FORESIGHT INSTITUTE’S

WORKSHOP ON ATOMIC PRECISION

FOR MEDICAL APPLICATIONS
May 29-31, 2015 | Palo Alto, CA
 ABSTRACT

The workshop on Atomic Precision for Medical

Applications aimed to promote the development and
use of atomically precise tools for medicine. About
50 people attended, with a range of experience (from
senior researchers to graduate students), institutions
(universities, government and industry) and expertise
(medicine, nanoscale tools, and computation).

The workshop identified potential interdisciplinary

collaborations among the researchers at the workshop.
It also developed several near-term research projects
that illustrate how precise tools can significantly
improve medicine.

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I
 TABLE OF CONTENTS

Introduction: 1-3
Opportunity 1-2
Challenge, Procedure, Purpose 3

Medical Benefits of Atomic Precision 4-7

DNA Repair 4
Stem Cell Repair 5-6
Precise Control of Blood Composition 6-7

Progress Toward Atomic Precision 8-11

Recent Tool Development 8-10
Future Tool Development 10-11

Realizing the Opportunity 12-14

Tools to Address Medical Challenges 12-13
Infrastructure 13-14

Criteria for Selecting Research Projects 15-17

Outcomes 15-16
Technical Feasibility 16-17
Resources, Project Evaluation, Funding, IP Status,
Investigators’ Interest 17

Example Research Projects 18-25

Artificial Immune System from Modular Molecules 18-19
Artificial Organs 19-21
Cancer Treatment Based on Telomeres 21
DNA Robots to Treat Type-1 Diabetes 22-23
Evolutionary Material Design Applied to Binding Heavy Metals 24
pH Sensors 25

Next Steps 26

References 27-28

Participant List 29-30

II
Self-assembling subnanometer pores with unusual mass-transport properties; X-Therma, Inc., Biomemetic Nanotech Nature Communications 2012, 3, 949

INTRODUCTION
An opportunity to significantly improve medicine

Medicine has progressed significantly in the last Opportunity

century, particularly for preventing and treating Two recent developments could lead to significant
infectious diseases. However, there remains improvement in medical care. These are the
an ever-increasing burden of chronic diseases identification of a relatively small number
associated with an aging population, as well of fundamental causes of diseases and the
as emerging infectious diseases. Current fabrication of increasingly precise tools for
approaches to these medical problems have sensing and manipulating biological organisms,
limited effectiveness, significant side effects tissues, cells and their molecular components.
and high cost.

To address this problem, significant resources

are devoted to developing better ways to
treat diseases such as cancer. This is leading
to incrementally better treatments, deeper
understanding of the biology underlying
disease, and increased personalization of
medical treatments to the biology of individual
patients [Collins and Varmus 2015]. However,
even if these approaches are successful to one
disease, they lead to only modest improvement
in life expectancy and quality of life, due to the
consequent increased incidence of other diseases
without effective treatments (e.g., Alzheimer’s).
There thus remains a need for broadly effective
and affordable prevention, diagnosis and
treatment of all diseases, and the ability to rapidly
detect and respond to emerging diseases.
Enzyme repairing DNA - A special enzyme encircling the
double helix to repair a broken strand of DNA. Image from Tom
These causes
Ellenberger, include:
Washington Univ. School of Medicine in St. Louis,
and Dave Gohara, Saint Louis Univ. School of Medicine.

INTRODUCTION 1
 Treating fundamental causes of disease could side effects [Freitas 1999]. Such precise tools
not only cure currently intractable diseases, but have been discussed theoretically for many
also lead to rejuvenation and halting damage that years. Recent developments have now produced a
accumulates during aging [de Grey 2007]. variety of demonstrated tools with precision at or
close to atomic scales [Kim et al. 2015].
These causes include:
An example is DNA self-assembly producing
• Advanced glycation end products (AGEs) complex structures through suitable choice of
• Aging clocks – e.g, accumulated damage and base pair sequence and their selective binding.
epigenetic changes These developments show the way toward a large
• Auto-immune problems range of new high-precision tools. Learning how
• Autophagy and “garbage collection” to exploit these new tools for applications, such
• DNA mutations (environmental and inherited) as medicine, requires significant study beyond
• Infections just learning how to make the tools in laboratory
• Inflammation settings. Since research plans and funding cycles
• Mitochondrial defects take years to mature, there’s an opportunity now
to identify high-value areas for precise tools.
Medicine is one such high-value area.
Fully addressing these causes requires improved
understanding of their molecular basis and tools Moreover, identifying clear applications will guide
that can sense and alter processes on that scale. tool development in directions most likely to have
major impacts, and have applications ‘ready to go’
Large scale manufacturing of tools created
as soon as tools become available. This will reduce
and operating with atomic precision could
the time between new tools achieving laboratory
significantly improve diagnosis and treatment of
demonstration and their use to help patients in
these fundamental causes, without significant
the clinic.

Examples of nanotechnology platforms used in drug development. Image from William C. Zamboni et al. Clin Cancer Res 2012;
18:3229-3241 © 2012 American Association for Cancer Research

INTRODUCTION 2
 Challenge These sessions involved:
Exploiting this opportunity requires close long-
• Listing medical benefits of specified precise tools
term collaboration among different research
communities, with different terminologies,
• Evaluating recent and likely future progress in
developing high-precision tools
interests and funding sources. Moreover, there
• Identifying tools and supporting infrastructure
are significant technical obstacles to developing needed for various medical applications
atomically precise tools and identifying how
• Discussing criteria for selecting research projects
to apply them to fundamental causes of disease.
• Developing research projects
These obstacles involve two major limitations
in current science and technology. First, for some The workshop aimed to characterize the
diseases we lack sufficient knowledge of the opportunity for improving medicine and suggest
underlying biological mechanisms to identify feasible next steps with a few representative
effective, curative treatments. Alzheimer’s research projects. The workshop focus was
disease is an example. Second, we often lack mainly on improving treatment for individual
sufficiently precise tools to apply our knowledge patients. In addition, the technologies discussed
to treat the disease without also causing harm here could improve public health, e.g., by quickly
to healthy tissues. and precisely tracking outbreaks of infections
For example, an inability to precisely target with harmless chemical tags or widespread
drugs to every cancer cell without also affecting environmental sensing. The workshop was not
many healthy cells. We also face challenges a comprehensive survey of the development of
arising from the complexity of planning, atomically precise tools or the full range of their
controlling and testing treatments with available possible medical applications.
tools, particularly treatments that require This report describes the outcome of these
customization based on large numbers of sessions, with particular focus on the research
patient-specific diagnostics. projects developed during the workshop.

Purpose
This Foresight workshop aimed to address the
scientific aspects of this challenge by bringing
together about 50 researchers from diverse
research communities to identify promising
medical opportunities as the precision of available
tools increases toward the atomic scale.

Procedure
The workshop consisted of a series of sessions
to explore and develop medical applications for
atomic precision.

INTRODUCTION 3
 MEDICAL BENEFITS
OF ATOMIC PRECISION
Increasingly precise tools could provide a wide tools could be created based on each patient’s
range of medical benefits. To understand these genome sequence.
potential benefits, this section describes
applications of several hypothetical tools that Applying DNA repair tools requires an ability to
could act within the body much more precisely deploy many tools throughout the body, that these
and over a larger range of cells than current tools can enter cell nuclei to make precise changes
technologies. In addition to physical precision of to DNA, and then the tools either harmlessly
the tools’ actions, effective use requires knowing degrade or can be removed from the body. Making
how to use the tools effectively. High precision these changes requires that the tool can access
tools would also be useful as research techniques and unravel the highly coiled DNA in the nucleus,
to obtain the necessary knowledge. For the make the specific required changes and return the
purpose of this discussion, the hypothetical tools DNA to its coiled state. In addition, effective use
were assumed to be widely available, affordable, of the tool requires sufficient knowledge of which
and safe to use. The primary focus of discussion edits to make for individual patients.
for medical application of precise tools is on
treating or preventing diseases, or using the tools
to learn more of the underlying disease biology.
Beyond these applications, precise tools could
enhance human performance and longevity.
These tools could also have cosmetic applications.

