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.

http://images1.wikia.nocookie.net/starwars/images/ e/e5/Clone_Troopers_Phase_I.jpg

 Recent advances in the biological sciences have made cloning, the production of a genetically identical copy of an organism, a reality. However, not everyone believes that scientists should attempt to clone human beings. Opponents of human cloning present a compelling case. First, they argue that cloning is an inefficient process that would likely produce an unhealthy clone. Furthermore, opponents warn that a clone would unfairly bear heavy psychological burdens. Finally, those against cloning caution that human cloning would be detrimental to society at large. However, those in favor of human cloning raise some valid points. For instance, advocates argue that cloning research may lead to medical benefits. They also make the case that cloning is just another form of reproductive technology that people should be free to use. Despite these arguments in favor of cloning, the negative aspects of human cloning outweigh any positive ones; scientists should not try to clone human beings.

Organismal cloning, the generic term for cloning that produces an entire human, animal or plant from a single cell, first emerged as a technology in 1958 when carrots were cloned from mature carrot cells. Like all clones, the cloned carrots carried the exact same genetic code as the mature carrot cells from which they were cloned (Petechuck). Cloning research continued to make incremental improvements over the next few decades, and in the summer of 1996 scientists accomplished the successful cloning of a mammal for the first time with the birth of Dolly, a cloned sheep, at the Roslin Institute (Nardo 35). Dolly’s birth spawned a media frenzy, and for the first time the public and politicians seriously debated the morality of organismal and human cloning. Shortly after Dolly, in June of 1997, President Clinton called on the U.S. Bioehics Advisory Commission to review the ethical and legal implications of cloning (Human Cloning). The debate on the ethicality of cloning, and specifically human cloning, hasn’t stopped since.

The technology that produced Dolly, and that could also create a human clone, is known as somatic cell nuclear transfer, often abbreviated as SCNT. In SCNT, the nucleus of an egg cell is removed, literally using a glass pipette. This nucleus is then replaced with the nucleus from a cell that contains the genetic material of the organism that is being cloned. Naturally occurring chemicals inside of the egg cell then cause the egg to develop into an embryo, just as it would if the egg had been fertilized naturally by a sperm cell (Sive). However, unlike a normal embryo, the embryo that results from SCNT is genetically identical to the organism that supplied the donor nucleus. In the case of humans, a clone would be a younger identical twin of the individual that had supplied his nucleus.

Though extraordinary, the technology of SCNT contains several peculiarities that create the first objection raised by opponents of human cloning; cloning is an inefficient process that produces physically abnormal clones. First, for reasons that remain obscure, the success rate of cloning experiments in producing organisms is extremely low. In a recent experiment that cloned human embryos through SCNT, only three out of twenty five attempts worked (Caplan). More generally, scientists estimate that the success rate of SCNT hovers around a mere one percent (Sive). Furthermore, animal clones almost always suffer physical problems that normal animals do not. For instance, Dolly suffered from extreme arthritis and lung disease that forced veterinarians to euthanize her at the age of six, when sheep normally live to the age of twelve (Petechuck). In addition to these physical problems, research showed that Dolly possessed DNA that was older than her chronological age. Carrying this older DNA made Dolly more susceptible to age-related illnesses, especially cancer. Old DNA and physical problems similar but not limited to those of Dolly have been observed in a wide range of cloned animals; nearly all clones have something wrong with them (Sive). Consequently, the pattern suggests that a human clone would be difficult to create and suffer many physical abnormalities.

As a consequence of the near certainty that human clones would bear many health problems, opponents of human cloning make the valid point that human cloning cannot be ethically carried out because it exposes clones to physical harm. Though future technology may be able to create healthy clones, the experimentation necessary to create such technology also violates moral principles, as the experimentation would likely produce physically damaged clones (Kaebnik).   Furthermore, regarding human cloning research, the President’s Council on Bioethics concluded that, “There seems to be no ethical way to try to discover whether cloning to produce children can become safe, now or in the future” (President’s). Since human cloning would produce clones with dramatic health problems, and any research that would make cloning safe would also produce babies with health problems, no situation exists where human reproductive cloning should be attempted.

Not only do opponents of human cloning argue that cloning would inflict physical health problems on clones, but they also warn that a clone would suffer psychological burdens to such an extent that cloning a person would be unethical. First, a clone would likely grapple with pronounced problems regarding his sense of identity and self. The President’s Council on Bioethics cautions, “Cloned children may experience serious problems of identity both because each will be genetically virtually identical to a human being who has already lived and because the expectations for their lives may be shadowed by constant comparisons to the life of the ‘original’” (President’s). Also, a clone may feel as if he had been denied an open future, as he would be constantly compared to the person he had been cloned from. Finally, any human clone will have to learn to handle the thought that he is a copy of someone else and not an original person (Wachbroit). Adversaries of cloning make the point that forcing a clone to accept his status as a copy and not his own unique individual fundamentally violates human dignity. Because a clone would have many painful psychological issues to confront, human cloning can only lead to suffering, and thus it should not be carried out.

