theiconoclast.info

http://toxicopoeia.com/?get=plants&page=&view=expanded&type=medicinal&show=D

Chemotherapy sucks. While it can buy the sick time and even produce cures, patients must endure hair loss, nausea and vomiting, weakened immune systems, nerve damage, and even the risk of secondary cancers, cancers that are caused by the very same drugs designed to treat them. And perhaps most tragically, chemotherapy often fails to cure a patient’s illness, as neoplasias often evolve to both become resistant to treatment and to spread, or metastasize, all over the body. However, there may be a non-chemo based drug, that’s already approved by the FDA and on the market, which can reduce the chance that a cancer will metastasize and develop resistance to chemotherapy. This drug is called digoxin.

Digoxin, which is derived from the flowering plant known as fox glove, is currently approved as a treatment for a variety of heart problems. And although digoxin, because it is not without side effects and risks of its own, is no longer the first choice for patients with heart problems, it remains a safe and effective drug when given at appropriate doses. So how could a drug used for heart problems be used to treat cancer? The answer lies in a condition known as hypoxia, which is oxygen deprivation within a tumor. Research has indicated that hypoxia both increases the chances that cancer cells will be resistant to chemotherapy and metastasize. Digoxin may benefit cancer treatment because it may be able to reduce hypoxia, and thus reduce chemotherapy resistance and metastasis.

How does digoxin reduce hypoxia? At the molecular level, the response of cancer cells to hypoxia is still not completely understood, but scientists do know that hypoxia causes hundreds of genes to become activated. However, many of these genes only become activated because of a transcription factor called HIF-1 a, or “hypoxia inducible factor 1 alpha”. HIF-1-a is one of the first proteins that a cancerous cell makes in response to hypoxia, and because it activates hundreds of other genes it can be viewed as a master regulator of a cancer cell’s response to hypoxia: expose cancer cells to hypoxia and they make HIF-1a, HIF-1a then turns on lots of other genes that make a cancer cell more likely to be chemoresistant and metastatic. Digoxin works because it has been shown to inhibit HIF-1a; turn off the master regulator and you inhibit the hypoxic response.

There are already clinical trials testing the use of digoxin as an adjuvant to chemotherapy and radiation. The hope is that digoxin will be able to prevent metastasis and sensitize cancer cells to treatment. I can’t wait to see the results.

Sources:

http://breast-cancer-research.com/content/10/6/R102

http://www.modernmedicine.com/modernmedicine/Nursing/ArticleNewsFeed/article/detail/574333

http://clinicaltrials.gov/ct2/show/NCT00281021

http://www.ncbi.nlm.nih.gov/pubmed/20671264

http://www.ncbi.nlm.nih.gov/pubmed/19938317

http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=682036&version=HealthProfessional&protocolsearchid=8036529

http://en.wikipedia.org/wiki/Digoxin#Clinical_use

The Mouse I Worked With This Summer (http://jaxmice.jax.org/jaxnotes/archive/489i.html)

I spent the last summer at the Jackson Laboratory in Bar Harbor, Maine as a summer intern. The program is amazing, and I had the chance to work in a lab that studies medulloblastoma, a type of brain cancer. I learned a lot of amazing biology, but as a good portion of it is not yet published I don’t really feel that I should write about it. So instead, today I’m going to write about an interesting topic of biology that I had never really thought about until I worked at The Jackson Laboratory: mouse models. Specifically, I can think of three amazing things about the mouse models at the Jackson Laboratory.

1.      They are virtually genetically identical, but only within strains. This makes them ideal for research. In science, one wants to find results that are consistent and can be replicated so that definitive conclusions can be drawn. However, wild mice are just like people; they are all genetically different. Consequently, if scientists conducted research on wild mice, their results would often vary and conclusions would be difficult to form, as each mouse would respond slightly differently because of its different genetic makeup. The mice studied at the Jackson Lab avoid the problem of genetic variation, as they have all been engineered to be genetically identical.