DNA repair
Many medical problems arise from errors in DNA.
These include heritable diseases as well as cancer
forming from successive mutations to DNA that
natural mechanisms are unable to repair. A tool to
repair or replace the DNA in cells throughout
the body could address these problems. These

MEDICAL BENEFITS OF ATOMIC PRECISION 4

 This level of DNA repair would be powerful, by Stem cell repair
effectively and precisely altering biochemical Organs sufficiently damaged by disease or
processes within cells throughout the body. For injury eventually fail. Transplants are a current
instance, DNA repair could eliminate fully or treatment for organ failure, but are limited
partially inherited genetic diseases, such as by a lack of compatible donors and require
Huntington’s, cystic fibrosis, Parkinson’s and ongoing immunological management to avoid
sickle cell anemia. The repair could also address organ rejection. Stem cells offer an alternative
diseases arising from genetic mutations such therapy to augment or replace failing organs, by
as cancer. using cells from the patient to ensure immune
compatibility. By assumption, such therapies
Moreover, in addition to treating existing
can accurately identify and extract appropriate
diseases, DNA repair could proactively repair
stem cells, and deliver them into the body with
pre-cancer cells. That is, repair cells that have
microenvironments that encourage proper
accumulated some mutations on the path toward
differentiation and growth. The techniques also
cancer but not yet all the changes required to
prevent any of the implanted stem cells from
become cancerous.
forming uncontrolled secondary growths. Instead
Precise DNA edits could also address some of repairing damaged cells, as DNA repair does,
aspects of aging. One example is repairing this stem cell therapy would replace those cells
telomeres that normally shorten as cells divide. with new, healthy ones as the stem cells
Such repairs often raise the concern of possibly differentiate and grow.
promoting cancer growth since shortening
telomeres provide one check on indefinite cell
growth. However, with precise DNA edits,
telomere repair would only apply to normal cells,
or be combined with repair to pre-cancer cells.
Alternatively, the edits could selectively enhance
telomere shortening in cancer cells.

DNA repair could not only alter genes, and hence

the resulting proteins, but also change regulatory
regions on DNA, thereby changing expression
patterns. This would allow altering interactions
among many genes. If these hypothetical DNA
editing tools operate quickly enough, these
changes could apply only when the cell is in
particular states, e.g., due to environmental stress This confocal microscopy image from a mouse lacking the Sept2/
ARTS gene shows a tail wound in the process of healing. Cell
or at specific points during the cell cycle. nuclei are in blue. Red and orange mark hair follicle stem cells
that cause hair regrowth, indicating healing. Image from Yaron
Fuchs and Samara Brown, National Institutes of Health.
Tools able to precisely edit DNA in many cells
throughout the body could be useful to repair
radiation damage. This could be useful, for This level of precise control of stem cell behavior
example, in aiding recovery from radiation would provide a range of benefits. For instance,
medical treatments and supporting space travel stem cells could aid the regeneration of injured
to other planets, which can involve long-term spinal cords and regrow limbs. This technology
exposure to higher levels of radiation than on could also grow new tissue in vivo for whole
the earth. organ replacement, and to reconstruct the
patient’s immune system.

MEDICAL BENEFITS OF ATOMIC PRECISION 5

 bloodstream could have significant benefits,
and such tools may be easier to develop than
those discussed above that involve modifying
cells throughout an organ or the entire body.
An example of the potential benefit of altering
blood contents comes from studies of supplying
blood from young animals to older ones. These
benefits include improved cognitive function
[Villeda et al. 2014].
High-precision tools include filters that could
remove specific chemicals or cells from the blood,
and delivery vehicles to add chemicals or cells
under precisely defined conditions. These tools
Advanced multistage synthetic assembly. Image from Ligandal,
Inc. www.ligandal.com/technology.html
contain sensors and controls to determine if,
when and how much to modify blood composition
on an ongoing basis with rapid reaction to
Growing stem cells with repaired DNA in tissue changes in the body. These devices could act
could replace cells with damaged DNA. This use as artificial blood cells, replacing the functions
of stem cells could achieve results similar to that of nutrient delivery, injury response and
of DNA repair of those damaged cells. immune surveillance. In general, combinations
of circulating and stationary devices may
Precise Control of perform these functions. This precise control
Blood Composition includes making different modifications to blood
composition in different parts of the body.
The circulatory system delivers nutrients and
removes waste from throughout the body.
Thus high-precision tools that act only in the

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Image from Nature Medicine 20,
659–663 (2014) doi:10.1038/nm.3569; Received 08 February 2014 Accepted 16 April 2014 Published online 04 May 2014

MEDICAL BENEFITS OF ATOMIC PRECISION 6

 Selective removal of chemicals and cells from Beyond addressing existing diseases, control of
blood could treat a variety of medical problems. blood composition could enhance performance.
While the liver and kidneys alter blood For instance, increasing oxygen carrying capacity
composition, new functions could be added. of the blood could allow people to function well in
low-oxygen environments (e.g., at high-altitude),
These included: and enhance endurance exercise. Moreover, the
sensors required for precise adjustment of blood
• Remove inflammatory cytokines to reduce composition could also provide ongoing, real-time
inflammation injury. sensing for diagnosis, and collect detailed person-
• Remove cholesterol to reduce cardiovascular disease. specific normal ranges of variation in blood
• Remove bacteria, viruses and parasites in blood, chemistry. This would improve diagnosis with
thereby eliminating some infections and improving early detection of deviation from normal ranges
the efficacy of the immune system.
for that person. This use of sensory information
• Remove toxins, including overdoses of alcohol requires that the sensors, circulating with the
and other drugs.
blood, can communicate their measurements
• Remove circulating tumor cells to prevent metastasis. outside the body, e.g., to a receiver a person
wears on his or her skin.
In addition, altering clotting and thrombosis
could eliminate vessel blockages underlying
stroke and heart attacks. Precise control over
blood chemistry could correct hormonal
imbalances, possibly leading to rejuvenation.
Applied to chemicals introduced into the body,
this capability could improve drug delivery,
including drug delivery across the blood-brain
barrier. Similarly, precise control over cells in the
blood could deliver stem cells to specific parts of
body as part of a procedure to rejuvenate organs.

More generally, the ability to precisely control

blood composition could substitute for or
augment the function of organs that support
the blood, e.g., the kidney, liver and pancreas.
Similarly, the tools could supply nutrients directly
into the blood, replacing the function of the
digestive system. Hence, precise control of blood
chemistry could substitute for organ failure for
long periods of time, perhaps indefinitely. This
capability could delay or avoid organ transplant or
repair. This is especially notable if the tools could
operate autonomously for long periods of time
within the body, providing the function of organs
without the inconvenience and infection risk of
current procedures, such as dialysis to support
failing kidneys.

MEDICAL BENEFITS OF ATOMIC PRECISION 7

Collage of nanomedical particles and devices developed by members of the NCI Alliance for Nanotechnology in Cancer. Image from William C. Zamboni
et al. Clin Cancer Res 2012; 18:3229-3241 © 2012 American Association for Cancer Research

PROGRESS TOWARDS
ATOMIC PRECISION
Advances in capability to create and deploy high- A broad area of advance is the increasing ability
precision tools provide the context for improving to combine sensing, computation and actuation
medical treatments. on ever-smaller scales. Such tools are often
referred to as “robots”, although their capabilities
Tools and techniques undergoing for computation and autonomous action are
significant improvements include: severely limited compared to conventional robots.
Nevertheless, such devices are potentially useful
• Sensors for diagnosis in medicine for minimally invasive surgery
• Drug delivery at small scales and in regions of the body not
• Analysis reachable by endoscopes [Sitti et al. 2015].
• Membranes for filtration
• Communication: among devices, and between One example combining local sensing and
devices and physician directed motion is attaching nanoparticles to
• Implantable devices bacteria, which can move toward or away specific
chemicals, light or magnetic fields [Martel et al.
2014]. In this case, the bacteria provide sensing
This section describes some of these recent
and local navigation, while external magnetic
developments and prospects for further progress.
fields can position the devices coarsely, e.g., in a
particular organ. These hybrid nano-biological
Recent Tool Development devices deliver particles to locally-defined
Ongoing developments by many groups are environments, e.g., for drug delivery or building
creating increasingly precise tools. These aggregates. Another approach to hybrid devices
advances illustrate the near-term potential for is modifying signals biological organisms use to
applying high-precision tools to medicine as coordinate their behavior, thereby changing the
the developments continue toward atomic group behavior [Halloy et al. 2007].
precision. This section surveys a selection of
At a much smaller scale, DNA robots sense
these developments as a guide for capabilities
specific DNA or RNA sequences and combine
available to near-term projects applying precise
those detections via a few logic operations to
tools to medicine.
determine when they act by releasing other
chemicals [Bath and Turberfield 2007].
PROGRESS TOWARDS ATOMIC PRECISION 8
 structures [Whitesides and Grzybowski 2002].
An example is increased flexibility in automating
small molecule synthesis, analogous to 3D
printing but at a molecular scale [Li et al. 2015].

