Foresight Update 38 Page 1

Nanomedicine: A "Classic-in-the-Making"

Multi-Volume Work Examines Medical Applications of MNT

by Richard P. Terra

In 1994, after reading every book and paper on molecular nanotechnology (MNT) he could lay his hands on, Robert A. Freitas Jr. was looking for an in-depth exploration of the potential medical uses of advanced MNT. "As soon as I'd fully absorbed Eric Drexler's 'bottom-up' paradigm," Freitas said in an interview, "I immediately realized that medicine would be the single most important application area of nanotechnology."

Then, Freitas said, he started asking around: Is anyone doing a book? Papers? Serious medical nanorobot designs? "I was astounded to discover that there weren't any. Worse, none were in progress and none were planned. This task needed doing, and I finally realized that if nobody else was going to do it, it was going to have to be me." Thus began work on what Ralph Merkle at Xerox PARC has called "a classic-in-the-making."

That year, Freitas set out to write Nanomedicine. After five years of work, the first volume of his projected three-volume treatise will be published this month by Landes Bioscience. Freitas, now a Research Fellow with the Institute for Molecular Manufacturing, has produced what is surely the most detailed technical examination of advanced molecular nanotechnology since the publication of Eric Drexler's Nanosystems in 1992. The book's impact on the perception and development of MNT could be enormous.

While Nanosystems laid the theoretical foundations for molecular manufacturing in general, Nanomedicine builds a grand structure on that foundation, in an immensely detailed look at the likely medical applications of MNT. As Drexler points out in his Foreword to the new work, "The coming ability to carry out targeted medical procedures at the molecular level will bring unprecedented power to the practice of medicine. Within a few short decades we can expect a major revolution in how the human body is healed. Nanomedicine lays the foundations for understanding this revolution and points to where it is taking us."

Though a technical work, Freitas begins with two chapters that provide context and perspective, and comprise one of the best short overviews of the basic concepts of MNT, and the myriad development pathways being followed toward its realization, to be published in recent years.

The availability of molecular nanotechnology will permit dramatic progress in human medical services. More than just an extension of "molecular medicine," nanomedicine will employ molecular machine systems to address medical problems, and will use molecular knowledge to maintain and improve human health at the molecular scale. Nanomedicine will have extraordinary and far-reaching implications for the medical profession, for the definition of disease, for the diagnosis and treatment of medical conditions including aging, for our very personal relationships with our own bodies, and ultimately for the improvement and extension of natural human biological structure and function. Freitas briefly but cogently addresses many of these implications in his introductory chapters.

The first molecular assemblers may be able to build only very simple nanomechanical systems, so the earliest functional nanomachines may be laboratory curiosities. As assembler technology slowly improves, progressively more complex and capable nanomachines will be manufactured in vastly larger numbers. Nanomedicine primarily investigates the rational design and operation of these more complex and capable nanomachines.

Even so, Nanomedicine should be very useful even to people who are most interested in non-medical applications of nanotechnology, for much of Freitas' analysis deals with nanodevice design and nanorobotics in general, and thus is much more widely applicable than to just medicine alone. Volume I: Basic Capabilities, discusses many features that will be common to a wide variety of MNT devices and applications. Many readers will likely be very impatient for the appearance of Volume II: Systems & Operations, which will deal with the issues of specific nanodevice design and operations in greater detail.

Despite its technical focus and exhaustive detail, Nanomedicine also asks us to deal with the ethical and socio-economical impacts that are likely to result from the application of MNT to health care. As Drexler writes in his Foreword, "Given its revolutionary potential, it is not too soon to examine the goals and potential consequences of nanomedicine."

In his Afterword, Ralph Merkle is even more forceful: "Nanomedicine is more than just a description of what might be, it is a call to action." Later, he adds, "Nanomedicine, working from the foundation laid by Nanosystems, develops the consequences of nanotechnology for medicine. These consequences are extraordinary, and must be both explained and publicly examined."

It is that public explanation and examination that may be one of the most forceful drivers behind the development of MNT. Questions about medical applications of nanotechnology are among the most frequent questions directed to Foresight. "History suggests that initial resistance to a novel approach is usually quickly overcome by any new medical technology that offers clear, safe, and immediate benefits to patients," said Freitas. "If nanomedicine can fulfill that promise, then its eventual development and public acceptance seems almost inevitable. And any positive results achieved by nanomedicine should reflect favorably on the larger nanotechnology enterprise."

But the potential of advanced MNT, applied to medicine and health care, also has very real and immediate personal implications. "Once nanomedicine becomes available," Freitas said, "we'll each have all the time we need to pursue our many other (non-medical) interests. But until nanomedicine becomes available, nobody can have any reasonable expectation that they will live long enough to pursue their longest-term and most interesting goals to fruition."

Hence Merkle's call to action: "The development of nanomedicine depends on us: what we do and how rapidly we do it." Merkle writes. "Research is not done by a faceless 'them,' nor is it something that happens spontaneously and without any human intervention. It is done by and supported by people. Unless we decide to support and pursue this research, it won't happen. . . . If we sit and wait for someone else to develop this technology, it will happen much more slowly. If we jump in and work to make it happen, it will happen sooner. And developing life-saving medial technology within our lifetimes seems like a very good idea—certainly better than the alternative."

