Northeastern is a center
of research
Four campus research centers
foster faculty visions
Slava Epstein, Electron Microscopy Center
By Susan Mellen
Slava Epstein spends his time studying relationships. The Russian-born
researcher is neither a psychiatrist nor social scientist, however. An
assistant professor of biology, Epstein uses the equipment of the Electron
Microscopy Center, located on the fourth floor of Mugar Hall, to study
surprising symbioses between microorganisms. Far from being beneath notice,
these win-win relationships have implications for the entire planet.
"The introduction of molecular biological tools has allowed us
to look at ecological relationships at the cellular level. One of the aspects
of this new research has been a whole category of relationships that have
positive value to each of the microorganisms in the interaction-when both
sides win. I'm very interested in how two completely different cells can
benefit because they can do together what they can't do alone," Epstein
says.
Epstein is currently focusing on the particularly amiable and critically
important relationship between two microbes: methanogens (methane-producing
bacteria), and a category of protozoa found in marine sediment taken from
Massachusetts's northern coast. By isolating individual pairings, Epstein
and his graduate students have been able to witness a remarkably successful
microbiological partnership.
Left to their own devices, methanogens are unfortunate little beings
with very little capacity to conserve energy. Yet-amazingly enough in the
microbe-eat-microbe world beyond human vision-methanogens exist everywhere:
in marine and freshwater sediments, wetlands, sewage sludge, municipal
landfills, and even the digestive tracts of animals. One key to their ability
not only to thrive in this highly competitive environment may well be their
symbiotic relationships with protozoa that release the exact substances
methanogens need for growth. By attaching themselves to the protozoa, the
methanogens are able to efficiently absorb necessary energy that would
be virtually unavailable in the microscopic world-at-large. In turn, by
absorbing the substrates released by the protozoa, the methanogens help
their partners process waste much more efficiently.
In the Electron Microscopy Center, Epstein has been able to produce
images showing the sac-like protozoa practically overrun with armies of
the much smaller methanogens. "The ciliate [protozoan] is really just
a bag filled with methanogens. It's like a little bag of potatoes,"
he says.
This prosperous relationship may account for the majority of methane
production worldwide, Epstein says. An understanding of this protozoan/
methanogen marriage is therefore critical to our ability to predict future
levels of methane, one of the major greenhouse gases in the atmosphere,
he observes.
"To make any prognosis about the greenhouse effect and global warming,
you need to understand methane's dynamics and how it is produced by these
organisms. This one instance alone shows how important these symbiotic
relationships are to the entire planet," says Epstein.
Since he garnered a faculty appointment two years ago, Epstein and the
Electron Microscopy Center have enjoyed a symbiotic relationship of their
own. The center's advanced equipment-including both transmission and scanning
electron microscopes and other equipment for cutting-edge research techniques-has
allowed Epstein to peer into the lives of individual microorganisms.
"It has been important for this work to view these relationships
from the point of view of individual organisms. This has been impossible
using traditional techniques," he says. "In the past, we've been
able to observe, but not really study these organisms. Although some of
the molecular biological techniques have been around for a while, they
haven't been applied to field microbiology until very recently."
Conversely, researchers like Epstein-the center's largest user-lend
the excitement of new and significant research to the twenty-six-year-old
facility. Over the years, the center has hosted a number of important studies
by faculty from many different disciplines. The center's equipment and
qualified personnel, coordinated by William Fowle, are also proving critical
to research outside the university's walls. A number of biotechnology firms
and hospitals now rely on the center for cell studies requiring advanced
electron microscopy (EM) techniques.
"A company would have to invest a lot of time and energy in learning
EM techniques. Researchers would have to spend a good three to four months
to become proficient," explains the center's director, Associate Professor
of Biology Daniel Scheirer. "It makes a great deal more sense for
people to come to us for this very specialized work. There are very few
places in the Boston area that can do this kind of work, so this has become
something of a niche for us, doing service work for clients."
For his part, Epstein talks about taking his research far beyond the
Massachusetts coastline, using the Electron Microscopy Center to examine
microorganisms in conditions ranging from equatorial to arctic. The importance
of this kind of wide-ranging research is virtually inestimable, he says.
