Defining “biocomplexity as the investigation of complex adaptive systems in all disciplines of biology,” the Life Sciences Commission stated in its report that this initiative “will be of foremost importance for developing a fundamental understanding of life.” It also will have “great integrative power” because the tools developed in pursuit of this initiative will be widely applicable to a range of problems and disciplines.

The Biocomplexity Initiative, which would be administratively based in an institute, will draw together theorists, biophysicists, mathematicians and mathematically-oriented biologists to develop models that integrate empirically derived information about biological systems ranging from single cells to complex organisms to many organisms interacting in ecosystems. Developing a theoretical framework for the study of complex systems will provide the foundation for this initiative.

Work done in this initiative also will help provide “an intellectual theme and integrative glue” between the other proposed initiatives, and “bridge the gap between existing strengths at the University in ecology, evolution and environmental science programs.”

A look at three different complex systems provides a hint of the opportunities afforded by this initiative:

• Most of the major events in cells are interrelated. Scientists must find a way to categorize the hierarchical structure of cells, determine how the parts interact and are controlled, and understand how the many cellular processes adapt or respond to changing conditions.

• The central nervous system is a complex adaptive system that has many parts that interact and learn, but it is impossible to assign function to individual parts or neurons without descriptions of interactions with other parts of the system. Advancing research in this area now depends on understanding the feedbacks and “circuitry” of the system, not just the component parts.

• Ecosystems—the integration of living things with their non-living environment—are changing rapidly, and understanding the causes and consequences of these changes is critical for sustaining and improving the quality of life and environment. Study in this area requires an integration of knowledge across ecology, evolution and environmental studies.

There is a “natural alliance” between the existing Program for the Study of Complex Systems (PSCS) and this initiative. The PSCS centers on the study of biological, social or physical systems in which feedback, regulation and adaptation play an important role in the system’s dynamics. PSCS and the initiative complement each other, and “together they offer an initiative and an educational effort not even approximated at any other university.”

Strong programs in a variety of University units—the museums, School of Natural Resources and Environment, College of Engineering, School of Public Health, Matthaei Botanical Gardens and the Biological Station—contribute to the foundation on which this initiative can be built.

Strength also is found in environmental studies, defined as an area outside the natural sciences that includes the humanities, economics, social sciences, and environmental policy and management studies.

Biocomplexity Initiative researchers will have to work through immense amounts of quantitative data to determine the principles and laws with predictive power that can be abstracted from the data and how best to apply the resulting information.

“This integration of theory and data . . . is the single most critical aspect of theoretical advancements in any field, and one major role of the Biocomplexity Institute will be to foster this integration in all aspects of life sciences at Michigan,” the report states.

This initiative would be responsible for launching a series of “Michigan Workshops” that would be focused on one or two interdisciplinary themes that would change from year to year. They would function as starting points for exploring and devising new themes and offer a “unique, high-visibility forum” for the University.

Other elements of this initiative include:

• Faculty Sabbatical Fellowships for six-month to one-year periods.

• Team-taught undergraduate and graduate courses on “Issues in Biocomplexity” and a program of graduate and post-graduate fellowships.

• A “superspeaker” series in which five to six scientists would visit campus, present seminars, and meet with students.

With most of the significant advances in the life sciences owing to novel enabling technologies, biotechnology can “dramatically enhance every aspect of the life sciences, and translational research can apply basic science advances to dramatically improved health care and enhanced quality of life.

Through this initiative, locally developed advanced technologies will provide basic scientists and clinical researchers with tools to conduct work not possible at other institutions. In addition, “technology-driven translational programs will stimulate countless opportunities for technology transfer.

This initiative has two foci—the use of physical science and engineering technologies to open new directions in research and the translation of basic biological knowledge into clinical applications. The Commission recommended two parallel courses of action—creation of an interdisciplinary Biotechnology and Translational Medicine Institute and significant enhancement of existing University units essential for biomedical and translational activities.

Success in this area will be based in part on the availability of research core facilities and “competitive and efficient” translation of successful innovations to the public sector. “Financial growth from capitalizing on innovations could additionally strengthen the research infrastructure and promote renewal of life sciences research support,” the report adds.

