Let’s start with the
question, “What is life?” Even as biologists, we sometimes struggle with this
question. Usually, life is considered to be self-contained and separate from
the external environment. As humans we are distinct from our surroundings,
protected by our skin. Life should also possess the ability to be different
from that environment. Warm-blooded animals, for example, are capable of
maintaining a constant body temperature despite the temperature of the
environment. In addition, living things can respond to the environment, as
plants grow toward the sun and birds migrate south in the winter. Usually, another requirement
for being alive is the ability to reproduce; however, even this is
controversial. Under this definition, mules are not alive! This rule is usually
why viruses are considered to be not alive – they cannot replicate on their own
and can only do so upon infection of a host. We often say that in order
for something to be alive, it must also be able to die, which means that
self-replicating robots from fantasies like Star Trek would not be considered
alive (although, could eventual break-down of parts be considered death?) The ability to take in
nutrients from the environment and use those nutrients to grow is also
considered an aspect of life. Why is it that viruses are considered not alive
because they cannot reproduce without a host, when fungi are considered alive
despite the fact that they rely on a host (usually a plant) to absorb nutrients
from the environment for them? These are just a few of the questions scientists
wrestle with in categorizing the organisms around us.
If the definition of life is
a bit hazy, things get more complicated as we forge ahead to describe what’s going
on at the cellular level. Cells are the “basic unit” of life. Some organisms
consist of only a single cell, such as bacteria, yeast, and amoebas. Since a
cell is usually no larger than one hundredth of a millimeter in diameter, these
organisms are only visible under a microscope. The macroscopic life forms we
encounter on a daily basis are all multicellular. Multicellular organisms
consist of many cells which have divided up the labor of survival. (An adult
human has approximately 100,000 billion cells). In such an organism each cell
now specializes in particular tasks. For example, in humans, we have nerve
cells that perform sensory functions, muscle cells that allow us to move, skin
cells that protect us from the environment, and immune cells that combat
disease, to name a few.
It may help to think of an
organism as a bakery that produces many types of baked goods and sells them to
customers to stay in business. Each worker in the bakery makes one type of
baked good: Luanne makes brownies, Heather makes cupcakes, Roy makes muffins,
Arnie makes cookies…I could keep going, this is becoming a game to name as many
baked goods as I can…but you get the point. Without each worker, the bakery
would not be as successful as it is because it would be missing a particular
product. The workers rely on each other to all contribute to the well-being of
the bakery, ensuring that they continue to have jobs in this rough economy.
Similarly, all the cells in
your body are specialized for unique functions, all of which are essential to
your survival (and thus your cells’ survival). And, like the workers in the
bakery, the cells in your body make things. The most functional type of
molecule produced by your cells is the protein. Proteins have many different
functions in your body – they can serve as hormones, they form structures (your
skin is formed on top of a dense layer of proteins, your hair is composed
mainly of proteins), and they perform tasks including digestion of your food,
transport of oxygen throughout the body, clotting your blood. Antibodies, which
attach to pathogens and help clear your body of infection, are also proteins.
Again, this could become a fun game for me. The analogy we come away with is:
baked goods are to the bakery as proteins are to your body. People don’t
usually line up to buy your proteins from you though…it’s too bad, because your
personal bakery is very productive. You end up eating all those baked goods
yourself.
How do the workers in the
bakery know how to make baked goods? They need a recipe that tells them what to
make. The bakery has a big file cabinet of all their recipes (because this
bakery is old school and doesn’t know how to store files on a computer). The
bakery has to guard this file cabinet carefully and make sure none of the
recipes in it get damaged over time so that the workers can continue to make
all the baked goods properly. So, the bakery has a policy. When workers are
going to make a particular baked good, they must take the recipe from the file
cabinet, Xerox it, and put the original back in the file cabinet. They can then
take a copy to the kitchen and use that during baking. Sometimes, if a certain
type of cookie is in high demand, the worker might make multiple copies of the
recipe so that more than one person can make that cookie at a time. Over time,
these copies get splattered with batter, burned, dripped on, and otherwise
destroyed. These copies can just be thrown away, because the original is safe
in the file cabinet.
