Killing brain cancer with electricity

Cancer is a disease that involves cells dividing faster than they should (check this out for a review of how cells divide) along with many other complicated processes.  But if you simplify cancer to this one concept – cells dividing too fast – then you can think of interesting ways to kill cancer cells by targeting cells that are dividing quickly.  In fact, many (if not most) current cancer treatments do just that  – they create too much DNA damage for the cancer cells to handle, so the cancer cells kill themselves. There is a bit of a problem with this though – cancer cells aren’t the only cells that are quickly dividing.  Hair follicles, cells in the lining of the gut and blood cells all also divide quickly.  This is why non-specific cancer treatments like chemo that go throughout the body also end up killing these fast dividing cells, which is why cancer patients often lose their hair, have low blood counts and have gastrointestinal issues.

spindles

By Kelvinsong (Own work) [CC BY 3.0], via Wikimedia Commons

Wouldn’t it be great if the cell division part of cancer cells could be more targeted, less toxic, and avoid many of the difficult side effects from cancer treatment?  Scientists are working on a number of different treatments that do just that, but in this post I’m going to talk about one that is particularly interesting because it’s being used in clinical trials in our backyard at the Barrow Neurological Institute to treat glioblastoma multiforme (abbreviated GBM). GBM is the most common form and aggressive adult brain cancer. GBM has a terrible prognosis – with 50% of patients diagnosed dying within one year and 90% dying within 3 years. Standard treatment involves surgery to remove the tumor, and then radiation and chemotherapy treatment.  Treatment is difficult, and because this is a brain tumor, there are additional challenges involving brain damage from surgery, radiation and/or chemo and getting drugs through the blood-brain barrier into the brain tumor.

NovoTFF

Thanks to MedGadget for the image

A new treatment called NovoTFF (TFF stands for Tumor Treating Fields) goes directly after the dividing GBM cells. Receiving FDA approval in 2011, it is a device that is worn as a cap (see image at left) and uses a battery pack that can be worn in a backpack to create wave-like electronic fields that penetrate the brain.  These fields disrupt the spindles that are responsible for separating the chromosomes during the cell cycle (see image above). There is also some evidence that these electric fields disrupt the cell membrane of dividing cells as well. Since the GBM cancer cells are dividing, they will be most likely to have their cell cycle disrupted and the cells’ natural response to this kind of major disruption is to die.  This treatment has amazing advantages.  Because it’s worn outside the body, NovoTFF isn’t invasive like surgery.  It’s also just worn on the head so it won’t have side effects like the ones from treatments that go throughout the body.  Also, the electric fields won’t affect cells that aren’t dividing (like most brain cells), so this treatment is less likely to cause damage to the non-cancerous brain cells.  But does it work?  Yes! In multiple clinical trials, this treatment was shown to slow the growth of recurrent GBMs and increase the length of progression-free survival compared to patients who did not use NovoTFF. The only disadvantage might be that the cap needs to be worn for 18 hours a day.  Then again, if that 18 hours a day can prolong a patient’s life, the inconvenience might be worth it.

NovoTFF has been so successful that it’s also be tested in clinical trials for pancreatic cancer, ovarian cancer, mesothelioma, and brain metastasis from lung cancer. Obviously in these cases the device has been changed so that it attaches to the torso instead of sitting on the patient’s head.  Research is also being performed by individual doctor’s  to see if NovoTFF may work for newly diagnosed GBM patients or for other kinds of cancer.

If you want to learn more about Tumor Treating fields and this fascinating new treatment, check out this Ted Talk 

 

Are vaccinations needed after a stem cell transplant?

Vaccines are a hot topic. Vaccines bring up lots of discussion, lots of false information, and a vitriolic passion rarely seen in matters of science and pseudoscience. My first post on this topic was about what vaccines are and and what they do. My second post  addressed some of the false information and controversy (with an added bonus of bringing in my lovely sister’s fabulous point of view as a mom of two!) This post will address a question I was asked about whether or not vaccinations are needed after a stem cell transplant.

A friend of mine asked me a question about her friend with non-Hodgkins who was getting a stem cell transplant. He was wondering if he has to get all new immunizations.  Since we have been talking about what immunizations (or vaccines) are and what they do, I thought this would be the perfect place to answer this question.  Before I start, please keep in mind that I’m a doctor, but not that kind of doctor.  This is NOT a medical opinion.  Nothing that I say here should be considered medical advice or used in lieu of talking directly to a doctor.