How do you create a genetically identical mouse? Well it turns out that mice don’t mind mating with their brothers, sisters, and parents. So you use this fact to your advantage. First, breed two unrelated mice together. When they have their litter, then have the brothers, sisters, and parents all mate. When the next litters are formed, repeat the process. Over time, around ten generations or so, the mice will become so inbred that they are virtually genetically identical.

Now, having genetically identical mice is ideal for replication, but not ideal for modeling what actually happens in people, as people are genetically diverse. So, the ideal system is one that’s called, “genetically identical inbred strains”, and this is exactly how mouse research is done. There are multiple “strains” or types of genetically identical mouse. The mice are genetically identical, but only within each type. This enables researchers to first test if an effect happens in one type of mouse, as each mouse of this type is genetically identical, but then see if they can replicate their findings in mice that are not genetically identical. This is called replicating your findings in a “different genetic background”, and it is the most compelling evidence for any biological effect or response.

2.      They can be genetically engineered to have amazing, science fiction like mutations. Overtime, scientists have developed an incredible amount of control over the mouse genome. They can inject genes directly into the fertilized egg of a mouse, creating what’s known as a “transgenic mouse”. Or, they can induce random mutations in the mouse genome and observe the effects. Together, these processes have enabled the production of mouse models for cancer, genetic diseases, and even some forms of mental illness. For instance, the mouse I worked with this summer has been genetically engineered to develop medulloblastoma, which is a tumor in the area of the brain known as the cerebellum, by 4 months of age. Scientists have also developed mice with some interesting mutations, such as glowing green (see the mice at the bottom of the article) and being very obese:

Finally, scientists have even learned to turn on and off genes only in specific tissues. For example, the brain of the mouse model I worked with this summer glowed green.

3.      Scientists can turn off their genes. How do you find out what a particular gene does? One way to do it is to turn off a particular gene, and then see what happens to the mouse when you do. A mouse that doesn’t express a particular gene is called a “knock out mouse”, and scientists have become amazingly skilled at turning off any mouse gene. Thousands of mouse genes have already been turned off to study their function, and scientists have the goal of knocking out every gene in the mouse genome within the next few years.

Ebola (historyfilms.net)

Evolution has created some nasty microbes…

Anthrax: Anthrax, caused by the bacterium Bacillus anthracis, is one of the most lethal microorganisms in existence, killing over 80% of those it infects. The antidote doesn’t always work.

When your firsts become infected, you’ll just feel like you have a cold. But after a few more days, you’ll have trouble breathing as the anthrax voraciously eats your lungs and grows in your blood. The anthrax soon reaches the brain and causes it to bleed.  You’ll then lapse into a coma and suffer massive internal bleeding, eventually suffocating to death in your own blood.

Botulism: The bacterium Clostridium botlulinum produces the neurotoxin botulinum, two ounces of which is enough to kill the entire United States. You can get botulism from expired canned food. Botulism kills by slowly paralyzing all of your muscles, so that eventually you can no longer breathe. However, you won’t lose consciousness; as you die from botulism you will be aware of the paralysis overtaking your entire body and feel yourself suffocating.

Ebola: Ebola is probably the worst of all. There is no known cure for ebola, and over 80% of those that contract if die. When you first become infected with Ebola, the symptoms aren’t that interesting: headaches, muscle aches, fever, fatigue, nausea, and dizziness. But after a few days, Ebola will simply start to dissolve your blood vessels, and you will begin to bleed rapidly from every orifice. You eventually die either from organ failure, or the simple absence of enough blood in your body. To this day, no one knows where Ebola comes from, or even how it was initially transmitted to humans.

Source: This Will Kill You: A Guide to the Ways in Which We Go by HP Newquist and Rich Maloof

http://f00.inventorspot.com/ images/Dividing_Cancer_Cell-small.jpg

You’ve heard of lung cancer… Breast cancer… Brain cancer… Pancreatic cancer… and cancers of almost all parts of the body. But have you ever heard of muscle cancer? Probably not. Although it does exist, muscle cancer is exceedingly rare and accounts for less than 1% of new cancers in the United States. Why?