Another area of progress is modifying biological

mechanisms to incorporate new molecules. One
example is incorporating new nucleotides into
DNA in E. coli, in effect, extending the genetic
code [Malyshev et al. 2014]. Using additional
nucleotides increases the range of structures
DNA self-assembly could produce and highlights
the long term potential for using DNA to make
structures [Sanderson 2010]. For instance, this
increases data storage in DNA by providing more
Biologically based devices already having options for each base pair. Additional nucleotides
working systems for power, locomotion and also have applications simply because they do not
sensing, which can be used or modified for new occur in nature.
applications. This contrasts with the greater
challenge of building small devices with all these For instance, a public health application could use
capabilities from scratch. In particular, such additional nucleotides as identifiers for foods,
devices currently lack capabilities for autonomous e.g., to trace food-borne infections more quickly
navigation. Instead, they can be useful when and precisely than is possible today. They could
passively absorbed by cells or moved with coarse also be incorporated into drug delivery, giving the
resolution by external fields. Magnetically guided ability to remove them if not working by targeting
devices are one example [Yesin et al 2005]. Such the new nucleotides. Because these bases do not
magnetic nanoparticles can deliver drugs to a occur in normal cells, such targeting would be
wide range of specific targets in the body. This specific to the introduced drug.
includes passing through blood-brain barrier by
New tools allow increasingly precise
local heating of a few degrees, which reversibly
measurements of individual cells, including using
opens gaps in the barrier, allowing large
and applying mechanical stress to cells [Huang
molecules and nanoparticles to move out of blood
et al 2004], and measuring electrical behavior in
vessels into the brain [Tabatabaei et al. 2015].
individual cells [Duan et al. 2012]. One application
In addition to complete functioning devices, relies on detecting mechanical operations
biology provides a wide range of machines and inside cells (e.g., the motion of protein motors).
components. Examples range in scale from These motions produce vibrations on cell walls,
molecular motors [Phillips and Quake 2006] to which may provide a novel sensing modality for
interlocking mechanical gears several hundred nanoscale devices investigating cell behavior and
microns in size [Burrows and Sutton 2013]. distinguishing between healthy and diseased
These examples show that self-assembly can cells [Pelling et al. 2004]. As another example,
produce small-scale versions of machines that measuring mechanical properties of cells aid in
are manufactured by directed placement at large identifying stem cells [W. Lee et al. 2014].
scales. Understanding the range of components
Manufacturing precise materials can improve
self-assembly can produce, and how to control
existing medical devices. For example, nanotube
the process, is important for the development of
coatings on stents prevent growth of unwanted
atomically precise tools because self-assembly
cells [P. Lee et al. 2014]. Another example is
is a promising route toward making small

PROGRESS TOWARDS ATOMIC PRECISION 9

 applying nanomaterials to improve drug delivery applications for future tools. This evaluation,
[Fox et al. 2015], such as using precisely-sized in turn, will motivate the development of those
nanotubes to constrain diffusion for improved tools and prepare applications for them to reduce
drug release kinetics (e.g., http://www. the time between tool development and their
nanoprecisionmedical.com/technology/the- medical applications. This section describes likely
goldilocks-effect). In addition to creating more improvements to available tools, though the time
precise tools, the ability to evaluate biological frames are necessarily somewhat speculative.
molecules and structures more precisely helps
identify fundamental causes of disease. One Sensors will decrease in size and increase in
example involves how two meters of DNA performance, i.e., increased signal-to-noise,
is packed into the small volume of a cell. A sensitivity and selectivity. New sensors will
recent study shows that incorrect packing provide this performance with label-free
(heterochromatin disorganization) can lead to detection, allowing their use in a wider range of
disease, such as Wiener syndrome. Adding the settings. Sensing will combine with real-time
correct protein fixes the packing and thus reporting, and allow safe, effective implants
offers a new approach to these diseases [Zhang for long-term continuous monitoring of a large
et al. 2015]. number of different simultaneous measurements
in the body. The sensors will improve disease
diagnosis. Similar improvements in medical image
resolution will provide more precise overview of
tissues and organs, complementing information
obtained from small, embedded sensors.

Drug delivery will provide increasingly precise

targeting, based on multiple measurements and
some logic operations to identify appropriate
release sites. As devices decrease in size, drug
release will involve computation at the level
of individual cells to identify targets. Delivery
devices will not only move passively through the
body, but can also be self-directed, extending
today’s capability move devices based on external
fields. Beyond delivering small molecules as
drugs, the devices will deliver engineered cells or
Hcp1 is a ring-shaped protein from Pseudomonas aeruginosa
that was engineered by scientists at the Molecular Foundry at viruses to cells recognized by specific chemical
Lawrence Berkeley Lab to form covalently linked nanotubes. markers or mechanical properties.
Image from Ronald Zuckermann.

Sensors and drug delivery devices used in the

body must be safely disposed of after use. In
Future Tool Development some cases, the devices will be small enough
Developing viable research projects on applying for removal via normal body mechanisms, e.g.,
precise tools to medicine requires understanding via the kidneys. For larger devices, improved
not just currently demonstrated performance of materials should allow making implanted devices
such tools but also how the tools and associated that dissolve into harmless smaller components
biomedical knowledge will likely improve over for normal removal by the body.
the next few years. This is important so projects Nanoscale surgery will provide precise
are not confined to capabilities of currently operations on individual cells, including editing or
demonstrated tools, but instead evaluate replacing a cell’s DNA. Combined with improved

PROGRESS TOWARDS ATOMIC PRECISION 10

 sensing, precise surgery will remove diseased As devices become smaller and more numerous,
cells and replace with new ones, while avoiding coordination of many devices operating
healthy cells. simultaneously in the body will become
increasingly important. This coordination can
In addition to direct repairs to injured tissue, arise from external commands sent to the
precise surgery could introduce materials in devices, e.g., by modulating magnetic fields the
specific locations that provide guides to aid the devices can sense. A longer-term development
body’s own repair processes. These guides will is devices communicating locally among
act as scaffolds, providing both mechanical themselves to coordinate activities. Even devices
support and chemicals necessary to guide the with limited computation and communication
repair, e.g., for faster and better wound healing. range can robustly organize activities over
The scaffolds could also include patient-specific large scales in space and time, e.g., as swarms
stem cells to grow specific tissues. [Rubenstein et al. 2014]. These behaviors will lead
Improved membranes will provide precise blood to devices forming a communication network to
filtration and other separations of specific relay information to and from external devices,
molecules. Such membranes could be part such as the patient’s cell phone.
of implantable bioreactors, which will create Large numbers of precise sensors measuring
molecules in response to changing conditions many values raise a significant challenge for
within the body. This will be much more data analysis. This will require software for
responsive than adjusting drug dosage based searching through and evaluating the large data
on intermittent testing, e.g., on a weekly or sets produced by sensors operating within a
monthly basis. single person.

Kilobot is a thousand robot swarm developed at Harvard University, Wikimedia Commons.