I won’t give medical advice, but I will explain what is known biologically about why immunizations would be needed after a stem cell transplant.  I won’t go into a lot of detail (in part because I’m not an expert immunologist) but also because there are some interesting resources I can refer you to:
https://www.fredhutch.org/en/treatment/long-term-follow-up/FAQs/vaccination.html
http://en.wikipedia.org/wiki/Vaccine#Developing_immunity
http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplantation

immune-system

The bone marrow is one of the main organs that makes immune cells required to mount an immune response after infection. Thanks to aids.gov for the image

Remember the description about how vaccines work.  They induce a “memory” in the immune system that recognizes the infectious agent if it is encountered and kills it before it can kill you. The cells that are responsible for the immune response and creating this “memory” are made in the bone marrow and circulate in the blood (it’s a convenient system because your circulating blood gets access to most of your body so it can find and attack infectious agents quickly).

Non-Hodgkin’s lymphoma is a blood cancer where white blood cells (also made in the bone marrow) divide out of control.  Chemotherapy, one of the main treatments for this kind of cancer, kills the cancer cells circulating in the blood but also kills cells in the bone marrow, including the stem cells responsible for making new blood and immune cells.  With high enough doses of chemotherapy, all of the stem cells in the bone marrow are killed along with the cancer cells. The stem cell transplant replaces the stem cells in the bone marrow which make new blood cells – replacing cancerous cells with healthy blood cells.  Researchers have found that the memory from immunizations often decreases after a stem cell transplant. Part of this is because the cells that have the memory may be killed as part of the chemotherapy and the new immune cells haven’t encountered the vaccine before so they won’t have the memory. Part of it may be because during treatment the patient is on immuno-suppressives.  Part of the reasons also are still being studied or aren’t very clear.

However, either way, it is suggested that immunizations are needed after the transplant – though not necessarily right after transplant.  Again, to reiterate, a doctor will have this information and will be able to provide medical advice.  I’m just giving some background as to biologically why immunizations may be needed after a stem cell transplant.

What is a cell? Based on a conversation with my husband

I was at an awesome brewery in Flagstaff over the weekend (shout out to Historic Brewing Company) with my husband.  Over a beer and homemade chips, we start discussing science.  Now, don’t imagine that just because I’m a scientist that I insist on talking about it all the time.  Most of the time we’re talking about our dogs or work or school or this blog.  This weekend, the science discussion actually started by taking about grading curves and how they are sometimes fair and sometimes not, and they sometimes measure student’s performance and sometime the teacher’s (sophomore year physics – I’m referring to you!).  From here, the discussion gets a bit fuzzy, but we eventually starting discussing cells and start arguing about the difference between eukaryotic and prokaryotic cells.

Before I get into the details of the argument, let’s talk about what a cell is. Cells are the lego blocks of all living organisms.  Cells contain the genetic material and can divide and replicate into new cells (in a process called the cell cycle).  If you take any part of an organism and zoom in, you will see cells. Cells don’t all look or function the same – as you may imagine because cells in your body do different thing than cells in a plant or cells in a fungus or a bacterial cell. And even different cells in your body look and function differently. Blood cells are round and flow through blood vessels.  Blood vessels are made out of multiple layers of cells surround by muscle cells to help contract and expand the vessels to move the blood. Muscle cells are different depending on where in your body they are located. For example, heart muscle cells look and function different than muscle cells found in your bicep. Nerve cells (called neurons) in the brain often have lots of branching so that they can connect to other nerve cells to transmit signals .  And just to clarify, I know I said that you could zoom into ALL parts of your body and see cells, however there are exceptions to everything.  For example, hair and nails are make out of a hard, tough protein called keratin and not cells.

shapesofcells

Thanks to Wikipedia and http://upload.wikimedia.org/wikipedia/commons/e/e5/414_Skeletal_Smooth_Cardiac.jpg

Even though cells may look different and function differently, all cells have a few things in common:

  1. All cells are surrounded by a membrane, often called the plasma membrane, that is typically made up of fats (called lipids) and proteins.  You can think of this as a plastic bag that can hold stuff inside of it.
  2. The stuff inside this cell membrane includes cytoplasm – you can think of this as a jello inside the plastic bag made up of lots of proteins.
  3. Inside all cells is the genetic material (DNA) that is required to make and replicate the cell and for the cell to function.

