“NANO” IS NOW”AT MICHIGAN — AND JAMES
BAKER IS LEADING THE WAY
by Eric J. Lerner
James Baker and His Colleagues at the Center for Biologic
Nanotechnology Are Using Nanoengineering to Fight Infections,
Deliver Genes, Destroy Cancer Cells and Completely Alter the
Way We Define Medicine.
James Baker |
Biology Meets High Tech: Forget Leeuwenhoek. Forget those glass
lenses that first brought you the magical sight of an amoeba
swimming in pond water. Forget the electron microscope. Shrink
your notions of small and travel into the world inspired by
the microchip, a world smaller than your teeniest notion of
small...a "nano" world where some of the biggest dreams
ever dreamed in medicine are being dreamed today.
Imagine tiny plastic balls a zillion times smaller than any-
thing you can think of. Imagine drops of ordinary soy bean oil
a zillion times smaller than anything you can think of. Imagine
the tinier-than-tiny plastic balls and the super-small drops
of soybean oil saving your life.
Welcome to the fantastic new world of nanomedicine — a world
where doctors, biological scientists, chemical engineers and
microchip builders are all speaking the same language, working
together in a new and very tiny world of truly cross-disciplinary
miracles.
"This is the start of the post-genomics therapeutic revolution,"
says James R. Baker Jr., M.D., an allergist and immunologist
by training and now director of the new Center for Biologic
Nanotechnology he founded at the University of Michigan Medical
School in 1998. One of the early believers in nanomedicine,
Baker is a convincing proponent of this nascent field. "What
we are doing is developing synthetic materials — not biologic
molecules — to form tiny structures, or nanodevices, that
perform medically important tasks," he explains. The
Center has pioneered research in nanodevices that perform
these tiny miracles. These devices are so small that they
can slip inside cells without being recognized, but at the
same time alter the function of entire organs "where
we specifically address problems identified by genetic analysis
using tailored therapies that restore normal molecular function." A
number of extremely promising avenues of research are underway
in the Center, including several that are advancing into
clinical trials.
The whole concept of nanomaterials is difficult for the layperson
to understand. By definition, nanomaterials are thousands to
millions of times smaller than the cells that make up our bodies,
and the ability to make materials this small is a recent accomplishment.
(The prefix "nano" actually means "billionth.")
Much of the basic research in these materials came from the
semiconductor industry, where the need for smaller circuits
and storage devices drove the miniaturization of engineered
parts. These studies have led to the assembly of materials,
literally atom by atom, into devices like motors and disk drives.
Many of the materials Baker works with actually self-assemble
into more complex arrays and devices. However, as difficult
as it might be to produce these materials, it is even harder
to visualize them and assure that the structure is correct.
This has spawned a new industry to develop machines that can
analyze and image nanodevices. "These materials are so
small they cannot be viewed with traditional tools, even electron
microscopes," Baker explains. "We often have to examine
them indirectly, as if we are observing a shadow. It makes the
whole process very difficult."
Despite the complexity of the manufacture and analysis of nanostructures,
the potential benefits are truly remarkable. "We believe
that most human afflictions can be addressed by nanotherapeutics,"
Baker says with the confidence of the laboratory-rooted dreamer
that he is, and he goes on to illustrate his point. "For
example, we have developed non-toxic nanoemulsions that penetrate
and kill infectious microbes from the flu virus to anthrax spores.
We are using synthetic molecules called dendrimers as machines
to detect and characterize cancer cells, then destroy them by
selecting and delivering a specific drug or gene therapy. Other
work is focused on developing polymers that replace defective
cellular proteins to treat genetic disorders, such as cystic
fibrosis. The possibilities are truly limitless." Not that
it will be easy. Scientists in nanomedicine are faced with the
challenge of not only developing materials, but also adapting
and inventing new tools. They have to bring a totally fresh
mindset to the treatment of disease. At Michigan they're doing
it with a uniquely integrated multidisciplinary approach, with
ongoing collaboration between scientists from materials science,
chemistry, pharmacology and medicine. "It is really more
of a think tank than a traditional medical research program,"
says Baker with a pride he finds hard to conceal.
Fighting flu with vegetable oil
Tarek Hamouda |
The project that has moved the furthest towards practical
application — using nanoemulsions of vegetable oil to kill
microbes — is perhaps the most dramatic demonstration of the
power of nanotechnolgy. Soybean oil in its standard form does
not kill any microbes — in fact quite a few use it for food.
But Baker and colleagues Tarek Hamouda, Andrzej Myc, Peter
Cao, Amy Shih and Brian Donovan found that if the oil is emulsified
with detergents to form nanodrops 400-600 nanometers (nm)
across, they act with devastating effect on nearly all pathogens.