Though the opposition of cloning makes the case that cloning should not be tried because it would cause the clone to suffer, human cloning also should not be attempted because it would have a detrimental effect on society. For instance, cloning creates the danger that some individuals may be cloned against their will. Since people give off cells everywhere they go, it would be nearly impossible to prevent someone from cloning another individual without that individual’s consent. Fans may try to clone actors or superstar athletes, and a woman could even clone an apathetic man that she wants to have a child with (Herbert). Moreover, human cloning may cause society to look at identity differently. “Cloning might force us to regard people as repeatable, and accepting that people are not one time occurrences is to allow the value of personhood to be diminished” (Kaebnick). Since a society that permits human cloning could not prevent individuals from being cloned without their permission, and also since the value of the person may be reduced, human beings should not be cloned.

While the stronger arguments do not support human cloning, those in favor of cloning raise some valid points. First, advocates claim that research on human cloning and SCNT may produce medical benefits. For instance, scientists may learn more about cellular differentiation, a process that often goes wrong in cancer, if they are permitted to study somatic cell nuclear transfer (Kaebnik). This is a valid point, but it only makes the case for allowing SCNT as a technology; it does not make the case that human beings should be cloned. On a more profound level, supporters of human cloning have argued that cloning is just a new form of human reproduction. “In general, why should a couple using cloning have a higher justification required of them than a couple using sexual reproduction?”(Pence). Likewise, cloning could provide infertile couples their only way to have biological descendants, and the ability to have biological descendants may fall under the rights granted to individuals in modern Western societies (Kaebnik). For instance, if cloning is just the newest form of human reproduction, then it is already protected in the United States by the Constitution (Pence). For the proponents of human cloning, its potential to help the sick, as well as those trying to become parents, is most compelling.

Though proponents of cloning raise substantial points, the arguments against cloning carry the day. Specifically, a clone would suffer immensely. He would be born with many health problems, and he would be forced to wrestle with many heavy psychological burdens. “Once the welfare of the clone is considered, the anti-cloning arguments far outweigh the pro-cloning arguments”(President’s). Furthermore, a society that allows cloning would experience detrimental effects, as it could not prevent cloning without permission and would see the value of personhood diminished. For all these reasons, the technology of cloning should not be applied to people; scientists should not attempt to clone human beings.

Works Cited

“Animal Pharming: The Industrialization of Transgenic Animals.” Center for Emerging Issues.      CEI.  Dec. 1999. Web. Feb. 2010.

Caplan, Arthur. “Human Embryos Cloned:  What does it mean?. MSNBC Health. MSNBC. 17     Jan. 2008. Web. 18 Feb. 2010.

Herbert, Wray, Jeffery Sheler, and Traci Watson.  “Ethical Issues Concerning Human Cloning.”                Contemporary Issues Companion. Ed. Lisa Yount. San Diego: Greenhaven, 2000.                                                                                                      

            129-134. Print. Excerpted from “The World After Cloning.” U.S. News and World.

“Human Cloning.” Issues and Controversies. Facts on File News Services, 29 Dec. 2006. Web.

22.Feb. 2010.

The Human Cloning Foundation. “The Medical Benefits of Human Cloning.” Contemporary        Issues Companion.  Ed. Lisa Yount. San Diego: Greenhaven 2000. 153-155. Print.        Excerpted from “The Benefits of Human Cloning.” 1998.

Kaebnick, Gregory and Thomas Murray. “Cloning.” The Concise Encyclopedia of the Ethics         of the Ethics of New Technologies. Ed. Ruth Chadwick. 1^st ed. Vol.1. San Francisco:          Academic Press, 2001. 51-64. Print.

Mautner, Michael. “Cloning Could Halt Human Evolution.” Contemporary Issues Companion.     Ed. Lisa Yount. San Diego: Greehaven 2000. 141-143. Print. Excerpted from “Will             Cloning End Human Evolution?” The Futurist. Nov. 1997.

Nardo, Don. Cloning. San Diego: Lucent, 2002. Print. Great Medical Discoveries.

Pence, Gregory. “Reproductive Cloning Does Not Demean Human Life.” Cloning: Opposing       Viewpoints. Ed. Tamara L. Raleef.  Farmington Hills: Greenhaven Press, 2006.  22-28.         Print.  Rpt. of “Ten Myths About Human Cloning.” 2001.