Even though different types of cells have different shapes and different functions, there are two main types of cells:

  1. Prokaryotic cells – these are cells that do not have membrane bound structures inside the cell membrane (floating around in the jello-like cytoplasm).
  2. Eukaryotic cells – these cells have membrane bound structures called organelles. We’ll discuss specific organelles in future posts, but some organelles that you may already be familiar with are the nucleus, which is another membrane-bound structure that contains the DNA, or mitochondria, which are the energy-producers of the cell, or chloroplasts, which are the organelle that converts sunlight into energy in plants.
kindsofcells

Thanks to Wikipedia for the images

So, if a cell has a nucleus, it’s eukaryotic and if not, it’s prokaryotic. And this is where the argument started.  My husband insisted that eukaryotic cells are defined by the fact that they are only found in multi-cellular organisms.  Multi-cellular refers to any organism that’s made up of more than one cell – like humans who have about 100 trillion cells, redwood trees, spiders, birds, seaweed, whales, algae, mushrooms, etc.  Although it is true that eukaryotic cells are mostly found in multi-cellular organisms, protists are single-celled and contain a nucleus – making them eukaryotic. Conversely, most prokaryotes are single cells – like bacteria and plankton.  However, some of these single-celled prokaryotes can stick together and work together as a community in a slimy biofilm that is very similar to being multi-cellular.

Why in the world does this matter? Why did I spend any of my energy on a Friday night (and a bit on Saturday when we rekindled the discussion) even discussing this point?  It’s because definitions matter and understanding the details matter – especially in science. But that ultimately isn’t the point of this post – it’s about cells.  Without cells, life as we know it wouldn’t exist.  Without an understanding of cells and how they work, we can’t understand what it means when they dysfunction and cause disease in humans.

Why can all of your cells commit suicide?

growth-death-balanceWe’ve discussed how cells can grow and divide through the cell cycle and a process called mitosis.  Equally as important to cells growing and dividing is the ability of cells to die.  Why do cells have to die? During human development cell death is necessary.  For example, in the womb fingers and toes are attached to one another by a webbing made of cells.  During development, these cells die so that your fingers and toes are separate. A great non-human example of cells dying during development is the tadpoleDevmetamorphosis of a tadpole into a frog.  The cells of the tadpole tail die to make a mature frog that does not have a tail.  As an adult, your hair, skin, gut and other cells constantly divide.  In fact ~ 60 billion cells are made each day. Imagine if cells didn’t also die each day – you’d be ENORMOUS!

This cell suicide is called apoptosis (pronounced a-pah-toe-sis) after the Greek meaning “dropping off ” or ” falling off ” of petals from flowers, or leaves from tree.  Apoptosis is  a mechanism that every single cell in your body has to commit suicide.  Why in the world would this mechanism exist? In part, it exists for the reasons mentioned above – to remove unneeded tissue during development or to balance out cell growth.  But apoptosis also provides a fail safe for cells to remove themselves if they become damaged so that they don’t damage the rest of the organism.

apoptosisSo how does apoptosis work?  Obviously your cells don’t just kill themselves willy nilly.  The cell must receive a trigger the initiates the process.  These triggers can either come from inside or outside the cell.  For example, UV light from outside of the cell can trigger damage to the DNA.  If this damage isn’t repaired, it will start the process of apoptosis.  As another example, when cancer cells are treated with chemotherapy, this often damages the DNA or messes with the cell cycle so much that it triggers apoptosis.  Once triggered, proteins are activated that act like protein scissors, cutting up proteins and DNA inside the cell.  This does a few things: it shuts down activity within a cell and makes the pieces of the cell smaller so that they can be packaged up and thrown away.  It’s like a kitchen demo (or any kind of demolition)  – you knock down the cabinets with a sledgehammer so that they don’t work to hold your dishes anymore and then break them into small enough pieces that they can easily be thrown in the dumpster.  Once cell pieces are broken down, the cell  packages up the contents (called blebs – see picture at right) and blebbingthese blebs are eaten (actually, they are absorbed…but “eating blebs” is more fun to say) by neighboring cells.  What’s so awesome about this process is that no trace of the cell is left.  It’s a clean suicide that leaves no trace of the body behind.  Why is this important?  We can compare apoptosis to another type of cell death called necrosis.  If you cut your arm, cells die by necrosis and they spill their contents everywhere.  When this happens, your arm can get inflamed and this inflammatory reaction can be bad for you.  During apoptosis, since everything is cleaned up nice and neat, there is no inflammation and the body can just move along as if nothing happened.