Scientists don’t know for sure, but many suspect that muscle cancer is uncommon for a simple reason: muscle cells can store glucose (sugar). Here’s why this matters:

1.      The first mutation that occurs in many cancers is a mutation that causes a cell to take up too much glucose.

2.      The more glucose a cell takes up, the more glucose a cell consumes.

3.      The more glucose a cell consumes, the more waste the cell produces. And unfortunately, a consequence of this waste is the production of reactive oxygen species, commonly abbreviated as ROS.

4.      ROS damage DNA and cause mutation. Eventually, ROS will induce mutations that create uncontrolled cellular proliferation, and cancer will have begun.

However, muscle cells differ from other cell types in a very fundamental aspect. When muscle cells take up extra glucose, they don’t consume it right away. Instead, they store the glucose as glycogen. Consequently, muscle cells have a much lower mutation rate if they are forced to take up extra glucose than other cells have if they consume extra glucose. It is this ability to store glucose as glycogen, instead of burning it and producing mutation inducing ROS, that protects muscle cells from cancer.

Sources:

http://www.canceranswers.com/Muscle.Cancer.html

“Fueling Cancer Cell Growth” Craig Thompson, Ph.D., M.D. Anderson Symposia on Cancer Research 2009

http://www.acellvet.com/img/tend_lig_pic.jpg

It would be the ultimate ideal of battlefield medicine: sprinkle some miraculous powder on an open wound, and, in mere seconds, the body heals itself. Sadly, this scenario is still science fiction. But it turns out that wound powder that speeds recovery by promoting the body to heal itself already exists…

A regenerative medicine company called Acell has developed an amazing product called MatriStem ™ Wound Powder. This wound powder, in initial tests, was found to regenerate the tips of fingers (people accidentally slice off bits of finger all the time) as effectively as skin grafts alone. The benefit of course was that no skin grafts were actually used; the body literally regenerated the finger tip. (It is important to note that MatriStem ™ cannot regenerate bone; we’re just talking the very tips of fingers here.)

Sources:

 ·         http://www.ncbi.nlm.nih.gov/pubmed/16159805?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_

ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

·         http://www.ncbi.nlm.nih.gov/pubmed/16826793?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_

ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

·         http://www.ncbi.nlm.nih.gov/pubmed/18837648?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_

ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

·         http://www.acell.com/files/Acute_Finger_Amputation.pdf

·         http://www.acell.com/sci_overview.html

·         http://www.acell.com/

I’ve always found medicine interesting. I’ve thought about the possibility of going to medical school to become a doctor, but I’ve never wanted to become a surgeon. It’s not that I don’t like blood and guts; I just never really found surgery that interesting. Plus, anyone who knows me will tell you that I lack any and all coordination. I also don’t think I’d like the pressure.

But after reading this: http://surgeonsblog.blogspot.com/2006/10/quick-to-cut.html , I wish I had the coordination. And the pressure would definitely be worth it. Take a look.

http://phantom-limb.org/images/Phantom2.jpg

A phantom limb is just what it sounds like: a limb that is not really there, but appears to be. Some amputees, and even some people who were born without limbs, have the uncanny, and often unpleasant experience of feeling like their missing limb (usually arm or leg) is still there. I’m not in the mood to write paragraphs, so here are the interesting facts about phantom limbs, in bullet form. I’ve always preferred reading bullets to paragraphs anyway…

·         Roughly ninety percent of amputees will experience the phantom limb phenomenon at some point after the amputation, though in most people the feeling goes away over time.

·         Unfortunately, in approximately 95% of cases, the phantom limb is painful. This is a huge problem, as how can doctors go about treating a patient that’s experiencing pain in a body part that does not exist? Until recently, there was no way, until recent methods using neuorplasticity (check out this: http://en.wikipedia.org/wiki/Mirror_box ) have shown some success.

·         “Phantom limb” can also occur in internal organs. There have been cases where people that have had their bladder removed suffer the feeling of a chronic and painful need to urinate.