Petechuk, David. “Clone and Cloning.” Gale Encyclopedia of Science. Ed. K. Lee Lerner and      Brenda Wilmoth Lerner. 4^th ed. Detroit: Gale Group, 2008. Web. 22 Feb. 2010.

Pinker, Steven. “How the Mind Works.” New York: Norton, 1999. Print.

President’s Council on Bioethics. “Reproductive Cloning Demeans Human Life.” Cloning:           Opposing Viewpoints. Ed. Tamara L. Roleff.  Farmington Hills: Greenhaven, 2006.    16-21. Print. Rpt. of “Human Cloning and Human Dignity.” Presidents’s Council on           Bioethics. New York: Public Affairs, 2002.

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://hplusbiopolitics.wordpress.com/2008/04/01/why-cant-i-have-wings/

“Would you rather be invisible or fly?” That question has become so ubiquitous that it has lost all of its originality. Here’s a better question: how could a person actually be given wings (so that they could fly)?

To come up with an answer to this, it is important to understand some background biology. There are certain genes, called Hox genes, that code for transcription factors, or proteins that turn on other genes. The transpcripton factors encoded by Hox genes turn on vast networks of genes responsible for limb and body segment growth. So basically, in order for a person to grow a leg during the course of their development, the right hox gene that says “build a leg here”, must get turned on.

Now here’s where things start to get interesting. Since hox genes have so much power, mutations in them have amazing effects. For instance, scientists have played around with hox genes in fruit flies and done the following:

1.       Grown legs where antenna should be

2.      Grown an eye on a fruit fly’s leg

3.      Grown extra wings

Did you notice example number 3? Growing wings… Of course, as people are not flies, the genetic modifications needed to grow wings on people would be more complex than those needed to grow extra wings on flies. And there are lots of ethical problems with manipulating human embryos (any wing growing genes would need to be added then) solely for the goal of producing a wing-endowed person. Still… the point is that with the existence of Hox genes, the problem of giving a person wings isn’t as complicated as one would initially expect.

Sources:

www.pbs.org/wgbh/evolution/library/03/4/pdf/l_034_06.pdf

www.coolsciencefacts.com/2007/homeobox_genes.html

http://hplusbiopolitics.wordpress.com/2008/04/01/why-cant-i-have-wings/

http://scienceblogs.com/pharyngula/2006/04/a_brief_overview_of_hox_genes.php

http://michaelscomments.files.wordpress.com/2009/10/bacon.jpg

Bacon is good. However, some people don’t like that you have to kill pigs for it. But what if you didn’t have to?

For the first time, scientists have grown bacon in a petri dish. Well… almost. Two Dutch scientists, Bernard Roelen and Henk Haagsman, at Utrecht University, have managed to grow small bits of pork in the lab. This lab grown pork still lacks the fat, blood vessels, and consistency (lab muscle is a lot weaker than muscle that has been exercised through movement) characteristic of normal pork; think mushy ground pork instead of a pork chop. But it is a step toward lab grown bacon nevertheless.

First, the researchers collected pig myoblasts, which are muscle stem cells. They then used a special nutrient broth (made from pig fetuses, but researchers think synthetic substitutes may one day be available) to stimulate the myoblasts to grow into large bits of pig muscle. This is essentially pork.

Besides the obvious application of allowing vegetarians to eat pork, scientists hope that this would be another way to feed the hungry. Also, since there is no reason this technique wouldn’t work on other animals, people may one day be able to go to the store and buy all kinds of exotic meat: lion, tiger, penguin, giraffe… Who knows?

Sources:

·         Skeptic’s Guide to the Universe

·         http://www.thestar.com/News/article/245446

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/

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

The Iconoclast: The Rise of Immunotherapy

I am by no means an expert or doctor, but cancer and molecular biology are my two favorite areas of science. So I read papers, listen to lectures, and study textbooks in these fields. Though I have an incredible amount left to learn, I definitely have accumulated some knowledge and opinions over the years. With that caveat, I’ve decided to write a four part series (it will be posted every Sunday) describing what I believe the future of cancer treatment will look like. Most of what I say will be speculation (duh), but it will be based on facts and current research trends. So, here we go…

“Immunotherapy, the use of the immune system to attack a patient’s cancer, will rise to the level of surgery, chemotherapy, and radiation as a fourth major treatment strategy for cancer.” Current cancer therapies include the use of surgery to remove tumors and the use of either chemicals (chemotherapy) or radiation to kill neoplastic (cancerous) cells. However, immunotherapy will harness the cells of the body’s immune system, and get them to recognize cancer cells as foreign, and eventually destroy them.