The Commission’s report identifies several “immediate targets of opportunity” in biomedical engineering:

• Bioimaging. Long considered a diagnostic tool, imaging now is an exciting tool for the researcher, with many of the advances in this area led by U-M researchers. “Over the next five to 10 years,” the Commission predicts, “‘imaging beyond diagnostics’ will become one of the major research themes for biomedical engineering at Michigan and elsewhere.

• Nanobiotechnology. The development of microdelivery systems, microanalytical systems and biosensors will enable researchers to monitor and provide feedback about biochemical and electrical events at the cellular level.

• Tissue engineering. Can we produce artificial organs that are functionally equivalent to native organs? In situ cell culture techniques may enable tissue regeneration for diseased organs. This would eliminate rejection problems and might serve to replace whole organ transplantation in some applications.

• Bio-Compatible Materials. Tissue scaffolds, on which cells arrange themselves to function as living tissue, are key to clinical applications of tissue engineering. A key question to be explored is whether artificial scaffolds can be developed that fully mimic the environment necessary for cell differentiation and growth and whether the tissues manifest appropriate characteristics for transplantation.

Similar opportunities are offered in translating basic biology into medical applications:

• The path from fundamental research in cell biology to medical treatment is often a long one, but has made possible many advances as in the treatment of cancer. We now know that cancer can have many causes, that vulnerability to cancer can be genetic, and that environmental events can play a role in inducing it. Armed with this information, scientists can devise a wide range of strategies for dealing with cancer.

• The genetics of human disorders is one of the most exciting areas of research, utilizing basic advances in molecular genetics and increasingly sophisticated technologies for understanding the genetic basis of both rare and common human diseases.

• Mouse models of human disease are expected to be employed by researchers in a vast array of relevant in vivo models to study human diseases.

• Bioinformatics will be a powerful central tool for researchers for analysis of large bodies of data, organization of databases and extraction of knowledge that might not otherwise be discernible in systems ranging from the subcellular to the ecosystem level.

The University, the Commission report notes, “is presently very well-positioned to make major advances in biotechnology and translational medicine. Key resources include the PET Center, the fMRI Center, the Center for Neural Communications Technology, the Solid State Electronic Lab and the Center for Ultrafast Optical Science, as well as the new Center for Biologic Nanotechnology.

Resources related to general medical translational research include the General Clinical Research Center, Comprehensive Cancer Center, Center for Gene Therapy and biomedical core research facilities, many housed within the Medical School but open to researchers campuswide.

The institute formed under this initiative would leverage the combined strengths of the Medical School, College of Engineering and LS&A, with the new Biomedical Engineering Department and Center for Biomedical Engineering Research at its heart.

It would operate flexible, revolving laboratory facilities to house multiple translational cores at different stages of development. Translational laboratories in bioimaging, biosensors, tissue engineering and drug discovery/delivery would provide bridging of primary scientific, clinical and engineering advances with the researchers utilizing the technology.

The Commission identified several areas requiring attention for this initiative to accomplish its multiple goals, including a program to sustain and enhance facilities critical to translational medical efforts, regular renewal of technological research equipment resources, and a concerted and multi-step effort of technology transfer to move advances to the commercial world. “It is absolutely critical for this to be done with efficiency, speed and agility,” the report states.

The Commission also recommended additional support of the General Clinical Research Center “for highly innovative, highly technical clinical trials based on new devices and approaches,” a human tissue procurement program, a biomedical core laboratory for a mouse genetics core and immune response detection and monitoring, additional space for the Unit for Laboratory Animal Medicine, and support for required oversight and regulatory committees.

“Genetic information provides the common language of life. A major increment in understanding the role of genetics in biology will require insight into how genetic information is translated and organized at increasingly sophisticated levels to sustain life processes. . . . a program in genetics represents a vital part of any future effort in the life sciences at the University of Michigan.”

The Commission identified three focal points for this initiative:

• Genomics—the study of genomes, including comparative genomics.

• The application of genetics to understanding complex systems and the genetic basis of human disease.

• Gene therapy and genetic approaches to biotechnology and drug discovery.