·         Phantom limbs sometimes feel like dead weight, while other times they can have lives of their own. Patients have reported feeling their phantom arm gesticulating, waving, and reaching for a ringing telephone.

·         Phantom limbs have a tendency to literally “shorten” over time. For instance, the patient may start out with a normal size phantom arm, only to have it begin to shrink to lengths as small as six inches.

·         People born without limbs can also experience the phantom limb phenomenon.

·         Phantom limbs can itch. In one case, a patient found he could scratch his itchy phantom arm by scratching a specific spot on his cheek. This is likely because the sensory maps in the brain that correspond to the face are close to those that correspond to the arm.

·         Researchers are just beginning to understand the cause of the phantom limb phenomenon, and there is still much debate. For the current theories, check out the sources below:

Sources:

·         http://serendip.brynmawr.edu/bb/neuro/neuro02/web2/tchen.html

·         http://psy.psychiatryonline.org/cgi/content/full/39/4/384

·         http://www3.interscience.wiley.com/journal/119520633/abstract?CRETRY=1&SRETRY=0

·         http://en.wikipedia.org/wiki/Phantom_limb

·         The Brain That Changes Itself Norman Doldge M.D.

http://www.media.rice.edu/images/media/2007RiceNews/0503_gleevec.jpg

In traditional chemotherapy, the goal is to kill cancer cells. However, the drugs that do this operate by only two mechanisms: damaging DNA and damaging the cell skeleton (the cytoskeleton). However, since all cells have DNA and a cytoskeleton, chemotherapy is not very specific to cancer cells. Consequently, chemotherapy is essentially poison; many different cells other than cancer cells are damaged and killed by it, leading to horrific side effects, and potentially, secondary cancers that have been caused by the chemo itself. Also, many cancer cells learn to repair their DNA and cytoskeleton, or pump out chemotherapeutic drugs. This renders them useless, as the cancer out –evolves treatment. Soon however, a new type of drug may change all of this…

Inhibitors. Inhibitors are drugs designed to block the function of specific biomolecules (usually enzymes or receptors) in or on cells. Usually, inhibitors are small, low molecular weight compounds that fit into the activation site of an enzyme, thus preventing it from binding its substrate and carrying out its function.

Inhibitors may be useful cancer drugs, as many cancer cells express and require oncoprotiens (cancer inducing proteins, the products of oncogenes, cancer inducing genes) and enzymes that normal cells do not express and need, or they express them at higher than normal levels. If inhibitors could be developed to these oncoproteins or enzymes, then theoretically, the cancer cells would die while the normal cells would be relatively unaffected. So, what‘s been done with inhibitors so far?

First, there is already an extremely successful cancer drug on the market that is an inhibitor: Gleevec. Gleevec is a drug designed to treat Chronic Mylogeneous Leukaemia (CML). It works by blocking the fuction of the Bcr-Abl tyrosine kinase, an oncoprotein that is only expressed in CML cells and stimulates their excessive growth and extended survival (i.e. makes them cancerous). Gleevec is highly successful in treating CML (though in most cases the patients relapse as the cancer evolves to overcome Bcr-Abl inhibition or prevent the drug from binding).

Furthermore, researchers have been trying for years to develop a telomerase inhibitor. Telomerase is enzyme, which in adult humans is only expressed in germ cells, activated lymphocytes, and cancer cells, that repairs the telomeres of chromosomes. The telomeres prevent apoptosis by preventing chromosomes from fusing to one another, and they degenerate slowly as cells go through replication. Since cancer cells divide so frequently, they have to develop a mechanism for repairing their telomeres; and roughly 90% of them express the enzyme telomerase to do this. If the function of telomerase could be stopped with an inhibitor, then cancer cells would die, as they would be unable to repair their telomeres. Though pharmaceutical companies have been unable to develop a telomerase inhibitor as of yet, such a compound would be a highly successful cancer drug with applicability to almost all cancer types.