It is not a chemical action, but a physical one similar to
what causes the oil and water in salad dressing to separate.
The droplets' surface tension makes them want to coalesce
with other lipid droplets, even though they are stabilized
so they cannot coalesce with themselves. The smaller the droplets,
the greater the surface tension and the stronger the urge
to merge. When the oil droplets contact the membranes of bacteria
or enveloped viruses, the surface tension forces a merger
with the membrane, blowing it apart and killing the pathogen. "Basically
what we have created are nanometer-sized bombs," says
Baker. "But the tissue
structure of the cells of humans and other higher organisms
prevents them from being disrupted by the droplets." As
a result, the emulsion is entirely safe when applied externally.
Only red blood cells and sperm cells lack tissue support
structure and are vulnerable to fusion and destruction by
the oil droplets. This means on the one hand that the emulsion
cannot be used intravenously, but it also makes it a potential
anti-microbial contraceptive that kills both sperm and sexually
transmitted disease organisms like HIV.
Amy Shih |
Tests in mice have been promising. When mice were given nose
drops of the oil nanoemulsions and then exposed to a lethal
dose of influenza virus, 75 percent were protected against the
disease, while 80 percent of the control mice died. "We
think the results in humans will be much better," explains
Hamouda, "because the virus dosages in the experimental
animals were far higher than people would be normally exposed
to."
In other experiments, mice were given wounds and then infected
with anthrax-like spores. Without treatment, the mice developed
large infected sores, similar to cutaneous anthrax. However,
mice whose wounds were washed with dilute nanoemulsion solution
hours after infection developed essentially no lesion at all.
It was particularly surprising in the nanoemulsion research
that bacteria spores, as well as active bacteria, were killed.
Spores are especially hard to kill because they have a hard
exterior coating rather than a membrane. "The oil emulsion
seems to trick the spores, because it looks like food to them,"
says Baker. "Once the spores become active and generate
a membrane, the emulsion kills them." This action has been
of particular interest to the Defense Advanced Research Projects
Agency that has funded some of this work, as it is a promising
way to fight the use of anthrax spores in biological warfare.
Molecular toolboxes
Andrzej Myc |
While the nanoemulsion works well as tiny bombs, for most
uses more subtle interventions are needed, using a variety
of molecular tools. To deliver these tools, the Center's researchers
have been developing a kind of all-purpose molecular toolbox
called a dendrimer. Dendrimers are spherical, branching molecules
whose structure looks like a very regular bush. They can be
made in various diameters, depending on how many shells or
branchings they have, and are covered with dozens of molecular "handles"(simple
amino groups) that researchers can use to attach a variety
of biochemically active molecules. The more shells, the larger
number of amino groups — two shells have eight groups, four
shells have 16, and so on. Dendrimers can act as nano-sized
tool kits, able to deliver the modular tools to the right
place, and even as nanomachines, able to use the tools in
the right sequence at the right time.
Brian Donovan |
Dendrimers were invented in the late 1970s by Donald Tomalia,
now scientific director of the Biologic Nanotechnology Center.
"I was looking for a way to make branching molecular structures
that imitated the branching of trees," Tomalia recalls.
Initially the molecules were applied for non-biological uses,
but in the mid-1990s Tomalia and Baker started to look at possible
medical applications, especially for gene therapy. "The
great advantage of dendrimers is that they don't trigger the
immune system," says Lars Piehler, a biochemist at the
Center. The amino groups that cover the molecule are not recognized
as foreign by the immune system, unlike the proteins of other
vectors such as adenovirus or adeno-associated virus (AAV).
Perhaps the most far-reaching potential application of dendrimers
in medicine is for gene and drug delivery. Despite its immense
promise, gene therapy has been stymied because of the problem
of getting genes into enough cells to make a therapeutic difference.
Carrying the gene into the cells as part of a virus, one widely
used approach, has the serious disadvantage that the virus,
even if benign, triggers an immune reaction by the body. If
fewer virus particles are used to minimize the immune reaction,
not enough cells are altered. Unfortunately, the larger virus
dosages required for most applications risk an overwhelming
immune response. This can have serious consequences, including
fatal reactions, as happened with the highly publicized case
of Jesse Gelsinger, a teen-ager who died following adenovirus
gene therapy.