PROGRESS TOWARDS ATOMIC PRECISION 11

 REALIZING THE OPPORTUNITY
Realizing the potential for precise tools to improve within the body have significant impact on some
medicine requires matching tools to applications diseases. Thus precise tools to quantify and alter
and identifying improvements in research the micro-biome should be useful additions to
infrastructure to support the projects. medicine. In particular, detecting changes to the
biome would help identify infections before they
spread throughout the body. This data collection
Tools to Address
would transform the biome into a continuous
Medical Challenges medical sensor.
Medicine could benefit from expanding the set
of substances that can be used as precisely Many diseases involve inflammation. Better
targeted drugs. For example, natural catalysts sensors as part of tools for drug delivery could
can have useful medical properties but are too help treat inflammation by identifying the
large to deliver effectively. Two approaches precise type of inflammation and hence suitable
are improved delivery vehicles that could treatment options. One approach to achieve this is
accommodate larger molecules, and designing for tools that mimic immune cell response such as
and synthesizing smaller, robust versions of ability to pass through vessel walls, allowing the
the catalysis so they can get to sites too small tools to get to and interact with cells involved in
for conventional catalysts. inflammation response anywhere in the body.

Combining information from multiple sensors Aging clocks underlie many of the fundamental
will improve diagnosis and drug targeting. For causes of disease. In principle, tools such as
example, sensors for multiple binding targets on DNA editors can alter these clocks. However,
cells will allow more specific identification than we currently lack sufficient knowledge of these
a single binding site. Such sensors will need to clocks and how they operate in the body. Thus
account for variation in the spatial distribution development treatments for these causes could
of multiple sites on different cells. These sensors benefit from precise sensors used as research
would be particularly useful for identifying tools to identify where clocks act. For example,
cancer cells that lack single specific markers that developing sensors to examine the methylation
distinguish them from other cells. status of DNA in various cell types and under
various disease conditions. In particular, it would
Recent studies of the body’s micro-biome indicate be useful to compare RNA expression patterns in
the ecosystem of organisms living on and young and old organs.

REALIZING THE OPPORTUNITY 12

 Interpreting RNA information accurately requires Web-based collaborative tools for scientific
knowing which cells and tissues produce the research are under development, e.g., the
observed RNA. The most direct approach is to use Galaxy Project (www.galaxyproject.org) for
a large number of small sensors that can get next data-intensive biological research, the Open
to or inside individual cells. An alternative is to Science Framework (https://osf.io) for managing
measure the RNA that cells release into the blood. research projects, and the Jupyter Project
This could use simpler sensors, e.g., confined to (jupyter.org) to support scientific data analysis
blood vessels, but does not directly identify which and interactive reports.
cells in which tissues produced the observed
RNA. One approach to gain this information In terms of spreading awareness of new tools,
would first use cell-specific drug delivery to one source of information on material and
target an RNA sequence of interest to specific device capabilities to guide medical application
organs, and connect to a ligand excreted by the developers is data collected by the National
cell. This would provide a bar code identifier with Nanotechnology Initiative (NNI) with indications
RNA sensed in blood that would tell where the of the quality of the data through emerging
RNA came from. standards of data readiness levels (described at
www.nano.gov/NSINKI).

Infrastructure Conversely, materials and computer scientists

A significant obstacle to progress with need convenient access to quantitative biological
interdisciplinary projects discussed at the data, at many scales, to inform the engineering
workshop is the difficulty of sharing information of tools and algorithms to exploit them. For initial
among diverse research communities. This evaluation of designs, even order-of-magnitude
arises through limited funding support for cross- values would be helpful. Beyond expanding the
disciplinary meetings and tool development. range of measured values and their accuracy,
In particular, there is a lack of easily-accessible a significant challenge is the large variation in
online resources that provide relevant biological systems: robust tools and algorithms
information in a form useful for researchers in need not only typical values but also an indication
other disciplines. Moreover, potential developers of the range of variation and how that variation
of medical applications for new, precise tools depends on other measurable properties. This
need to be aware of the rapidly improving variation occurs among individual organisms
capabilities of these tools. This is gradually as well as within a single individual, including
improving. This workshop is an example of stochastic variation in behavior among
how to engage researchers to take time from genetically identical cells even in identical
their schedules to explore potential collaborations environments.
with researchers in other fields, for projects with
large potential payoff for medicine involving
high-precision tools.

galaxyproject.org https://osf.io jupyter.org

REALIZING THE OPPORTUNITY 13

 Currently, such quantitative biological data is One way to help address this problem is
widely scattered in the literature, and presented improving accessibility and significantly reducing
as results of a variety of experimental protocols the cost of performing biomedical experiments.
whose differences are not readily apparent This would be especially useful at early stages of
to non-specialists. This makes it difficult a project to evaluate potential outcome quickly
for researchers in other fields to collect the and cheaply.
comprehensive sets of measures relevant for
designing high-precision tools for medical An example is Emerald Cloud Lab (http://www.
applications. Nevertheless, large-scale data sets emeraldcloudlab.com) which is attempting to
are becoming more available, such as for protein improve availability of biological experiments.
and gene interactions. Another example is the If successful, such approaches could significantly
Bionumbers project (at http://bionumbers.org), reduce the costs for research groups to perform
which provides quantitative values, and ranges, initial evaluations of applications of new tools.
for many cellular processes. This approach is analogous to Amazon Web
Services (http://aws.amazon.com) providing
In cases where values useful for engineering new scalable computing platforms, significantly
devices are not known, higher-precision sensors reducing the upfront capital cost of compute-
could be useful tools to collect the information. intensive projects.
This is somewhat a chicken-and-egg situation
where better data is needed to inform device
design, but the data is not readily measurable
until higher-precision sensors are available for
widespread in vivo use. This relates to the project
selection criteria supporting tool development
even if it is not immediately apparent whether
or how those tools will be medically useful. This
applies both to new sensors to collect information
and better computational approaches to make
the data available to non-experts, e.g., extending emeraldcloudlab.com

from keyword-based searches to natural

language queries.

New tools and medical knowledge can suggest

a large number of possible new applications.
The number of possibilities is far too large
to systematically evaluate each possibility
with a detailed research project. Researcher
experience and intuition can help focus on
the most promising possibilities. However,
the rapid development of more precise tools
opens opportunities for approaches that were
not feasible before, and therefore for which
researchers have little prior experience. This
could lead to overlooking some significant
benefits of newly developed tools.

REALIZING THE OPPORTUNITY 14

 CRITERIA FOR SELECTING
RESEARCH PROJECTS
The continuing improvement in tool precision and large risks of not achieving the goals due to
opportunity to use them to address fundamental challenges of fabricating tools, especially with
causes of many diseases favors relatively long- atomic precision, the complexity of biological
term, interdisciplinary projects, and steps to systems at the molecular scale these tools could
simplify those collaborations by improving access, and the high cost of translating laboratory
infrastructure to support such projects. While demonstrations into effective and affordable
such projects have large potential payoffs, they clinical practice. Thus the discussion of selection
are also risky and require sustained effort from criteria focused primarily on the technical
people with differing expertise. This risk, and the questions of evaluating project outcomes and
need for people from different fields to contribute technical feasibility. Additional important practical
(e.g., medicine, biology, nanoengineering, and issues involve the required resources, availability
computer science), make it difficult to identify of funding and compatibility with researchers’
funders willing to devote some of their budget individual goals. The remainder of this section
to such projects. In particular, the tools applied discusses these criteria.
to fundamental causes of disease could, if
successful, help with many diseases while Outcomes
funders of medical research tend to focus on
The outcome of the project, if successful, is a
one or a few specific diseases, and so are less
major criterion. This emphasizes aiming for major
willing to devote resources to a project with a low
advances to identify and exploit the full potential
chance of addressing their particular disease
of new, more precise tools for a variety of medical
even if, aggregated over multiple diseases, it has
problems, rather than incremental improvements
reasonable prospects of helping with at least some
for individual diseases. Long term benefits (e.g.,
of them.
in terms of lives saved per dollar) instead of focus
Main criteria are the benefit of successful on incremental progress on high-profile diseases
outcome vs. the risk of not achieving that that, even if cured, would have relatively little
outcome. As described above, high-precision improvement on life expectancy. This motivates
tools could have significant medical benefits focusing on fundamental causes of disease, e.g.,
and address many diseases through treating potentially leading to a solution to aging, rather
fundamental causes. With this potential comes than each disease individually.