For Robert Freitas, his personal stake in the endeavor is clear: "Like many in the Foresight community, I have a great intellectual curiosity about many things that may take decades or even centuries to unfold. . . . And nanomedicine can allow each one of us, personally, to survive long enough — not merely to see that distant future, but to participate directly in it. What could possibly be more exciting than that?"

Nanomedicine will be published in three volumes over the course of several years. The present Volume is the first in this series. The Foresight Institute has provided major funding in support of Freitas' research and writing of this ground-breaking examination of the medical applications of molecular nanotechnology. Continued support will be critical to the successful and timely completion of the remaining volumes of Nanomedicine. For more information on how you can contribute, see the notice about the ongoing challenge grant.

Nanomedicine, Volume I: Basic Capabilities will be available from Landes Bioscience by mid October 1999. The book can be ordered directly from the publisher via their web site.

Additional Resources

Other references on the medical uses of nanotechnology:

"Nanomedicine: Will trillions of tiny robots in our bloodstreams do physicians' work for them?" by David O. Weber, Health Forum Journal, July/August 1999. Available on the HFJ Online web site.

Biotech Futures in Berkeley

by Tanya Jones

The Krutch Theater on the UC Berkeley campus was the location for a gathering of 150 scientists, philosophers, computer professionals, and engaging individuals. The occasion was Extro4, the Extropy Institute's conference on Biotechnology Futures: Challenges of Life Extension and Genetic Engineering. The conference was held over the weekend of August 7 & 8, 1999. A diverse array of presentations were made, which we can only touch on in this brief report.

Abundant Aging Research

The rate at which age-related disorders increases depends on both genetic and environmental factors. Replicative senescence — the variable loss of a cell's replicative ability with each new generation — has been implicated in aging and is an area of expanding study. An infinite replicative cycle is seen in tumors and some rodent cells, and a reduced cycle has been associated with uncommon aging disorders. Understanding and controlling this cycle — having the ability to both encourage and prevent cell division — is critical to eliminating many forms of cancer and extending lifespan.

Dr. Judith Campisi, Senior Staff Scientist of the Cell and Molecular Biology Division of Lawrence Berkeley National Laboratory, gave the event's first presentation. She spoke on her departments' efforts to unravel the cellular and molecular basis of aging, to identify and understand the elements of genetic structure that impact the human lifespan.

Dr. Campisi suggested that the limits to reproduction may have evolved as a form of cancer protection and drew our attention to three modes of senescence: DNA damage, inappropriate oncogene expression, and telomeres.

People affected by Werner Syndrome exhibit premature aging and often suffer from at least one form of cancer. Research has indicated a "Werner gene" may be responsible for controlling the number of times that human cells are able to divide before terminal differentiation. The search for this gene is converging on a family of genes that is involved with the " degrading and unwinding" of DNA and yet is usually related to DNA repair.

For those with Bloom Syndrome, the aging deficit appears more obscure and has been linked to several different chromosomes. Bloom Syndrome has been linked to telomeres. Advanced staining techniques are revealing damage and offering high correlation to expressed behaviors.

Dr. Calvin Horley, Chief Scientist of Geron Corporation, began his presentation boldly. "There is no fixed limit to longevity," he asserted. Mortality is caused by aging mechanisms, and treatment must address both the symptoms and the underlying processes. Studies of regenerative medicine may look at the mortality (using telomerase therapy), the source of cells (using stem cells), or at histocompatibility (using nuclear reprogramming methods).

On his investigation into the growth rate of hTERT clones, Dr. Horley reported that the clones appeared normal, telomere length had been preserved, and that the simple introduction of telomerase had not introduced malignancy. This continued to be the case, even when introduction occurred late in life (within 5 doublings of senescence). Therapy caused improvements in both the maintenance and the restoration of function. Additional experiments proved that stem cells implanted in mouse muscle tissue triggered differentiation and growth of identifiable structures.

Dr. Cynthia Kenyon, of the Department of Biochemistry and Biophysics at the University of California, San Francisco, spoke of her work with the inimitable Caenorhabditis elegans.

It's public, if specialized, knowledge that mutation of the daf-2 gene (which promotes growth to adulthood) doubles the lifespan of C. elegans. Extro attendees learned that Kenyon's work has been expanded to expose daf-16 as an additional regulator in aging activity. Further examination revealed a daf-2 / daf-16 interdependency.

Kenyon also spoke on a more general level, relating a link between sensory agents and longevity. Pursuing this apparent connection using germline therapy could result in complicated and flexible treatments.

Professor John Campbell (UCLA School of Medicine) discussed just such potential in his talk on the feasibility of Germline Genetic Engineering. Changes in the germline are expressed in every cell that descends from the zygote to which that mutant gamete contributed. If an adult is successfully produced, every one of its cells will contain the mutation.