"We know that, of all the microorganisms that exist on the planet,
only about one percent of the species has ever been cultured. So all the
textbooks, the entire biotech industry, and all the antibiotics on the
shelves have come from this small percentage. Imagine what we could do
if we could find ways to study even a little bit more of the microbial
world. There would be an unimaginable biotechnological revolution."
Susan Mellen is a freelance writer in Tyngsborough, Massachusetts.
Nicol McGruer, Microfabrication Laboratory
By Micky Baca
Associate Professor of Electrical and Computer Engineering Nick McGruer
and his research colleagues at the Microfabrication Laboratory have carved
out a big place in a shrinking world. McGruer and more than a dozen staff
members and graduate students are developing a new generation of miniature
technology called microelectromechanical systems, or MEMS.
MEMS technology applies techniques refined in manufacturing computer
chips and microprocessors to create miniature devices with both electrical
and mechanical properties, such as switches, relays, and "smart"
sensors. Much as the semiconductor and the integrated circuit revolutionized
the electronic world, MEMS promises to transform the fields of sensors
and mechanical devices, says McGruer, who directs the Microfabrication
Lab.
MEMS sensors are already used for a variety of functions in automobiles,
including the triggering of air bags when impacts occur. MEMS devices have
far-reaching potential for everything from robotics to medical equipment,
McGruer says. They could, for example, be used to create "smart cars"
that would sense the temperature or road conditions and make mechanical
adjustments accordingly. Or they could be employed in more mundane ways,
such as sensing when a washing machine load is off balance.
At the heart of the Microfabrication Lab's expertise with MEMS is a
manufacturing technique, the Northeastern University Metal Micromachining
(NUMEM) process. Researchers fabricate miniature switches by building up
layers of metal on an insulating sublayer of silicon dioxide or glass.
The painstaking process, using photolithography, wet and dry etching, and
electroplating to get the materials in the right place, took years to perfect.
The resulting microswitches, McGruer explains, perform the same mechanical
and electrical functions as light switches-essentially turning electrical
signals on and off by opening and closing. But these switches are about
as wide as a human hair is thick. Even so, they are not as small (or as
fast) as transistors, but MEMS switches are more efficient at controlling
electrical current because of their mechanical component. Once a MEMS switch
is turned off, McGruer says, there is no path for a current to continue
flowing, and the capacitance (the storage of electricity) is very small.
A comparable transistor, on the other hand, has a larger capacitance. Likewise,
when a transistor is switched on, it poses a larger resistance to the flow
of electrons than the microswitch. That "ideal switch" quality
of the MEMS device is particularly important in testing sensitive electronic
devices.
The Microfabrication Lab has worked for several years
to develop MEMS switches for use in automated test equipment for the semiconductor
industry. A major semiconductor manufacturer, Analog Devices of Norwood,
Massachusetts, which has backed the Microfabrication Lab's research for
several years, is about to begin commercializing the switches.
Paul Zavracky, a former electrical and computer engineering faculty
member, invented a preliminary version of the MEMS switch in 1984. Zavracky,
who recently left N.U. for a company he founded, developed the technology
while working at a process control equipment company. Back in the late
1970s, Zavracky says, only about twenty people in the world were working
on MEMS. Research initially focused on creating miniature mechanical devices,
such as pressure
sensors, in silicon, the same material that is etched and layered to
create computer chips. The new micromechanical
sensors were ten times smaller and much less expensive to produce than
the previous generation of devices. The next step was to add an electrical
component. Thus MEMS technology was born.
Zavracky came to Northeastern in 1991 to establish a lab to pursue MEMS
research. He teamed up with McGruer, who was teaching students how to make
integrated circuits. Since then, their Microfabrication Lab has grown five-fold
in space and has leapt to the forefront of MEMS research, drawing millions
of dollars in research grants and contracts. Its facilities are now split
between the Dana Research Center and the Egan Engineering/Science Research
Center. Zavracky notes that Northeastern now "leads the field"
in the quality of its MEMS switches and relays.
The game has just gotten under way, however. "MEMS technology is
still in its infancy," Zavracky says. "It is finally getting
devices out into the field that are useful. There are just zillions and
zillions of MEMS applications."
In addition to its research success, the Microfabrication Lab remains
true to its teaching roots. It still hosts undergraduate engineering students
in a course on integrated circuit fabrication. McGruer wants to involve
other disciplines and departments from around the university as well. "Microfabrication
is getting to be more ubiquitous," he says. "The lab can be a
resource for the whole university." He is currently working on proposals
for joint research with chemistry and mechanical engineering faculty.