Finally, research is currently underway to develop inhibitors to other oncoproteins and enzymes, notably, tyrosine kinases. Kinases are essentially “on” switches in cells; they turn on other proteins by adding phosphate groups to them. Tyrosine kinases, of which there are about 90, are kinases that are often involved in causing cancer. Much research is in progress to develop inhibitors to them, in hopes that they will serve as effective and specific cancer drugs.

So, why will inhibitor therapy become common place in cancer treatment? Inhibitors are already being developed, and they offer two huge advantages over traditional chemotherapy. First, although they will likely not be entirely cancer cell specific, they will definitely be more so than traditional chemo, and thus they will have fewer side effects.  And, more importantly, they will provide a different method to kill cancer cells, thus making the probability that a cancer would be able to out-evolve ALL our current treatments less likely. In my opinion, this will be their largest benefit.

Sources:

·         http://www.oncologychannel.com/leukemias/types.shtml

·         http://www.nature.com/leu/journal/v19/n9/abs/2403881a.html

·         The Biology of Cancer by Robert A. Weinberg

http://www.healthsystem.virginia.edu/internet/hematology/images/AML-M4e3-website.jpg

An extremely unexpected thing will happen over the next few decades of cancer research: more types of cancer will emerge. Fortunately however, this will not be the result of pollution, novel genetic mutations, or any increased disease incidence. In fact, it will be a consequence of something that will lead to new treatment strategies and thus save many lives: better classification.

In the 1950s, researchers began to suspect that acute leukemia may come in more than one form, as some cases responded much better to treatment than others. However, most leukemia samples looked the same under the microscope, so scientists reasoned that the only difference must be biochemical. And, after roughly 40 years of research, research revealed that acute leukemia did in fact come in two forms: AML and ALL.

The distinction between AML and ALL has had a vast amount of therapeutic benefit, as ALL patients and AML patients must be given different treatments to ensure the best response to therapy. This raises the possibility that if doctors could classify other types of cancer into more specific sub-groups, then they may be able to provide more effective treatment for them as well. And indeed, this is what is already beginning to happen today…

Recently, scientists have learned that classic ALL can be broken down into two types of cancer. The first type carries a mutation in a gene known as MLL, and it is associated with infant leukemia, as well as a poor prognosis, while the second type of leukemia does not have a mutation in the MLL gene and is associated with a better prognosis. Furthermore, doctors believe that the first type of leukemia should be sensitive to a drug that inhibits the Flt kinase (I’ll cover the potential for inhibitors as a cancer treatment strategy in the next article), while the second type will not. Flt kinase inhibitors are currently in clinical trials. However, the key point is that identifying Flt kinase inhibitors as a potential drug would not have been possible without better classification. This is the type of research that will continue in the future. Furthermore, lymphomas, breast, ovarian, and colon cancer have all been further classified as of yet. There is no doubt that investigation in this area will continue, and hopefully many new drugs will be produced as a result.

Sources:

http://www.ncbi.nlm.nih.gov/pubmed/18282363

http://www.ncbi.nlm.nih.gov/pubmed/15680584

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A65007

http://www.nature.com/leu/journal/v19/n9/abs/2403881a.html

http://www.innovations-report.com/html/reports/life_sciences/report-110666.html

http://www.oncologychannel.com/leukemias/types.shtml

MIT Open Courseware: Eric Lander’s Lecture #34 on Human Polymorphisms and Cancer Classification (in Course 7.012: Introduction to Biology, Fall 2004)

http://www.news-medical.net/images/breast%20cancer%20cell.jpg

In any movie that involves cancer, the story always ends with the patient, “doing well and in remission”. They never say cured. Why? Well, the sad truth is, most people diagnosed with cancer will relapse (the cancer will return) within five years after the cancer is no longer detectable. Even worse, the cancer often is now resistant to chemotherapy and radiation, and has begun to metastasize (spread). Tragically, as a result of this, death often follows shortly after relapse.

As horrible as this sequence of events is, it raises several interesting questions. First, why are some cancer cells able to survive the original treatment (chemotherapy, radiation, or surgery)? Also, why does the cancer return in a resistant and metastatic form?