Peter (Zhengyi) Cao |
Dendrimers can carry genes into cells without setting off the
body's immune response. "In effect, they are stealth proteins,"
says Tomalia. Although they are big enough to carry genetic
material, as a virus would, their bushy surfaces lack the complex
folds that allow antibodies to bind and alert the body's immune
defense. Instead, they appear as blobs of amino acids. This
allows them to carry large amounts of genetic material into
the body without undue stress. In addition, the size of a dendrimer,
which is adjustable depending on how many shells they have,
is in the right range to wrap genetic material around them.
So far, the dendrimer-based delivery or transfection of genes
has been demonstrated successfully in vitro and is now being
tested intensively in animals. "We've found that the
efficiency of transfer — the percentage of cells that get
working genes — is almost as high as with viruses," says
Baker. But substantial challenges remain. Dendrimers may
interfere with genetic transcription, which could prevent
the transferred genetic material from functioning within
cells. In addition, despite the fact that dendrimer-carried
genes did not produce pneumonia when inhaled into animals'
lungs, some of the animals died. This appeared to be the
result of the dendrimers pulling fluid into the lungs of
the animals.
"All new materials will have some toxicity, often unexpected,
and require extensive toxicity testing. The important thing
is not to take anything for granted," remarks Baker.
So several hurdles will have to be overcome to reach the
goal of a general-purpose gene-delivery system using dendrimers.
A cancer-fighting nanomachine
Lars Piehler |
The most ambitious avenue of research in the Center is to
adapt the dendrimers' toolbox capabilities to produce a multi-functional
anti-cancer nanodevice. In cancer therapy, the long-sought
goal has been a treatment that attacks only the cancer cells
and not the healthy cells. Piehler and colleagues are working
on ways to do just that — with a dendrimer that locates cancer
cells, shows where they are, enters them, confirms they are
cancerous, and then kills them.
"Because the dendrimer has so many attachment sites, we
can put different chemicals on different sites for a variety
of functions," Piehler points out. In the approach now
under development, targeting groups on the dendrimer would attach
preferentially to cancer cells rather than healthy ones. A second
attached group would be fluorescent, so that the cancer cells
can be viewed by surgeons using a weak laser light, or labeled
for use with MRI imaging techniques. Once inside the cells,
another dendrimer will confirm the "signature" of
cancer within the cell, to assure normal cells have not been
targeted. Inside another part of the polymer structure, the
dendrimers will carry a cytotoxin, such as cisplatin. The poison
will be bound up with the dendrimer and be inert until release.
Then, release of the poison, which can be triggered by several
methods including laser light, kills the cancer cells and gives
a readout that the tumor has been killed. In this plan, laser
light could be introduced to an internal tumor through a narrow
fiber, minimizing surgical damage to healthy tissue.
"One of the great advantages of dendrimers is that you
can bind chemicals at precise locations, including in the interior
of the molecule, because of the way they are built up from the
inside out," explains Tomalia. Each time a new shell is
added to the dendrimer, new functional groups can be attached
and then incorporated within the molecule as an additional shell
is added. With multiple attachment points, several copies of
each functional chemical can be used, increasing the effectiveness
of the group.
Tomalia, Piehler and others are pursuing a number of possible
strategies for anti-cancer nanomachines. In another version
the dendrimers carry boron clusters into the cancer cells. Boron
is a heavy absorber of neutrons, so when the tumor is irradiated
with a neutron beam, the boron nuclei absorb energy, releasing
it as short-range, but deadly, X-rays, killing the cells they
are in. But the neutrons pass relatively harmlessly through
the healthy cells, producing little damage.
Wrapping up a virus
The Center is also investi-gating the possibility that dendrimers
might be used in novel ways to fight viral infections. A first
step in many viral infections occurs when a virus attaches itself
to the sialic acid molecules found in the human cell membrane.
(Sialic acid is a sugar-coated lipid known as a glycolipid that
is a component of human cell membranes.)
By coating dendrimers with low concentrations of sialic acid,
it is reasoned, one could "fool" the virus into attaching
itself to the dendrimers instead of to the cell itself. "We
can grow dendrimers to be long and rod-like instead of spherical,"
explains Tomalia. "If we cover them with sialic acid, they
can wrap themselves around the virus in such as way as to prevent
the virus from binding to the cell." Tomalia and his collaborators
have found in laboratory experiments that these multiple-branched,
linear dendrimers, which vaguely resemble ivy vines, have been
most effective in preventing various strains of flu viruses
from binding to cells.
While much work remains to be done in this area, Tomalia and
his colleagues at the Center share the heightened enthusiasm
that comes from exploring a true frontier, both medical and
scientific. They feel confident that the incredibly small world
of nanotechnology is opening up a giant new world of medicine,
one with possibilities never even dreamed of before now.
Baker, the nano-man of the moment, finds inspiration in a quote
from Sir Arthur Conan Doyle: "I think that little things
are infinitely more interesting."