Likewise, your cells have a
“file cabinet of original recipes” for making all the proteins they need to
make. This is your DNA. DNA has all the information necessary to make any
protein. However, this information is precious. If it were to be damaged, the
cell would no longer be able to make the proteins it needs. So, instead of
using the DNA to make proteins, the cell uses RNA. RNA is like the Xeroxed copy
of the one recipe you need out of the file cabinet. When a cell wants to make a
protein, it selects the region of DNA with the information to make that
protein, makes an RNA copy of that region of DNA, and uses the RNA as instructions
to make the protein. The cell will usually make multiple RNA copies at a time,
allowing many proteins to be produced simultaneously. Just like the temporary
copies of the baked goods recipes, RNA will degrade over time and new RNA will
have to be made.
These are the basic
principles of information storage and use in cells. My research is interested
in how cells communicate with each other – how does information get sent
between cells? One way cells can communicate is through exosomes.
What are exosomes? Again, we
are going to have to rely on one of my super-fun analogies. Imagine now that
instead of a bakery, your body is the corporate office of a very large company.
Again, this is an old school company – they don’t know how to send emails. So,
a common way that messages get communicated in between workers is via memos. If
a manager needs to communicate something to one of his team, he sends a memo to
that person. That person then takes the information in the memo and modifies
his behavior accordingly.
Exosomes are like memos for
cells. Exosomes are packets of proteins and RNA that can be sent between cells.
Because your body has a very active immune system that recognizes free RNA and
proteins in your blood as pathogenic, cells have to package the information to
protect it from the immune system. This would be equivalent to janitors who
come around the office and throw away any memo that is lying around
unprotected. Exosomes are basically oily balls that can avoid activating the
immune system and safely deliver proteins and RNAs from one cell to
another. This is like having a
protective envelope for your memo that tells the janitors not to throw it away.
There are many interesting
properties of exosomes. One is that they are tiny. As small as a cell can be
(remember 1/100 of a millimeter in diameter), exosomes are 1% to 0.25% the size
of cells! This makes it easy for them to travel around the body and slip into
small spaces between cells. Just as
different people send different kinds of memos in the office and these memos
have a large variety of effects on the people that receive them, exosomes can
be produced by many different types of cells and have a wide variety of effects
on the cells that take them up. Because exosomes contain RNA and proteins, they
can change the behavior of the recipient cell. It’s almost as if one worker at
the bakery handed his recipe to another worker and said, stop making what
you’re currently making, and make this instead.
We don’t currently know if
the information in exosomes is specifically selected by the cell that made the
exosome, or if it is a random sample of the RNA and protein made by that cell.
Going back to the office analogy, we don’t know if workers are sending specific
memos out, or just randomly putting papers from their desk into the memo
envelopes with little interest in what happens to them after that. Exosomes may
even be “trashcans” for excess material in the cell. In the office, maybe a worker is just
clearing off his desk of old papers that are completely unnecessary to him and
sticking them into the memo envelope.
We also don’t know if
exosomes are targeted to specific recipient cells. We don’t know if office
workers are addressing memos to specific other workers, or jus throwing the
memos in to the hallway where other workers are randomly picking them up.
We do know that exosomes are
secreted in increased numbers by cancer cells, and doctors are beginning to use
exosomes to diagnose and determine the prognosis of certain cancers. This is
like a consulting agency being able to come in and read some of the memos that
are circulating in the company and deduce whether or not the company is in
trouble.
While these are all
interesting questions, the drive of my research is to take what we do know about exosomes and make something
useful out of it. (I may have joined a biology department but I’m an engineer
at heart). The idea of my research is to
see if we can use exosomes to deliver therapeutic information. Again with the
office analogy, imagine the business is failing and an outside consulting
company can come in and strategically insert a few memos into the office
building that will increase efficiency of the workers and help the business
become successful. Furthermore, it would be good if the memos could be
specifically addressed to people who can have the greatest impact on the health
of the company. This is the goal of my research. In order to do this, I have to
develop a method for putting specific RNA and proteins into exosomes. I also
have to develop a method for targeting exosomes to specific recipient cells.
For now, the idea is to target exosomes to immune cells and deliver RNA and
protein that instructs those immune cells to fight cancer.
