world.
  • Strategic partnerships and international networks in science will allow us to attack big scientific problems.

It's hard not to be stirred by Hood's expansive vision of what systems biology and P4 medicine might - he would say "will" - achieve. Time will tell.

 
 
 
 

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SBNL ARCHIVES


A Tour of the Systems Biology Landscape
June 13, 2007

Entelos' First Year as a Public Company
May 9, 2007

Lilly: Why Singapore Is Right for Systems Biology
April 18, 2007

Towards a Cancer Interactome
March 21, 2007

Entelos Strikes Deal with J&J
February 14, 2007

Burning Questions in SB; Executives Look Ahead; Trends
January 10, 2007

The Novartis Conjurer; Outlook 2007: SB Execs Survey; Trends
December 13, 2006

Systems Biology DREAM(s) Big
November 13, 2006

Pfizer SB Chief David de Graaf Looks Back and Ahead
October 18, 2006

SB in the Hot Seat; Regulomics Conference 
September 13, 2006

Pfizer's Progress, GNS Growth, and more
August 24, 2006

Conversation with Genstruct's Keith Elliston 
July 27, 2006

Sunrise for Systems Biology 
June 15, 2006


Bio-IT World SB Links

Pathway Pioneers

Marvelous Models of Biological Systems

Pharsight Lands CRADA to Assist FDA with Modeling Initiative

FDA Mulls Drug/Disease Model Library

Welcome MIRIAM: Researchers Propose Modeling Standard

Contact the Editor
We invite your comments and feedback for this edition of Systems Biology.

John Russell
Executive Editor
 
 

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