Targeted Gene Substitution is currently the preferred method for modifying DNA, and requires the corrective gene be delivered to the nucleus. Foreign DNA can enter a cell directly through injection or indirectly using chemical or electrical stimulation. Early germline efforts have produced this procedure, with its distinct, implementable steps. The disadvantages include that it is costly, intrusive, and enables only a single modification at a time.

Professor Campbell and collaborator, Dr. Gregory Stock, envision a new strategy for engineering change. This proposed "double addition" method would involve adding genetic modifications to an artificial chromosome and then adding that chromosome to the egg. If successful, this technique would offer two improvements: as a system of addition using the existing genetic system, it is less intrusive; and you may introduce many changes each time.

Campbell regards the technical concerns about advancing development as nearly solved. Inheritance is divorced from the alterations, as the gene pool would be unchanged if the chromosomal changes didn't enter the sexual cycle. A "lock" may be put on expression, if the chromosome was to remain unexpressed until the introduction of another agent, say. an artificial hormone.

Many questions remain, and we must continue to guard against the inappropriate use of these emerging technologies. The appropriate expression of the appropriate genes at the appropriate moment is a lofty goal, and there is much we don't know about gene regulation.

Social Scheming

"The selfish gene is a fiction," challenged Bear. Humans are shaped by both competition and cooperation. Our model should include both, and Bear suggests we have underappreciated the development of the "social gene". One of the implications of a competitive system is that the strong will grow and the weak will be weeded out. How to devise a means of social apoptosis that is kind to strangers?

Technology is driving this question, and cellular immortality approaches. Individual immortality may follow shortly thereafter, and we are ill-prepared to manage this transition gracefully. Bear is concerned that we will be elevating humans to this plateau with insufficient understanding of life and death.

"Stories on immortality are lacking," Vinge agreed. This lapse in enthusiasm may be reflected in the 3/10 of a year per year gain on extended lifespan calculated by the Centers for Disease Control.

"If we can get past the start-up phase, people will like it;" Vinge says, "The real risks are all the other changes." People will become more stable and happier when released from certain time pressures, but in 15 or 20 years, superhuman intelligence may exist. Can we hope to understand these intelligences when we don't understand our own, and will they help us or hinder us in our struggle to survive and flourish?

Foresight's Chris Peterson stood up with a host of others to form a panel called "Reports from the Front". Chris caused the crowd to chuckle when she contended, "Foresight Institute is both more and less radical than ExI."

Foresight is less radical from the standpoint of the technical conferences and association with the NSF and other agencies; and more radical when comparing content. The ramifications of nanotechnology development are significant and have continued to drive advances. Social acceptance of MNT memes has brought both responsibility and respectability, which may be seen in increased government funding and is evident in the leading role being assumed by the National Science Foundation.

Foresight is responding. With a major part of Foresight's original mission — increased awareness of the coming development of molecular nanotechnology — accomplished, the institute is turning toward policy issues and expansion of the hypertext publishing vision explored in Engines of Creation.

Panelists were united in their support of collaborative effort. Art and science are part of the same ecosystem, and perhaps the combination of their resources would lead to a brighter future.

And the Rest

Past attendees of Extropy Institute conferences may have met or heard Christopher Heward, a molecular endocrinologist by day who was bitten by an aging spiral some years ago. Dr. Heward spoke on treatment of the non-disease symptoms of aging as a direct way to impact long term health and survival. He returned to report that a new Phoenix-based clinic has been established to offer extensive, personalized health recommendations to prolong the individual lifespan.

Attendees also heard from Gregory Stock on the creation of a prize, similar to the Feynman Prize, for longevity milestones. (Possible candidate goals include the creation of a DNA chip to assay aging or a heterogenous mouse strain with a doubled lifespan.)

Robert Bradbury stepped forward to remind us of the need for controls when applying the principles of nanomedicine. Roy Walford discussed his investigation of the mechanisms of aging and his experiences in caloric restriction, and still there was more.

Despite the high bandwidth exchange in the lecture hall, everyone craved more, self-assembling into groups to discuss the potentials of biotechnology, genetic, intelligence, and whatever else seemed a good idea at the time. Extro conferences have become known for their interesting material and even more interesting attendees; and like Foresight Senior Associate events, these conferences have achieved some notoriety for quality parties. This community overlaps Foresight's in many ways, and we encourage you to take a look.

Extropy Institute's Conference on Biotechnology Futures

Jan Heward, Jose and Beatrix Salgado share a moment with Greg Stock	Max More, Tom W. Bell, and Simon Levy: founding Directors of Extropy Institute

Roy Walford, who brought us lessons from the Biosphere	A full and rapt audience in the Krutch Theater

Foresight Update 38

page 1

Nanomedicine: A "Classic-in-the-Making"

Multi-Volume Work Examines Medical Applications of MNT

by Richard P. Terra

Additional Resources

Other references on the medical uses of nanotechnology:

Biotech Futures in Berkeley

by Tanya Jones

Abundant Aging Research

Social Scheming

And the Rest

Extropy Institute's Conference on Biotechnology Futures

Foresight Programs