CRITERIA FOR SELECTING RESEARCH PROJECTS 15

 For projects advancing the use of atomic may have a variety of medical applications that
precision for medicine, the most direct focus are not apparent until people gain experience
is on medical outcomes, i.e., demonstrating the using the tools. One way to pursue this criterion
efficacy of treatment. In addition, the outcome is to view the project as creating a combinatorial
should have reasonable potential to transfer platform that other research groups could use.
from demonstrated efficacy in research studies For example, a device capable of carrying a
to widespread clinical use. This includes variety of sensors in the bloodstream could
affordable per-patient cost of the procedure be useful for other groups testing various
(as opposed to research and development cost), combinations of sensors.
which is particularly relevant for applications
in developing countries, e.g., treating tropical Finally, a useful outcome for short exploratory
infectious diseases. projects is evaluating whether a potential set
of collaborators can work effectively together.
Projects involving advanced applications enabled This is particularly useful for interdisciplinary
by precise tools may raise significant ethical groups who have not previously worked on
or public policy concerns. This is especially projects with researchers from those other fields.
important for outcomes that already trigger Gaining this experience from a short, low-cost
such concerns, e.g., editing germ line DNA or project addresses this question with minimal
enhancing human performance rather than just commitment of time and funds.
curing recognized diseases.

Due to the high risk the project may not fully Technical Feasibility
reach its goals, a good project will have secondary Trading off with the desirability of the project
outcomes that will be useful whether or not outcome is the risk of not being able to deliver
the intended clinical outcome is successful. For that outcome. For projects involving new tools
instance, the project could be a useful learning and aspects of biology that are not well-
opportunity and develop knowledge and tools understood, technical feasibility is a major
useful to other researchers. Or the project could component of this risk. This includes the ability
inspire additional research and train the next to develop the precise tools, along with their
generation of researchers, e.g., so they are ready safety and efficacy in clinical use.
to move quickly if and when tools improve to
the point of enabling this or similar projects to Another aspect of technical risk is competing
succeed in the future even if the current attempt approaches. That is, to what extent could
does not reach its goals. incremental improvements of current methods
achieve similar clinical outcomes? This requires
Another useful outcome is a project to remove estimating how the other techniques might
a bottleneck in the technical feasibility of an develop. Moreover, existing techniques already
approach to fundamental causes of disease, even have an established group of clinical users and
if that result would only be part of an overall acceptance in standard practice.
treatment that requires additional work.
This comparison with existing techniques
Projects need not attempt complete solutions to requires identifying situations where the new
clinical problems: a project limited to improve tool has a large, fundamental advantage over
performance or manufacturability of high- existing practice. That is, to what extent does
precision tools could be useful in demonstrating high precision actually improve outcomes. For
practical feasibility of the tools, thereby enabling example, nanodevices can target specific cells,
other researchers to use them for biomedical e.g., killing cancer cells.
research and later clinical applications. New tools

CRITERIA FOR SELECTING RESEARCH PROJECTS 16

 However, when many cancer cells are close to acquiring the resources to transition to
together in large tumors, surgical removal of the clinical use.
tumor mass all at once may be more effective
than using many nanodevices that each target Project Evaluation
one cell at a time, and then require the body to
It is helpful if a project has intermediate,
dispose of a large number of necrotic cells. In this
measurable goals to monitor progress. This
case, the best use of the new tools could be to
encourages devoting some resources to many
combine surgery for large, operable tumors with
different approaches, with the knowledge that
nanoparticles to target small remaining cells that
less promising ones will be identified early.
are too dispersed for surgical removal.
Moreover, early results could usefully inform
Technical feasibility is difficult to determine for the direction of other projects.
projects that involve combining techniques and
expertise from different fields. Furthermore, Funding
for new tools, there will not yet be prior clinical
The feasibility of obtaining funding is a
experience to guide the assessment of clinical
practical constraint on projects. This includes
effectiveness. The proposed tools for the project
evaluating the attractiveness of the project to
may not even yet exist. Thus evaluation is
conventional funders (government, industry
uncertain and may require interdisciplinary
and specific disease advocacy foundations) as
committees to have the range of relevant
well as emerging ones (crowd funding and use
expertise. This can require substantial time
of prediction markets to allocate funding). This
commitment from members to learn enough
requires finding a balance between pushing
about aspects of the project outside their field
well beyond incremental improvements while
of interest and expertise.
remaining within the scope and time frame
of funders.
Resources
Required resources are an important criterion IP Status
for evaluating projects. This includes the
For potential commercial use of project outcome,
number of people, their expertise, lab facilities,
a company would likely need to negotiate license
project duration and funding requirements.
agreements with others owning relevant patents.
Another aspect of the resource evaluation is
Thus an important issue is the likely cost of
the availability of supporting infrastructure.
such licenses.
This includes the extent to which required tools,
techniques and relevant biological data are
already available or need to be created as part Investigators’ Interest
of the project. Projects should engage the interest of the
researchers involved, providing the excitement
The projects discussed at the workshop are
and challenge of addressing problems with
relatively small, in terms of people and funding.
innovative science and technology, and the
Such small science projects could demonstrate
potential for large medical benefits. The project
technical feasibility of tool development and
must fit with the researchers’ technical and
application. However, much larger efforts and
career goals. This includes educational goals
funding will be necessary to bring successful
for academic groups to motivate and train new
outcomes to clinical use, not least due to the
researchers. For an effective interdisciplinary
cost of clinical trials. Partnering with large
collaboration, the project should have appealing
pharmaceutical companies is a possible approach
scientific challenges for all the people involved.

CRITERIA FOR SELECTING RESEARCH PROJECTS 17

 EXAMPLE RESEARCH PROJECTS
Six projects were selected for further study molecule drugs are not a useful technology for
during the workshop. These illustrate how inhibiting or otherwise altering the biological
interdisciplinary teams could pursue the function of most proteins. This severely limits
opportunity of atomic precision for medicine the available targets for medical intervention in
over the next few years. Additional projects networks of protein interactions.
were briefly presented but not considered
further: improved immunotherapy, enabling This project addresses this limitation by creating
drugs to cross the blood-brain barrier, larger molecules that bind to a wide variety of
developing energy sources for nanoscale proteins by wrapping around them instead of
implanted devices and extending databases binding to just one small part of the protein.
of biomarkers for various disease conditions. Such molecules will interact with the protein
over a considerably larger surface area than
This section describes the rationale and research small molecules, potentially resulting in much
plans for the selected projects. Each project was higher binding energies than small molecules
discussed as a proposal for academic research can achieve. This is analogous to the binding
or a new business. Much of these discussions achieved by antibodies.
focused on specific diseases and new tools
with high, if not atomic, precision. This focus Achieving this goal requires both the ability to
made the projects more compatible with the make a wide variety of large molecules and the
interests of funders. Nevertheless, experience ability to design such molecules for particular
from projects will likely transfer to addressing targets. This project will use a set of modular
fundamental causes of disease and applying molecules to exploit the rapidly improving
atomically precise tools. capability to synthesize large molecules
precisely with reasonably high yields.

Artificial Immune System Instead of attempting to custom design a

from Modular Molecules molecule for each application, the project will
create a combinatorial library of 1010 molecules,
Drugs are typically small molecules that bind
each about 5% the size of antibodies. These
to pockets of enzymes, thereby interfering
molecules will be tested for their binding to
with their activity. However, most proteins
various proteins. Ideally, a molecule will bind
are not enzymes and have no pocket for a
specifically to a single protein. Thus the screen
small molecule to specifically bind. Thus, small

EXAMPLE RESEARCH PROJECTS 18

 process will include testing for binding to the instance, the 3D printing requires additional
desired target and for undesired bindings to supporting structures, such as struts, to maintain
other molecules. its form while the cells grow.