“An obvious aspect of future genetic studies relates to the complexity of multicellular organisms,” the report states. “The Commission feels that new approaches and integrated interdisciplinary efforts will be required to reduce the complexity of higher order biological events and provide concepts which can be readily understood.”

• Comparative genomics. Work being done in comparative genomics “is in the process of revolutionizing our understanding of the evolutionary process, and has provided biologist with a powerful new arsenal of weapons to use in the analysis and understanding of biological phenomena,” the report states. “In this work, information concerning the similarity as well as the differences in function of related genes in evolutionary related organisms will be critically important.”

• Biological complexity and complex disorders. Organisms thought of as relatively simple exhibit complexity, defined by the interaction of whole groups of genes to cause certain functions. This role of gene-gene and gene-environment interactions is more pronounced in the study of humans.

Novel tools are needed in genetics and genomics to unravel the mysteries of this biological complexity, including microchip or array technology that makes it possible for researchers to examine “patterns” or “profiles” of gene expression across thousands of genes.

Work in this initiative will rely heavily on bioinformatics, which would provide the necessary powerful algorithms for pattern recognition that will help interpret the data, and much of the data derived here will be of value to theoretical approaches described in the Biocomplexity Initiative.

Research in this area holds promise in the development of new drugs, as well as the development of interventions using sophisticated techniques to replace defective genes that lead to specific disorders.

Although suffering from recent erosion due to the departure of key researchers, the University nonetheless has a number of strengths that create a strong foundation for work in this area.

The Center for Gene Therapy coordinates gene therapy research and draws on the strengths of a variety of other programs and centers. A number of targeted clinical and basic research programs have been established, as have several specialized core facilities.

The Commission recommends expanding current cores and adding a molecular diagnostics core facility. The University also must address the significant loss of key scientists and the loss of the Human Genome Center, which has had a number of repercussions, including the loss of some infrastructure that facilitates research for the genetics and biomedical community at-large and a loss of momentum in the development of state-of-the-art technologies relevant to this field.

The Commission calls for bolstering of core facilities and programs through the addition of a family studies core, sophisticated data management facilities, genotype and sequencing facilities, microarray technology, and expanded facilities for transgenic animal models.

Building on strengths in medicine, LS&A, public health, engineering, law, education and the Institute for Social Research, this initiative includes a section to address ethical, legal and educational issues.

“The Life Sciences Commission,” the report states, “feels that there is a very narrow time window for Michigan to recoup its losses in this area. This is a critical choice point: either we move forward forcefully, or we slide back significantly.”

“It is imperative that this and other initiatives not only recruit the very best scientists, but that the University establish optimal conditions for the retention of top-notch scientists among our ranks.”

Our growing ability to study the molecular details of biological macromolecules provides fundamental insight into the functional properties of biological molecules and suggests routes by which they can be manipulated.

There are strengths in several areas to support launching this initiative. They include the Department of Biological Chemistry; the Biophysics Research Division, which gives the U-M a substantial presence in structural biology; increasing strength in chemical biology in the Department of Chemistry; and a strong group in biological structure and function in that department.

This initiative would complement and enhance recruitment efforts in chemistry, pharmacy and biological chemistry and serve as a focal point to bridge biology and chemistry.

Three areas of “intellectual excitement,” the Commission’s report notes, “capture the essence of leading research at the chemistry-biology interface and represent significant targets of opportunity.”

• Discovery and design of small molecule regulators of biological function. Chemical genetics uses natural products and other small organic molecules to probe the biological functions of proteins and other biological assemblies, affording a unique way to probe and modulate function at the genetic level.

“Combinatorial chemistry,” the report notes, “has already revolutionized drug discovery in the pharmaceutical industry by providing new therapeutic leads more rapidly than in the past.”

A program in this area would enhance traditional strengths and provide numerous translational opportunities.

• Macromolecular structure and function. A true understanding of biology can only come from knowledge of macromolecular folding and structure. As more gene sequences become available, methods to uncover the structure and function of the proteins and RNAs encoded from these DNA sequences must be developed. This is now possible due to advances in molecular biology, protein/nucleic acid chemistry and analytical instrumentation.

