Ovararian Transplants in Cancer Patients & Their Implications: Are we challenging nature too much?

By: Helen Beilinson

Cancer results from the accumulation of mutations within normal cells in our bodies that result in their abnormal and uncontrolled growth. These cells replicate very rapidly and amass to form tumors. Two of the most common treatments for cancer, chemotherapy and radiation therapy, function to eliminate cancer cells. Chemotherapy works by delivering chemical substances (such as anti-cancer drugs) into the patient, where they act as cytotoxic agents, killing cells that divide very rapidly. Chemotherapy is unfortunately not specific for cancer cells, just dividing cells, so it kills healthy cells as well. An infamous side effect of chemotherapy is  hair loss, or alopecia, which happens due to the cytotoxic effect of chemotherapy on hair follicles, a rapidly dividing cell type. Radiation therapy uses ionizing radiation, which takes advantage of high-energy rays, to kill cancer cells. Radiation can be targeted to a particular area within the body, as opposed to chemotherapy, which is predominantly administered into the blood stream. However, it still leads to the death of healthy, noncancerous cells, surrounding the tumor location.

Although cancer is predominantly known as a disease associated with age, youth doesn’t protect entirely from cancer. Teenagers and young adults can still be diagnosed with a variety of cancers. An unfortunate side effect in female cancer survivors is that chemotherapy and radiation therapy can often result in infertility, rendering the women unable to have children.

In an article this week in Human Reproduction, authors explored whether they could restore fertility in women who had survived cancer. To do this, before beginning cancer treatment, doctors removed either entire or partial ovaries from these patients who decided they would want to have children after treatment. They then cryopreserved the ovaries, freezing them at subzero temperatures for long-term preservation. After successful treatment of the women’s’ cancer, the surgeons transplanted the cryopreserved ovarian tissues back into their patients.

The doctors found that of the 32 women who chose to try to become pregnant after transplantation, 10 (31%) were able to conceive one or more children. Doctors estimate that women who do not undergo ovary transplants have a maximum of a 5% chance of conceiving after cancer treatments. A 25% increase is not too shabby.

Though it involves two additional surgeries, the treatment is very safe and has provided a lot of comfort to women diagnosed with cancers early in life. As Claus Yding Andersen, a reproductive physiologist who was involved in this study, said in an interview with Capital Public Radio, “Obviously, the thing that interests [patients] the most is to survive the cancers, but immediately after that they would say they are really interested in maintaining their fertility.” This advancement in transplantation medicine has provided cancer survivors with the ability to continue their life plans after the jolting reality of cancer.

This study, however, raises many moral questions. In 1970, the average age of a woman to have her first child was 21.4. Nearly half a century later, today the average age is 25.2. As women are having children later in their lives due to a variety of social, political, and economic reasons, many have considered freezing their eggs as a way for them to retain their fertility until a time when they are ready to have children. In light of the success of cryopreservation of ovaries of cancer patients, physicians have began asking whether it should be available for women who are not cancer patients, giving them the chance to preserve their ovaries until a time when they are ready to have children.

Due to how egg cells develop in women, which I will not go into detail here, eggs that are released from ovaries earlier in life tend to be more healthy and have less potential mutations, compared to those released later in life. It is also believed that the uterus is not as affected by age as other reproductive parts. Thus, in theory, if a woman freezes her eggs and undergoes in vitro fertilization later in life, the woman is very likely to have a healthy pregnancy and a healthier child than if she chose to have children without in vitro fertilization. In theory, this idea is also applicable to transplanted cryopreserved ovaries. However, many other problems deserve consideration. For example, due to decreased estrogen production later in life, the mother will be less able to produce milk to feed her child.

 

Of course, advances in medicine are always incredible—especially when we are able to protect and conserve such a complex system as pregnancy. However, there may be unknown consequences to having children later in life, especially by more medically aided means. Evolution has shaped the way our bodies work for millions of years. Evolution functions not only to advance traits that are helpful in a particular organism, but also to maintain a balance between all systems within that particular organism. Medicine has changed how our bodies interact with the outside world (with treatment of infectious diseases) and how our bodies handle changes within us, such as cancer or pregnancy. Medicine is able to target specific problems or concerns of patients, however, targeting one problem can off set known and unknown factors leading to unforeseen consequences. There is still a lot to be learned about how offsetting the age at which organisms have children can affect the offspring. Although medical advances have been incredibly helpful in some situations, such as allowing women who have lost their fertility do to cancer treatment to mother children, they also raise moral and ethical questions that should be considered before allowing such treatments to be used by everyone.