The result of these tests will be a library Second, the liver is the most structurally simple
of molecules, each of which can be readily of the major organs, with only a few types of
synthesized and has known binding to particular cells. Since each cell type will need to grow in
proteins. These molecules could form the basis the artificial structure to produce a new organ,
of drugs that target these proteins, giving a starting with an organ having relatively few
much larger range of possible drug targets than cell types reduces the research effort required
currently available with small molecules that to create suitable growth environments for
require binding pockets. The project’s estimated the cells and hence increases the likelihood of
cost is $3 million over several years. producing a functional organ. At a higher level of
organization, the liver consists of a set of modules
Artificial Organs which could help simplify the engineering of an
artificial organ by first producing similar modules
Many patients who could benefit from organ
before attempting to create a full organ.
transplants do not get them due to lack of
available donors. An alternative is to grow new Third, the liver is primarily a venous organ.
organs from the patient’s stem cells [Badylak Thus its oxygen demands are far lower than
et al. 2012], thereby avoiding the need for other for other organs. This could be important in
donors and for continual suppression of immune the early stages of the growth if the initial
rejection of the transplanted organ. artificial vascular structure provides less oxygen
and nutrients than the normal blood supply to
the liver.

This project requires finding suitable stem cells

that can differentiate into liver cells. Alternatively,
with the development of sufficiently precise DNA
editing tools, any cell type could be converted into
suitable stem cells.

Liver cells (hepatocytes) do not divide in

Kidney organoid (5.7 x 6.4 mm in size) generated from human culture. Thus growing a liver requires a
induced pluripotent stem cells contains all renal cell types.
Image from Minoru Takasato.
scaffold to support the distribution of cells into
a fully functional organ replacement matrix.
Constructing such scaffolds is difficult for
As a proof of concept, the project will focus on vascular organs such as the liver. This project
an artificial liver. The liver has several advantages addresses this challenge by 3D printing the vessel
as a first demonstration of this technique for structure first, with the vascular component
growing organs. filled with hydrogel to support it from inside,
with sufficient branch points to strengthen the
First, the liver has a relatively simple vascular
vascular network so it can, with the internal
structure, organized mainly in layers that are
hydrogel support, stand on its own, surrounded
well-suited to reproduce with 3D printers.
by “empty space” (liquid medium only).
The structure also appears to allow significant
departures from its natural form without Prefabricated organizing extracellular structures
detriment to the liver’s function. This degree are then inserted into that empty space. This
of flexibility in structure could be useful if, for

EXAMPLE RESEARCH PROJECTS 19

 organizing structure includes binding sites to Alternatively, in a second-generation version,
guide non-vascular cells of different types to myelin sheaths containing living Schwann cells
their correct locations in the organ. can be installed into the organ during fabrication,
as part of the extracellular matrix. Nerves
The hepatocytes and other non-vascular cells matched to empty myelin sheaths maintained
are then slowly infused into the extravascular by Schwann cells can grow through the sheaths,
space until they occupy most of its available following them like water flowing through a
volume, all the while amply supplied by nutrients conduit, thus re-innervating peripheral structures
and oxygen from the cell-infusing solution. such as limbs. The same process should enable
Subsequently, rapidly photodegrading the re-innervation of vascular and other key areas of
hydrogel inside the vessels, perhaps using two- the artificial liver.
photon technology, allows prompt perfusion of
the entire structure with nutrients and oxygen This observation on the artificial organ having
through the vascular system to maintain viability, only some of the functions of the natural organ
thus avoiding the “vascular limitation” problem is an instance of a more general property of
of current organ printing methods. Ideally, the artificial organs: a lifesaving treatment does not
scaffold is constructed at least in part of normal require that the artificial organ perfectly replace
extracellular matrix molecules for the liver, which all functions of the original organ. This trade-off
are both biodegradable and replaceable by normal is particularly relevant for organ transplants,
liver cell mechanisms. where waiting for a donor organ can only provide
for a few patients.

The estimated cost for the project is $40 million

over 3 years. The three-year time horizon is
based on parallel processing on all of the different
sub-problems that require engineering solutions.
Human epithelial cells self-organizing in different conformations
as a function of the microenvironment experienced. Red = Keratin
14; Green = Keratin 19; Blue = Nucleus. Scale bar = 50um
An extension of this approach to organ
[Adapted from: Cerchiari et al. PNAS 2015]. replacement is an organ bank of artificial organs.
This involves growing artificial livers as described
above and then cryopreserving them for later use,
For testing purposes, the cells can contain added
when patients require them. In addition to the
bar code markers. This will allow identifying cells
challenges of growing the organ, this extension
that are part of the new organ rather than from
requires overcoming chilling injury of liver cells,
the original one. This identification will help test
so that banked organs perform as well as newly
whether the artificial organ is working correctly.
grown ones. This organ bank will reduce the time
This project creates the new organ’s vasculature patients must wait for their transplant, which
and bile ducts, but the artificial organ will not is particularly important in the context of acute
have nerves. Thus the artificial organ will not liver poisoning, in which the liver must be ready
have nerve-mediated feedback control. For liver to go within hours or a few days at most of the
replacement, however, the lack of regulation by poisoning event, which can only be achieved by
nerves may not be significant. This is because being able to stockpile the organs.
blood flows into the liver primarily from veins,
On the other hand, an artificial organ from such
which are at a low and nearly constant pressure
an organ bank will not have been grown from
independent of most body activities. Thus an
the patient’s own cells, so will require managing
artificial liver may perform reasonably well
immune response to the new organ, similar to that
without feedback control.
required when using donor organs. Fortunately,

EXAMPLE RESEARCH PROJECTS 20

 however, for recipients who can schedule their lengthening telomeres. Unfortunately, cells have
transplants a few months in advance, new two mechanisms to increase telomere length,
techniques promise to enable donor-specific and it has proved difficult to develop drugs that
tolerance induction while the designated organ reliably block both methods, do not harm healthy
remains in the freezer, enabling the recipient cells and avoid cancer cells developing resistance.
to receive an organ of any tissue type without
the need for life-long immunosuppression and As an alternative to inhibiting proteins involved
without ever rejecting the organ. in telomere repair, this project aims to stabilize
the folded structure of telomeres, preventing
The techniques developed in this project could their elongation, and hence preventing cellular
extend to more complex vascular organs, such as repair mechanisms from accessing the telomeres
the heart or the kidney, based on the experience to increase their length. This requires designing
derived from the liver. molecules that selectively and strongly bind to
folded telomeres, and that can be delivered into
the cell nucleus. The therapy must also avoid
modifying telomeres in healthy cells, either
because the molecules only act when inside
cancer cells or they can be selectively targeted to
cancer cells.

Currently, some compounds are known stabilize

the folded structure of telomeres. These
compounds can be manufactured with 90% yield
and appear safe for use in cells. This approach
is an example of targeting large-scale DNA
structure rather than its primary structure (i.e.,
Multiphoton fluorescence image of HeLa cells stained with the sequence of bases) [Luedtke 2009].
actin binding toxin phalloidin (red), microtubules (cyan) and cell
nuclei (blue). Nikon RTS2000MP custom laser scanning micro-
scope.Image from Tom Deerinck, National Institutes of Health. Starting with variations of these compounds, the
project will perform in vitro tests of how well
the compounds bind to folded telomeres based
Cancer Treatment Based on existing techniques [Monchaud and Teulade-
on Telomeres Fichou 2008].
A major challenge for chemotherapy cancer
treatment is the harm done to healthy cells by
insufficient precision of targeting the drug to
cancer cells, and the resistance of some cancer
cells to the drug. One approach to dealing
with this problem is to focus on the ends of
chromosomes, i.e., the telomeres. In most healthy
cells, telomeres shorten with each cell division,
which prevents cells from dividing indefinitely.
To avoid this limitation, cancer cells need to
maintain their telomeres as they divide.