"We're good at what we do," McGruer says. "It's satisfying
to see things on which you've worked so hard become useful."
Micky Baca is a freelance writer in central Massachusetts.
Carolyn Lee, Center for Biotechnology Engineering
By Judy Stringer
It has long been known that plants are a rich source of important pharmaceuticals.
One of the most important anticancer drugs, taxol, is derived from the
bark of the Pacific yew tree, for example. But in many cases, compounds
found in plants are produced at such low levels that supply is limited
and isolating even small amounts can cost millions, making them less than
ideal as commercial drugs.
At the Center for Biotechnology Engineering, assistant professor Carolyn
Lee and her students are exploring ways to "engineer" new plant
cell cultures-rather than whole plants-to produce targeted therapeutic
compounds in higher quantities and at lower costs. Working at the molecular
level, Lee is beginning with two promising cancer-fighting compounds, vinblastine
and vincristine, found in minute quantities in the leaves and flowering
organs of a common bedding plant, the periwinkle (Catharanthus roseus).
"Our ultimate goal is to supply these important pharmaceuticals
commercially," says Lee, who joined the chemical engineering faculty
last September. "But we have a way to go because today this cannot
be done on a large scale."
Vinblastine was first isolated in 1959, and vincristine one year later.
The compounds are structurally very similar and are well understood biochemically.
Both are known to have tumor-killing properties. They are used today to
treat childhood leukemia, Hodgkin's disease, and other cancers of the lymphoid
tissue (lymphomas).
But C. roseus produces vinblastine and vincristine in very small quantities-less
than 0.0005 percent by weight-which drives up market prices. Pharmaceutical
companies isolating vincristine charge up to $1 million per kilogram. Vinblastine
goes for a whopping $3.5 million per kilogram. At these prices, use of
the drugs has been restricted.
The production of these valuable compounds in cell cultures of C. roseus
is one potential solution to the supply problem, Lee says. Pharmaceutical
companies already use cell cultures of bacteria to make drug compounds,
in essence turning the cultures into biochemical reactors. Plant cell cultures-mimicking
a plant's natural processes in a laboratory flask or in large vats when
scaled up to the commercial level-hold the same potential. First, though,
researchers must overcome a number of challenges that have plagued the
production of plant-derived compounds from cell cultures.
One such challenge is low growth rates. Given the right conditions,
a bacterial culture can double its weight in as little as twenty minutes.
Plant cell cultures, on the other hand, grow much more slowly; doubling
time is on the order of three days. What's more, scaling up plant cell
production from a lab-sized flask to an industrial bioreactor has been
a problem in the past. Today's commercial bioreactors employ large propellers
to stir tanks, mixing the required nutrients and transferring the necessary
gases into the bacterial brew. But plant cells are more delicate than their
bacterial cousins, and the "shear stress" caused by mixing can
damage them. Finally, cell cultures produce the sought-after compound in
quantities that are too low to be commercially viable.
The potential to produce valuable pharmaceuticals from plant cell cultures
of C. roseus has attracted many researchers. For instance, teams have explored
how small changes to the composition of a culture's medium or alterations
in light and pH affect growth and production. Researchers have had limited
success in speeding the cell growth rate or increasing compound production.
Another approach, injection of a vaccine-like fungus, has also been moderately
successful.
Lee's current focus is to understand the mechanism by which these and
other strategies have been able to increase production and apply her insights
toward the design of a commercially viable C. roseus cell culture system.
"We need to understand what catalysts are required to make the production
of the compounds greater. In essence, we need to understand what is happening
inside the cell," she says.
Lee is particularly interested in modeling an immobilized cell system,
in which the cell culture is suspended in a gelatin-like material. The
advantage of encapsulating the culture is that cells are forced to interact
with one another, much like in the natural plant system. The effects of
shear stress can also be minimized by surrounding the culture with a gel
substrate. In addition, Lee envisions the compound products being extracted
continuously onto a resin located outside the immobilized cell culture.
"These are slow-growing cells, so you do not want to have to break
them open in order to recover the compound," she says. "The resin
can draw the product out of the cell, continuously extracting it without
killing the cells." The constant extraction also would eliminate another
obstacle to high production rates: the cell sensing that the compound has
already been produced and turning its resources elsewhere.