First, what evidence do scientists have that the immune system can kill cancer cells? After all, if the immune system could recognize and kill cancer cells, wouldn’t cancer patients eventually fight off their cancer, just as people regularly fight off and recover from the flu? Though this is a valid question, and its answers have hindered the development of immunotherapy as of yet, there is strong evidence that the immune system can recognize and kill cancer cells to some extent. Amplifying this ability will form the core of immunotherapy.

The first piece of evidence that the immune system can fight cancer comes from a depressing statistic: people who have received organ transplants are significantly more likely to get cancer than members of the normal population. How significantly? It varies for different cancer types, but we are not talking about small numbers. People who have received transplants are 14.3 times as likely to get thyroid/endocrine cancers, 13.8 times as likely to get some form of mouth cancer, 10.3 times as likely to get Non-Hodgkin’s lymphoma, 9.1 times as likely to get kidney cancer, and 5.5 times as likely to get bladder cancer. The incidence is dramatically increased in other cancers as well. (Source: The Biology of Cancer by Robert A. Weinberg, page 680). Why is this the case? As it turns out, most patients who receive organ transplants must take immunosuppressant drugs in order to keep their immune system from attacking their new organ. The thinking is that, since a suppressed immune system seems to correlate with an increased risk of cancer, then the immune system probably plays some role in preventing cancer development. The same increased cancer risk is found in AIDS patients. Correlation does not ensure causation, but such strong correlation is extremely suggestive. There have also been many experiments in mice that show that a reduced immune system makes them more easily develop cancer.

So what exactly is immunotherapy? Immunotherapy currently comes in three main forms:

1.      Cancer vaccines. See this previous Iconoclast interview for an explanation: http://theiconoclast.info/?p=102.

2.      Passive immunization. Passive immunization consists of injecting a patient with an antibody to their cancer cells. Certain neoplastic cells have an abnormal pattern of antigens on their surface. Abnormal antigens may be present, or normal antigens may be present in increased numbers. Passive immunization consists of injecting an antibody to such an antigen, thus causing the antibody to bind the cancer cell and (1) prevent it from growing and replicating and/or (2) target it for destruction.

3.      Bone marrow transplantation. The immune system is generated by cells in the bone marrow. A common treatment for many hematological cancers, such as leukemia, is to give patients what is known as a bone marrow transplant. This usually results in a cure. In a bone marrow transplant, the patient’s own immune system is either partially or completely eradicated (using drugs and radiation). They are then given new bone marrow from a completely different person (known as a donor). This bone marrow then regenerates the immune system, and the patient ends up with a replica of the donor’s cancer free immune system.

The original intent of bone marrow transplantation was to cure cancer by simply replacing the cancerous immune system with a noncancerous one. However, though cures were being achieved, scientists soon realized that the cures were not entirely a result of simply “replacing the bad with the good”.  There was a much more exciting phenomenon going on…

The graft versus tumor effect. As it turned out, some cancer cells still remained inside the body after the attempts to destroy the immune system. However, the newly generated immune system of the donor recognizes these cells and destroys them. This results in a long term cure. Though the graft versus tumor effect does not cure solid tumors (large tumor masses create an environment near them that renders many killing cells of the immune system useless), research is currently underway to understand exactly why this is, in hopes that one day the graft versus tumor effect may be used to treat solid cancers.

So, has immunotherapy been tried yet in humans? Has it been successful? The answer to both questions is yes. Passive immunization is already in clinical use. The vaccine Herceptin is being used to treat some forms of breast cancer, specifically those that over-express the HER-2 antigen. Many more passive immunization procedures are being investigated. The other type of cancer vaccine, the kind described in the interview with Dr. Parcells that relies on immunostimulatory molecules, is currently in clinical trials for a variety of cancers. And finally, researchers have begun to report preliminary evidence (just a few case studies) in which bone marrow transplants have caused remission in solid cancers (breast and ovarian so far). Though there is much work left to do, and still huge obstacles to overcome, I believe that one day immunotherapy will be a common and effective type of cancer treatment.

Brad Rybinski

Sources:

·         The Biology of Cancer by Robert A. Weinberg

·         http://www.herceptin.com/pdf/AdjuvantCorePatientBrochure-NEW.pdf

·              http://cancerres.aacrjournals.org/cgi/content/full/68/8/2561

·         http://www.ncbi.nlm.nih.gov/pubmed/12531922

·         http://jco.ascopubs.org/cgi/content/full/22/19/3846

·         http://annonc.oxfordjournals.org/cgi/content/full/18/10/1751

·         http://www.nature.com/bmt/journal/v25/n6/full/1702206a.html

·         http://www.centocor.com/centocor/images/immunology.jpg