This observation suggests that an effective drug

target would be to inhibit proteins involved in

EXAMPLE RESEARCH PROJECTS 21

 Small molecules interacting with DNA quadruplexes (DNA Circular DNA nanomachine operating in whole human blood (the
structures investigated as new genomic switches that may have fluorescent dye indicates the mechanical state of the machine).
great therapeutic applications). Image from D. Monchaud & M.-P. Image reproduced by permission of Elton Graugnard from
Teulade-Fichou, Org. Biomol. Chem. 2008, 6, 627 Nanoscale, 7, 10382 (2015), DOI: 10.1039/C5NR02283E

DNA Robots to Treat Chemical modifications of DNA robots affect

Type-1 Diabetes binding kinetics – hence the time required for the
device to detect its input and release its output.
Ideally, medical treatments would occur only at
Thus DNA robots not only perform abstract logic
the specific cells and times requiring treatment.
operations but can also respond, with a delay,
Drug delivery aims to achieve this using drugs
based on the duration of the signals.
targeted to particular cell receptors. Improved
Extending this behavior to multiple robots allows
precision for devices allows improving targeted
responding to a series of chemical events within
drug delivery with logic operations based on
the cell that occur with specific time delays and in
sensed chemical environment. This can combine
a given sequence.
multiple signals to determine target cells.
DNA robots are cheap to manufacture. For
As a current example of this capability, DNA
example, $20 buys a trillion DNA robots at
robots can determine whether to release a
current prices. Thus enough robots to tag all
chemical inside a cell based on a few logic
~10 trillion cells in the body with 1-100 DNA
operations on sensed RNA in the cell. Minimal
robots would cost about $200-$20,000.
robots consist of a few strands of RNA,
Moreover, design software for DNA robots is
chemically modified to be stable inside cells.
available (e.g., at www.nupack.org and
They can be delivered into specific cells, e.g.,
cadnano.org).
via nanoparticles [Bath and Turberfield 2007;
Pinheiro et al. 2011]. More complex devices can This project investigates extending the simplest
consist of DNA origami with thousands of base- DNA robots to act based on information from
pairs assembled from hundreds of individual multiple interacting cells. This capability relies on
strands [Douglas et al. 2012, Katsnelson 2012]. detecting inter-cell communication. Specifically,
surface-bound DNA robots produce a chemical
The actions of DNA robots can be combined, with
signal when robots on the surfaces of different
the output of one being the input of another. In
cells come in contact.
this way, the final chemical output to change
behavior in the cell can be the result of multiple An application of this capability is to identify the
logic operations. This process can include signal subset of immune cells that attack beta cells in
amplification, where one output signal releases type-1 diabetes. Surface antigens are known for
many others in the next stage of logic operation. beta cells and immune cells, allowing targeting of

EXAMPLE RESEARCH PROJECTS 22

 DNA robots to the surfaces of each of those procedure. The second version of the procedure,
cell types. by contrast, combines the identification and
elimination of target cells without further human
An immune cell remains next to a target cell intervention. This combination requires target
for several minutes if interacting, while the identification with a high degree of reliability.
contact time is much shorter if the immune cell
is not activated. For this application, chemical This research project requires people experienced
modifications for DNA robot operation must have with methods to attach DNA robots to the
a similar time scale to trigger the sensor. This surface of cells with specific markers. The DNA
timing avoids false positives from an immune will require chemical modification so the robots
cell that briefly touches a beta cell but does not remain on the cell surface long enough for the
interact with it. inter-cell interactions to take place. Since these
robots will be applied to many immune cells,
In more detail, the proposed procedure is as the procedure for attaching the robots and the
follows. First, tag immune cells and beta cells with duration of their stay on the surface must not
DNA robots. Then wait for the immune cells to harm the immune cells. Moreover, after sufficient
circulate. Immune cells that target beta cells bring time for immune cells to circulate and find beta
DNA robots close together on their surfaces for cells, the body must harmlessly degrade and
long enough to trigger the reaction, resulting in remove the DNA robots.
releasing the signal into those immune cells.
Once suitable DNA robots are available, the
In one version of this application, the signal project must verify that cell-to-cell
released by the DNA robots on the immune cell is communication takes place, and this results in
a fluorescent marker. Since only those immune the exchange information between DNA robots
cells that target beta cells will have this signal, on interacting cells. Subsequently, this technology
subsequent fluorescent-activated cell sorting will can label immune cells that attack beta cells.
isolate those immune cells. Examination of those
cells will identify specific markers on immune In vivo testing will collaborate with diabetes
cells that target beta cells. This information research groups, who already have animal models
enables selective removal of just those immune and test procedures for evaluating safety and
cells from the patient, e.g., through drugs that efficacy of new treatments.
target cells with those markers. This procedure
will remove the attacking immune cells without This project has an estimated cost of $0.5 million/
affecting the rest of the patient’s immune system. yr over several years, with a team consisting of a
few post docs.
Another version of this application uses a signal
that disables or kills the immune cell. Since the This procedure generalizes to other autoimmune
signal is only released into immune cells that diseases, making it a powerful approach to
attack beta cells, only such cells will be affected. applying a small amount of computation to
greatly increase the precision of diagnostic or
The first version of this procedure provides therapeutic medicine.
information on the target immune cells without
harming them. This allows the attending
physician to evaluate the information before
acting on it. This separation of an information-
gathering stage from treatment allows checking
the accuracy of the targeting procedure before
proceeding to the treatment stage of the

EXAMPLE RESEARCH PROJECTS 23

 Evolutionary Material Design One approach is to mix DNA, dendrimers and
Applied to Binding Heavy Metals nanoparticles; assemble them randomly; select
the best ones; and replicate them with some
The increasing capabilities for synthesizing
variation. For example, this evolutionary
complex molecular structures highlights the
process could automate the process of finding
difficult design challenge of identifying useful
ligands that bind specific molecules with high
structures to make. This project addresses
selectivity.
the design challenge by applying evolutionary
methods to combinatorial variations of This project will focus on peptoid chains,
compounds. This involves creating many with molecular weight of about 5 kilodaltons,
variants within a class of molecules, testing consisting of precise sequences of blocks made
them for efficacy, selecting those with the best of amino acids. Attaching these compounds to
performance and repeating the process with gold nanoparticles will create a combinatorial
variants of the selected population of molecules. library of molecule shapes, with up to 1015
variations. These molecules will then be tested
for how well they bind to target molecules of
interest, e.g., virus particles. As an example
application of this use of evolutionary design,
the project will search for compounds that bind
heavy metals.

The project will proceed in three phases. The

first phase uses the evolutionary method to
explore many combinations of known peptoids
that bind metals. Selection pressure will be
applied by environmental stress, such as how
they react to fluid shear or how cells respond
to the particles. For instance, when using fluid
shear, those compounds that bind strongly will
resist disruption by the fluid flow.

Crystal structure of parallel quadruplexes from human telomeric

The second phase is a systematic study
DNA. The DNA strand (blue) circles the bases that stack together of effective compounds found through the
in the center around three co-ordinated metal ions (green).
Image from Thomas Splettstoesser.
evolutionary exploration. This study will
identify binding mechanisms and suggest

EXAMPLE RESEARCH PROJECTS 24

 variations of the successful compounds that power, such as a small battery, to allow collecting
could improve binding. These variations will be and storing information over a period of time for
created and tested. eventual download to a cell phone.

The final phase will develop applications for the This would allow providing more sensor readings
resulting molecules. These could include bio- than just when the user decides to interrogate the
mining, environmental remediation and treating sensor with a cell phone.
heavy-metal poisoning. The molecules could also
be a platform for highly specific metal sensors for This project will design, fabricate and test the
use in other applications. sensor. In particular, the team will evaluate the
sensor’s measurement stability and develop a
The project will require $3 million/year for calibration procedure to produce accurate
5 years, and an interdisciplinary team of about readings.
12 post doc positions with skills in chemistry,
data analysis and applications for heavy- The project team will collaborate with other
metal binding. companies to create health apps using the
information provided by the sensor. This will
involve finding correlations between repeated
pH Sensors pH measurements and medical diagnoses. Since
The increasing precision of fabrication these applications may require considerable time
technology allows large-scale manufacture of and funding to obtain FDA approval, the company
cheap sensors with better accuracy, smaller size will also identify entertainment applications for
and greater stability than current sensors. This people interested in tracking daily changes to
is leading to a wider range of feasible medical their oral environment, e.g., based on their dietary
diagnostics, including sensors that patients can choices. Such applications could reach market
use for extended periods of time. Such sensors soon after the sensor is available. These will
can capture variation over days or weeks, thereby also provide feedback on the user interface and
providing better indication of patient health data on normal variation in pH, which could later
and response to treatment than is possible with improve the interpretation of sensor readings for
occasional sensing limited to when a patient sees medical diagnosis.
a medical professional.