DENDRIMERS CAN CARRY GENES INTO CELLS WITHOUT SETTING THE BODY'S
IMMUNE RESPONSE. "IN EFFECT, THEY ARE STEALTH PROTEINS."
- DONALD TOMALIA
THINKING SMALL ON A GRAND SCALE:
From AIDS to Desert Storm, Jim Baker's Life in Medicine
Has Not Been an Indifferent One. Perhaps That's Why Nanomedicine,
with Its Bold New Death-Defying Promises, So Much Fascination
for Him.
By Jane Myers
James Baker |
For James Bond fans around the world, the number "007"
tells a story all its own, signifying the derring-do associated
with the intrepid secret agent invented by the pen of Ian Fleming
and romanticized by dozens of popular film adaptations. For
James Baker Jr., the number that begins his story of adventure,
though of a seemingly more restrained sort, is "003."
Baker, who in 1971 went from his comfortable middle-class youth
in the Chicago suburb of Oak Park to equally comfortable Williams
College, nestled in the bucolic, purple, rolling hills of the
Berkshires, remembers the day his mother called his dorm room
to tell him what she'd just learned about his place in the nation's
draft lottery. "Your number is 003," she said. "You're
going to be killed."
It was a time when there were no college deferments, and the
war in Vietnam was still raging, so an immediate call-up loomed
large for the young Baker. Fortunately for him, Army Reserve
duty delayed his going to Vietnam, and Saigon fell to the Vietcong
a few months before his college graduation.
But while America's costly involvement in the Vietnam War was
over, Baker's life was changed forever. Having options for duty
in the Reserves post-Vietnam, and with his scientific aptitude
and interest in medicine already clearly identified, Baker began
(at the behest of the U.S. Army) the first 12 years of his medical
life. This involved medical school at Loyola Stritch and a residency
in internal medicine at Walter Reed. A clinical fellowship in
immunology and research at Walter Reed and the National Institutes
of Allergy and Infectious Disease followed. After completing
the fellowship, he returned to Walter Reed to participate in
the transplant and HIV programs there.
Since then, those first 12 years with the Army in the Washington,
D.C., area have evolved into a rather extraordinary saga —
one that even the highly inventive Ian Fleming would find
in many ways astounding. The plot twists are not minor — and
they are not fiction. They involve the real stuff of life
and death, but life and death on a dramatic scale that the
young Jim Baker could never have envisioned as he contemplated
his future career as a doctor. It was his lot to watch hundreds
of young men (and older Army generals), and then eventually
women, die in the prime of their lives of a disease no one
had ever heard of — AIDS. "All my patients died," he
says, and then finds the positive filter he seems to use to
help maintain his steady focus on the work ahead: "It
was a good experience to go through as a doctor; it defines
you as a physician and gives you a healthy respect for nature
and how tenuous life can be."
One of the men he watched die had helped save Baker's own life
when they were part of a group of soldiers on a misguided training
exercise in Virginia. Due to a commander's error, Baker and
his fellow trainees had been put in a life-threatening situation
in a swamp, and this man had gotten them out. "He was a
gutsy guy and the commander's aide," Baker says. "He
was also exactly my age. Four years later he came down with
Kaposi's sarcoma."
It was also Baker's lot, since he was still in the Army Reserves,
to be called back to duty for the Gulf War and to then find
himself contemplating the possible deaths of thousands of the
young men and women sent off to fight a war there. Here the
issue was not gunfire but the more silent and invisible killers
made from deadly germs and chemicals. "I'd go into a meeting
and they'd be talking about 100,000 burn victims or 10,000 inhalation
injuries," he remembers vividly. "It forces you to
want to make a difference."
Tarek Hamouda, Amy Shih
and James Baker |
It's not that Baker has always sought the monumental personal
or professional challenges that have come his way. In the early
1980s he changed his specialty from oncology to immunology just
because he couldn't stand to administer any more of the extreme
doses of anti-cancer drugs that were being used in clinical
trials at the time. "I watched exceedingly toxic reactions
from one particular drug, adriamycin, which was administered
into almost every imaginable portal. It was so disturbing I
still can't make red Kool-Aid (the color of the drug) for my
daughter," he says. But such have been the powerful twists
of fate to which he has been subjected that a member of his
own family was administered the very same drug, in more limited
dosages, for breast cancer less than two years ago.
These world events, unpredictable and jolting, on both a professional
and a personal scale, have shaped Jim Baker. Part of him is
still the teen-ager dazzled by laboratory work, the young man
with a mind open to every possibility, always scanning the data
("I like data much better than hypotheses.") for the
new ways of thinking that might be suggested.