Both of these questions have a similar answer. When doctors treat a tumor, with a chemotherapy drug for example, there will be a small number of neoplastic cells that will be resistant to the drug, and those cells will survive. How are the cells resistant? There are a variety of ways. Perhaps the drug works by damaging DNA, and a few cells happen to have mutations in genes that code for DNA repair enzymes, thus making DNA repair more efficient.  Or perhaps the drug works by targeting a specific cellular antigen (like Herceptin does), and certain cancer cells do not have this receptor. There are many other mechanisms that can grant cancer cells drug resistance as well. Whatever the case, the important fact is that small numbers of cancer cells often survive the initial chemotherapy and/or radiation regimen. (In the case of surgery, the surgeon may miss some cancer cells during surgery, which is why surgery if often followed by radiation/chemo.)

Once some cells have survived the initial treatment, they will begin to grow again. However, this time, the entire new tumor will be resistant to treatment, as it has originated from cells that were themselves resistant. The cancer has, in a sense, evolved to overcome the therapy. Furthermore, evolution favors any mutations in cancer cells that make them survive better. The ability to metastasize is such a mutation. Since any cancer cells that survived the initial treatment have had the chance to replicate far more often than the cancer cells that existed pre-treatment, they are far more likely to have acquired the necessary mutations for metastasis. This explains why tumors that recur after therapy are often metastatic.

So, what can we make of all this? Surgery, radiation, and chemotherapy can be successful in curing cancer. But often they cannot achieve durable cures, as they are selecting for any cancer cells that are resistant to them. For instance, there has been one case where a man’s CML (chronic mylogeneous leukemia) was kept in remission for eleven years, using a highly successful drug known as Gleevec. However, his cancer eventually developed resistance to Gleevec, and he died.

Since the development of resistance is such a common and deadly problem, what can be done about it? Well, first, it helps to think about the cancer cells in a person’s body in evolutionary terms. All the cancer cells vary slightly in their genotype and phenotype, and those that are best suited for survival (i.e. those that have mutations conferring therapy resistance and metastasis) will survive and reproduce the most. The cancer therapies of the future will utilize this knowledge to their advantage, and thus be better designed to eradicated all neoplastic cells and prevent relapse. They will likely do this in some of the following ways:

1.      A wider variety of chemotherapy drugs will be developed that work by many different mechanisms and are chemically distinct from one another. They will be chemically distinct and act by different mechanisms to prevent cancer cells from being resistant to both of them. This is already occurring today, and it is the reason that chemotherapy protocols involve more than one drug. Theoretically, any cancer cells that survive a chemotherapy regimen must be resistant to all the drugs it includes. Since the probability that a cancer cell will be resistant to two or more drugs is much less than the probability that it will be resistant to a single drug, cancer cells are less likely to survive, and thus relapse is also less likely to occur.

2.      The “Sucker’s Gambit” approach may become useful. This is an extremely theoretical approach at the moment, and it is just now being evaluated in cell culture. In the Sucker’s Gambit, those cancer cells that are not resistant to chemo and radiation would be somehow given an evolutionary advantage over those that are. For instance, perhaps those cells would be given a nutrient or growth factor that the resistant cells would not respond to. The nonresistant cells would then grow more than the resistant cells, and eventually out-compete them for resources, causing the resistant cells to eventually die off. The patient could then be given chemotherapy and/or radiation treatment, and relapse would be less likely, as resistant cells have already been killed off by evolution. See this link for a more thorough explanation of the research: http://www.wistar.org/research_facilities/maley/research.htm

3.      Certain cancers may one day be treated less aggressively but longer, in an attempt to keep resistant cells from proliferating too much. The goal would be to turn cancer into a chronic disease, like HIV infection, and to keep a tumor at a certain size instead of eradicating it. See this article for a longer explanation: http://www.sciencebasedmedicine.org/?p=518#more-518.

As always, just some speculation…

Brad Rybinski