apoptosis_diseaseNow what if the trigger is defective or the machinery is broken and cells don’t die when they are supposed to?  This is one of the causes of cancer.  Of course cancer is a result of too many cells, but this can either be from cells growing too fast OR from cells not dying when they are supposed to OR a combination of both.  On the other hand, what if too many cells die when they aren’t supposed to?  This can cause the neurodegeneration found in Alzheimer’s disease or the loss of immune cells in HIV/AIDS infection.  Therefore, understanding apoptosis and the exact way that cells die can help scientists to induce cell suicide (e.g., to kill cancer cells) or prevent it when needed.

How and why do cells divide? The cell cycle!

You started off as one cell: one tiny little zygote containing a full set of DNA (23 pairs of chromosomes).  As an adult human being, you are now made up of over 37 trillion cells. This means that that one cell  divided to make two cells, each of those cells divided to make 4 cells, those 4 cells divided to make 8 cells and on and on until the 37 trillion cells that make up you today. Even now, your body makes around 60 billion cells each day to create new skin cells, intestine cells, hair cells and and nail cells. When you cut yourself, the body needs to make new cells to heal.  And if your cells divide out of control, this can cause cancer and if they stop diving this causes of aging. So understanding how cells divide is super important!

The cell cycle, which is the process of one cell and one set of DNA turing into two cells with two sets of DNA.  There are three main parts of the cell cycle:

1.  To make two cells from one, you can imagine that a few important things need to happen.  First, you need the cell to grow to get bigger and to accumulate enough nutrients to support two cells.  Second, you need to replicate the DNA so that when the cell divides, each “daughter” cell gets one copy of the DNA. These two things happen in the interphase part of the cell cycle.  Interphase is separated into 3 parts

  • Gap 1 (usually just called G1 phase) where the cell grows
  • Synthesis (usually just called S phase) where the DNA is copied so that two complete copies of DNA are now in the cell
  • Gap 2 (usually just called G2) where the cell grows some more

Metaphase

The chromosomes (shown in blue) condense and line up before being pulled into two cells by microtubules (shown in green)
By Roy van Heesbeen (Roy) [Public domain], via Wikimedia Commons 

2. Once the cell has copied the DNA and grown big enough to split into two cells, the cell undergoes mitosis.  Mitosis is when the copied chromosomes are separated into two different cells.  Remember that if you took all the DNA in a cell and stretched it out from end to end that it would be 6-10 feet long? Since this DNA is already replicated by the time the cell gets to mitosis, there are 92 chromosomes (two copies of the two pairs of 23 chromosomes) and 12-20 feet of DNA that needs to be organized and sorted into two separate cells.  How does the cell make this nearly impossible sounding task happen?  First, when each chromosome makes a copy of itself, it stays connected to the orignal (kind of like if there were little protein magnets holding them together). mitosis Second, when the chromosomes are ready to separate into different cells they “condense”, getting much, much smaller (see the blue DNA in the photo above).  Third, there are mechanisms in the cell that make the chromosomes line up.  So what you end up with are all of the chromosomes in tight little bundles lined up in a row.  At that point, the cell creates “ropes” out of a protein called microtubules that pull the copied chromosomes apart into the two separate cells.

cytokinesis3.  Finally, now that the DNA is separated into the two new cells, these cells have to officially split into two in a process called cytokinesis.  You can imagine this is like pulling a drawstring closed to pinch the space between the two cells until they have completely split apart.

If this sounds like a complicated process, you’re right.  It is.  But it happens flawlessly 10,000 trillion times in a lifetime.  Part of the reason why this is a flawless process is because the cell puts checkpoints into the process.  It’s like when your bank calls you because they observed a strange transaction on your credit card and they put your card on hold.  If the cell sees something strange happening when the cell is trying to undergo cell division, it puts a hold on the whole process until it gets fixed.  We’ll discuss this a lot more in the future because when the cell cycle isn’t running flawlessly and these checkpoints aren’t working, this contributes to causing cancer and other diseases.