As an example of the benefits of such sensors,

this project will develop a cheap, real-time oral pH
sensor. It will consist of a patch to stick on a tooth
for a few days. After use, the patient will remove
and dispose of the patch.

An important design issue for sensors is whether

and how they obtain power. One possibility is an
unpowered sensor that, for example, reports pH
by changing color. A cell phone camera detects
the color change and provides the sensor reading.
Alternatively, a sensor could obtain power
intermittently via an RF antenna in the patch. In
this case, the sensor gets power when read by a
nearby device, such as a cell phone. For greater
sophistication, the sensor could have onboard

EXAMPLE RESEARCH PROJECTS 25

Visualization showcasing the form and function of the Chromallocyte and the various onboard subsystems. The main chasis of the Chromallocyte consists
primarily of diamondoid. © 2007 Robert A. Freitas Jr., Images created by Stimulcra LLC

NEXT STEPS
The development of atomically precise tools is requires sustained funding for interdisciplinary
a significant opportunity to improve medical teams to develop strong collaborations and
treatments of a wide variety of diseases create and apply the new tools. In particular,
and their fundamental causes. The research at the early stages of development, funding
projects presented at the workshop illustrate will be mainly for creating new tools and basic
near-term potential directions for investigating biological knowledge to apply them effectively.
this opportunity. In aggregate, these projects Only later will these developments become
require a few tens of millions of dollars per viable clinical approaches to fundamental causes
year over 5 to 10 years, to advance development of disease. Thus the initial stages of the projects
of atomically precise tools and evaluate their may not appeal to funders with focus on near-
potential medical application. term treatment of specific diseases.

A useful follow-up on these projects would be Other practical issues are the regulatory
quantitative estimates of the performance of environment for bringing new treatments to
their required tools, to compare with current market and the IP process blocking innovation
advances. For instance, exactly what must by making it expensive for a single group to
sensors measure, and how accurately and identify, negotiate and pay for the wide variety
rapidly must they deliver their measurements. of patents that could be involved in creating and
These would be relatively small, low-cost studies using high-precision tools. Although beyond the
that could reduce risk by testing whether the scope of this workshop, the next steps should
ideas are feasible with precise tools becoming include addressing these practical concerns.
available over the next few years.
Projects discussed at the workshop are not
The workshop’s focus was on the technical the only possibilities for exploiting atomically
feasibility of atomically precise tools and their precise devices. Thus, small interdisciplinary
application to medicine. However, the workshop groups could explore possibilities for additional
also briefly discussed the practical issue of projects. Especially useful would be projects
funding exploratory, high-risk and high-reward likely to address fundamental causes of disease,
medical projects. which could help treat multiple diseases.

For instance, developing and applying atomically

precise tools to fundamental causes of disease

NEXT STEPS 26
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 PARTICIPANT LIST

Demir Akin, DVM, PhD Ouajdi Felfoul, PhD Alice Lay, PhD
Deputy Director Pediatric Cardiac The Dionne Group
Center for Cancer Nanotechnology Bioengineering Lab Stanford University
Excellence Children’s Hospital Boston
Stanford School of Medicine Harvard Medical School Joseph Lyding, PhD
Lyding Research Group
Tural Aksel, PhD Steven Fowkes Beckman Institute
The Douglas Lab, UCSF Co-Founder, Chief Science Officer University of Illinois
Nanopolymer Systems
Amanda Barnard, PhD San Francisco Bay Area Sylvain Martel, PhD
OCE Science Leader Tier 1 Canada Research Chair
Virtual Nanoscience Laboratory Rob Freitas in Medical Nanorobotics
CSIRO Materials Science Institute for Molecular Manufacturing Professor and Director
and Engineering, Australia Palo Alto Ecole Polytechnique of Montreal

Aaron Becker, PhD James Gimzewski, PhD Hareem Maune, PhD

Swarm Robotics Lab Gimzewski Lab IBM Almaden Research Center
Harvard Medical School Distinguished Professor
University of Houston UCLA Chemistry & Biochemistry Dept Huan Meng, PhD
Dept of Medicine,
Keith Brown, PhD William Goddard, III, PhD NanoMedicine Member
MIRKIN Research Group Materials & Process Simulation Center UCLA Johsson Comprehensive
Northwestern University California Institute of Technology Cancer Center

Tejal Desai, PhD Si-Ping Han, PhD Ralph Merkle, PhD

The Desai Lab Dept of Chemistry Institute for Molecular Manufacturing
Bioengineering & Therapeutic California Institute of Technology Nanotechnology Co-Chair
Sciences School of Pharmacy, UCSF Singularity University
Huang, Possu, PhD
Jennifer Dionne, PhD The Baker Laboratory Stephanie Morris, PhD
The Dionne Group University of Washington Program Manager
Stanford University NCI Office of Cancer Nanotechnology
A.T. Charlie Johnson, PhD Research, NIH
Anne-Sophie Duwez, PhD Director
NanoChemistry & Molecular Systems Nano/Bio Interface Center Andre Nel, PhD
University of Liege Penn Arts & Sciences The President’s Council of Advisors
on Science and Technlology (PCAST)
Martin Edelstein, PhD Nazila Kamaly, PhD Working Group Member
Covalent / Biophiltre Instructor, Laboratory of Division Chief, NanoMedicine Dir.
Nanomedicine and Biomaterials California NanoSystems Inst, UCLA
Greg Fahy, FSC, FAAA Harvard Medical School
Vice President and CSO Brigham and Women’s Hospital Lizanne Nilewski
21st Century Medicine Graduate Student
Southern California Mark Kline, PhD James M. Tour Group
X-Therma Inc. Dept of Chemistry
Lawrence Livermore National Rice University
Donglei (Emma) Fan
Dept of Mechanical Engineering Laboratory
University of Texas at Austin Aleksandr (Alex) Noy, PhD
Amy Lam Bionanoscience and
Graduate Student Biotechnology Division
Biomedical Engineering Lawrence Livermore National
Columbia University Laboratory

29
 PARTICIPANT LIST CONT.

Matthew “Oki” O’Connor, PhD Xiaoxi Wei, PhD

Senior Research Scientist CEO & Founder
MitoSENS Lead X-THERMA Biomimetic Nanotech
SENS Research Foundation San Francisco Bay Area

Gayle Pergamit Colin Zamecnik, PhD

Covalent / Biophiltre The Desai Lab, UCSF

Kevin Perrott Alex Zettl, PhD

Co-Founder Zettl Research Group
SENS Research Foundation UC Berkeley

Benjamin Ricca, PhD Ronald Zuckermann, PhD

Postdoctoral Scholar Senior Scientist
Fletcher Lab Molecular Foundry
UC Berkeley Lawrence Berkeley National
Laboratory
Mehmet Sarikaya, PhD
The Sarikaya Research Group Yang Zhao, PhD
GEMSEC-Labs The Dionne Group
An NSF-MRSEC Stanford University
University of Washington

Christian Schafmeister, PhD

Associate Professor
Dept of Chemistry
Temple University

Milan Stojanovic, PhD

Associate Professor
Columbia Systems Biology
Columbia University

Ennio Tasciotti, PhD

Co-Chair
Dept of NanoMedicine
Methodist Hospital Research Institute

Meni Wanunu, PhD

Wanunu Lab
Dept of Physics and Chemistry
Northeastern University

Andre Watson
Founder & CSO
Ligandal, Inc.
San Francisco Bay Area

30
 REPORT CREDITS

Miguel Aznar - Knowledge worker

Delara Chizari - Knowledge worker

Travis Dirks, PhD - Knowledge worker

Allison Duettmann - Graphics and layout editor, whitepaper review

Tad Hogg, PhD - Whitepaper writer

Markus Krummenacker - Knowledge worker

Jim Lewis, PhD - Whitepaper review

Joseph Lyding, PhD - Whitepaper review

Stephanie Malone, PhD - Knowledge worker

Paul Melnyk - President

Max Sims - Knowledge worker

Edwin Urey - Knowledge worker

Amber Webster - Graphic design and layout

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