Mass spectrometry has become an essential complement to classical methods of molecule characterization. For the U-M to make significant strides in this area, it must embrace the new technique of electron crystallography. Computational approaches also will play a significant role in work done under this initiative.

• Evolution of structure and function. Comparing gene sequences from subjects as different as bacteria and humans gives us a brand new molecular glimpse at evolution. This information will help provide the fundamental information on how life on Earth evolved and is changing in response to environmental influences.

Experimental, computational and theoretical approaches can be envisaged for research in this area, with bioinformatics enabling comparative analyses across a range of organisms or across a range of functionally related macromolecules.

The proposed Chemical and Structural Biology Institute would provide a focal point for investigations of high resolution structural and functional properties of important biological molecules and complexes. It would house equipment necessary for structural biology research and specialized, high-tech facilities for learning about structures.

The Institute also would serve as a focal point for graduate training in chemical and structural biology. The University already has a successful undergraduate biochemistry concentration and a joint graduate program in this area is being discussed.

Research through this initiative would have a natural overlap with bioinformatics, functional genomics, neurobiology and biotechnology.

This initiative will focus on the study of the biological basis of cognition, the process of “knowing”—how one learns, remembers, perceives and recognizes objects, how one reasons, solves problems and uses language.

Historically rooted in the field of psychology, work on understanding cognition now is moving to the biological level, and represents a new frontier in the fields of psychology and neurobiology.

The goal of this initiative is to bring closer together two approaches to the study of cognition—bottom-up or molecular, and top-down or integrative—by making the molecular approach more integrative and the integrative approach more molecular. This will make it possible for scientists to achieve a more complete understanding of the biology of cognitive processes.

Commission members note in the report that this work “is not only of intrinsic interest, but it will likely have profound implications for understanding daily human behavior. In addition, this knowledge will be directly applicable to the understanding and treatment of many brain-related disorders,” including age-related memory disorders and Alzheimer’s disease, psychiatric disorders such as schizophrenia; and mood disorders such as severe depression.

Since more than one-half of the human genome is expressed in the brain, the Genome Project will have a huge impact on the field of cognitive neuroscience. The development of increasingly sophisticated neuroimaging instruments, such as MRI and PET, makes possible visualization of the living brain—in terms of structural features and functional activity.

A broad range of unanswered questions in cognitive neuroscience are amenable to biological analysis. The major challenge is the rarity of establishing a one-to-one correspondence between a given gene and a function of the brain. A large number of genes, interacting in the context of complex circuits, are responsible for orchestrating any given behavior.

A number of questions can be addressed through this initiative:

• What genes are responsible for memory in animals, how are they expressed in the brain, how do they interact with each other? Are there different patterns of genes activated in different brain locations depending on the content of the memory being studied?

• How do we link the molecular information in animals to more complex types of memory and cognition seen in humans?

• What goes wrong in certain memory diseases?

• Can we generate new treatments, including new drugs, to treat specific types of memory deficits?

The Commission envisions this initiative as “the building of a critical bridge spanning two areas of existing strength—neuroimaging of human cognitive processes and molecular and functional neurobiology.”

The University has more than 75 laboratories distributed across many schools, departments and units, along with the degree-granting Neuroscience Program that serves to link this community of labs.

The existing strengths on which this initiative can be built include a strong presence in molecular neurobiology, cell biology and neuronal signaling, strong clinical departments (psychiatry and neurology) and the Cognition and Perception Area of the Department of Psychology.

Commission members write in the report that the “neurobiology of cognition is a true research frontier” that is relatively unexplored and offers “exciting opportunities for great discoveries.” They also note that “given the central theme of the Life Sciences Initiative, cognitive processing offers one of the most intriguing manifestations of the complexity in life processes.”

This initiative will be structured as a Center for Cognitive Neuroscience designed to link the various resources on campus in a productive manner, “while respecting the fact that many of these entities carry out functions that go beyond cognitive neuroscience.”

The Center will need a critical mass of investigators as well as rodent facilities and an open attitude with respect to the acquisition of technological tools as advances are made.