Part of him is ancient bearded philosopher. He uses the words
"tenuous" and "ephemeral" to describe the
precariously delicate nature of our lives with an authority
that few people can muster. He does not understand those who
worry about not having tenure, those who think that a secure
life can be imposed by formal structures. But his ability to
distance himself in a thoughtful way from the world of medicine
still has its limits. Supporting his immune-deficient patients
who have what he calls the "real" problems keeps him
firmly grounded in the here and now, and he remains troubled
by the death last year of his mother from Graves' disease, finding
it hard to let go of the notion that small corrections in how
she was treated could have changed her outcome.
Part of him is hardened soldier, although Baker suggests with
a wry smile that "hard-headed bureaucrat" would
be a more apt description. Still, he admits to understanding
clearly that victory will go to the side that is best prepared,
to the side that has the best resources, to the side that
is least naive and most importantly to the side that has
the greatest resolve. "I'm not the smartest person in
the University of Michigan Health System," he says, "but
I am among the most determined." These qualities have
helped him become a savvy grantsman since arriving at the
University in 1989.
"I sort of knew where I needed to go" is how he modestly
describes his ability to find the funding he needs — now totaling
an astounding $20 million in projects currently underway at
Michigan.
Baker had been at Michigan only for a year and a half when he
was called away from his faculty position to go off to Desert
Storm, a wrenching change of venue for someone just getting
settled into the academic world. Everything since that time,
he says, has felt "like a second chance, an opportunity
that I am very lucky to have."
He is not letting the opportunity go to waste. A serendipitous
twist, one not in the harrowing category of so many of Baker's
life turns, happened when he was called in to consult about
a patient who, as it turned out, was suffering from a severe
drug allergy. The patient, who survived, and the doctor who
helped keep him alive established a bond. He was, by chance,
a retired Dow Chemical executive. Hearing about Baker's new
work with tiny virus-like lipids and their ability to kill bacteria,
he told him about the work of Dow chemist Donald Tomalia, who
was just then making something he described as "a new form
of matter"- extremely small nanoballs of nylon. The meshing
of Baker's and Tomalia's ideas was so complementary that the
two men were soon working together, and Tomalia joined Baker's
team in the Center for Biologic Nanotechnology at Michigan last
year. The nano-scale work being conducted there, where the organic
and the synthetic meet on a level not even imaginable a short
time ago, is opening up a new world of medicine.
While the work is smaller than small, the extraordinary possibilities
for the future are allowing Baker's visions for the future to
grow larger and larger. For "003," life in the fabulously
adventurous world of nanomedicine promises more excitement than
Ian Fleming imagined in his most inventive moments.
MICHIGAN'S RESEARCH POWER
Total R&D Expenditures for Fiscal Year 1998
University of Michigan: $497 M
UCLA: $447M
University of Wisconsin: $444 M
University of Washington: $432 M
University of California, Berkeley: $420 M
University of California, San Diego: $419 M
Massachusetts Institute of Technology: $413 M
Johns Hopkins University: $411 M
Stanford University: $410 M
Texas A&M: $394 M
(Source: National Science Foundation; total excludes R&D
expenditures for the federal Applied Physics Laboratory at Johns
Hopkins University)
Top Ten Academic Institutions Ranked by Article Citations
1. Harvard University
2. Stanford University
3. California Institute of Technology
4. Yale University
5. University of Michigan
6. Massachusetts Institute of Technology
7. University of California, Berkeley
8. University of Washington
9. University of California, Santa Barbara
10. Cornell University
Top-Cited Fields of Study at the U-M in order of frequency of
appearances, with Medical School fields noted in boldfaced type:
education, psychology/psychiatry, astrophysics, immunology,
computer science, pharmacology, economics/business, law, materials
science
(Source: Institute for Scientific Information; based on frequency
of appearances in 21 scientific fields, 1993-97)
Faculty Serving on National Boards and Commissions:
Harvard University: 95
Massachusetts Institute of Technology: 69
Stanford University: 68
University of California, Berkeley: 57
University of Michigan: 51
University of Washington: 49
Cornell University: 40
University of Wisconsin: 39
University of Colorado, Boulder: 37
UCLA: 36
(Source: Survey conducted by U-M Office of the Vice President
for Research)
The National Institutes of Health have nearly doubled funding
awards for medical research at the University of Michigan Medical
School in the past 11 years. The Medical School now ranks 9th
in the nation among all academic research institutions, public
and private, and 3rd among public universities in total grants
from the NIH.
All information courtesy of the University of Michigan Office
of the Vice President for Research.
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