Ultimately, Lee believes immobilization and recovery of the products
from the medium rather than from the cells themselves will be important
steps toward the breakthrough of making plant cell cultures an economically
viable process.
Judy Stringer is a biotechnology columnist for Mass High Tech weekly
in Boston.
Richard Deth, Molecular Modeling Center
By Judy Stringer
When pharmacology professor Richard Deth's Molecular Modeling Center
set out more than three years ago to create three-dimensional models of
a "super family" of 2,000 chemical receptor sites in the human
brain, their interest was in finding receptors that played a role in cardiac
disease.
What the research uncovered, however, was a unique amino acid chain
that is found only on the brain's receptor for D4 dopamine-a receptor that's
believed to play a significant role in attention and cognitive behavior.
The finding has taken Deth on an exploration of D4 and its potential role
in the formation of attention, attention deficit, and neuropsychiatric
disorders like schizophrenia.
Last spring, a team of researchers led by Deth published research findings
that, for the first time, specified a pathway linking the D4 receptor and
attention. The paper, which appeared in the May 1999 edition of Molecular
Psychiatry, highlights how deficits in the D4 receptor might contribute
to mental illness.
Deth calls the finding the "missing link" in understanding
the effects of the dopamine receptor on behavior. Ultimately, this insight
might open new avenues to the treatment of conditions like schizophrenia
and attention deficit hyperactivity disorder (ADHD).
"It is widely accepted that the D4 receptor plays a role in attention
and the lack of attention, as in disorders like ADHD, but the mechanism
by which it exerts its influence had not been understood," Deth says,
"Our work provides a description of a pathway involving D4 that can
account for attention or, if something goes wrong, psychiatric disease."
The Molecular Modeling Center is located in the Department of Pharmaceutical
Sciences, part of the School of Pharmacy in Bouvé College of Health
Sciences. The center's users come from other disciplines besides pharmaceutical
sciences, including biology and chemistry, to conduct "rational"
drug design, which is a new approach to designing pharmaceuticals based
on a better understanding of the human biological targets with which the
drugs will interact.
To that end, the center maintains a computer graphics station that creates
3-D computer models of biological targets from their known compositions.
The 3-D models are used for structural comparisons (like the one that unearthed
D4's unique amino acid chain) and simulations of molecular-level interactions
(another technique used in the D4 study).
"We used software tools to build and evaluate a molecular model
of D4," Deth says. "Dopamine was docked into the [receptor's]
binding site of this model to create a molecular hypothesis about how the
presence of dopamine would alter the small area around the D4 receptor."
Deth's hypothesis was that, when activated by dopamine (a chemical produced
by the human body), the unique amino acid chain seen on the D4 receptor
was responsible for transferring methyl groups from nerve membranes. Once
these molecules were transferred, the density of the nerve membrane would
be reduced and its fluidity increased, altering the activity of its neighboring
proteins and creating what we know as attention.
Virtual experiments led to a series of laboratory studies, which have
confirmed his hypothesis. Specifically, Deth and his team have demonstrated
that D4 receptors are intimately involved in a process called phospholipid
methylation (PLM), a unique mechanism of signaling. PLM increases the fluid
properties of membranes, allowing certain fatty acids present in the fluid
to have greater mobility and interact more readily with proteins that are
highly sensitive to the perturbances. When this process is defective, it
can lead to schizophrenia or other psychiatric disorders.
Deth's findings tie together a number of past observations. The D4 site,
for one thing, is known to be one of the most variable of the brain's biological
receptors. A person can experience anywhere from two to ten repeat firings
of D4. High numbers of repeats have been correlated with ADHD. Deth suspects
that in high-repeat people, dopamine activation falls short, causing attention
to suffer. Several antipsychotic drugs are known to work by acting on the
D4 receptor. Deth's recent findings provide the first glimpse into how
these commonly used drugs might be working.
Nearer term, new diagnostics might be developed using Deth's findings.
Schizophrenia is a difficult disorder to diagnose, but the recent research
suggests that a simple blood test measuring PLM in the white blood cells
could provide an accurate indicator of the disease.
"It is nice to know things in the abstract, but to make a difference
in people's lives by relating the information to new drugs and diagnostics
is the real goal of our research," Deth says.
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