 

The Extinction of Tasmanian Devils: Sometimes It's Better to be Different

By: Helen Beilinson

Australia has an incredibly unique list of animal inhabitants. From massive pythons to flying foxes (the largest bat species in the world) to ridiculous spiders and centipedes to some of the largest, smallest, and most poisonous jellyfish, Australians definitely have more interesting backyard fauna than I do here in New Haven (although the black squirrels are pretty cute).

Aside from its slightly more terrifying creatures, Australia is home to a huge amount of marsupials. Marsupials are mammals, meaning they feed their young with milk, like humans do. Unlike humans, however, mother marsupials do not carry their young in their uteri until birth. Instead, after a certain time of developing in utero (meaning, in the uterus), marsupial young will climb into a special pouch on their mothers’ belly to continue developing. These pouches contain the mother’s nipples, to feed the young, and offer protection while the baby marsupials continue growing. Some of the best known marsupials are kangaroos, koalas, and the happiest animal on Earth, quokkas. One marsupial that’s predominantly known more for its cartoon depiction is the Tasmanian Devil, which is currently the largest carnivorous marsupial. Unfortunately, their population is at high risk of extinction. Extinction of species is nothing new; it happens all of the time. Extinction can be caused by high predation, changes in food or climate, high rates of disease or infection, or a slew of others reasons. The pathway to extinction of devils is particularly interesting because their population is threatened by a rare type of disease—a transmissible cancer.

That’s right, the devils are transmitting cancer to each other, like humans can spread a cold.

Before the 1400s, Tasmanian Devils populated the entirety of Australia. However, due to heavy predation by dingoes and indigenous people, the devils were isolated to the Australian island of Tasmania. Since then, major population crashes have continued to affect the devil population. From 1830 to 1930, locals made efforts to exterminate the devils because they preyed on their livestock. In 1909 and 1950, there were smaller epidemics of infectious disease that hurt the devil population. In 1941, however, laws were enacted to protect the devil population because half a decade prior, another carnivorous marsupial, the Tasmanian Tiger, went extinct. These laws aided the devil population drastically, until about half a century later.

In 1996, the first case of Devil Facial Tumor Disease (DFTD) was documented in the Tasmanian Devils. This cancer, as the name suggests, causes large facial tumors on the devils. These facial tumors eventually cause the devils to die of thirst and starvation, as they are unable to eat, drink, or see. The fascinating thing about these tumors, as I previously alluded to, is that they are passed from devil to devil through biting. This transmissibility is incredibly rare in cancer. Usually, cancerous cells develop within one individual and cannot be passed from one person to another. Curiously, the same phenomenon helps to explain why cancer cannot be spread in most species and why it is spread through the devil population.

Each of our cells contains markers (these are basically proteins that cover the exterior of the cell such that other cells can “see” them) on its surface to tell other cells that they are part of the same organism. They mark our cells as “self” as opposed to other cells, that either have “nonself” markers or have no “self” markers. One self marker is the Major Histocompatibility Complex (MHC) molecule. These molecules are critical to our immune responses because they will hold motifs (kind of a protein pattern) that allow other immune cells to recognize what is infecting the body. Because they need to bind to so many different kinds of proteins (they have to be able to display features of all the bacteria, viruses, fungi, etc. that invade our bodies), you can imagine that have different forms is a good thing for your immune system, because you can bind various forms of such proteins, instead of a smaller subset, which would allow you to react to a greater variety of things. Mammalian immune systems have this taken into account. MHC genes are some of the most diverse, or polymorphic, genes out there. This means that there are many, many forms of it throughout the population (don’t worry, they still work great!). Because you have two copies of DNA (one from your mother, one from your father), you get two copies of these MHC genes. This means that the more different your mom and dad’s MHC genes are, the greater variety of foreign proteins you can display on your MHC. This positive aspect of MHC genetic variety can be more greatly appreciated when you see a population where this variety doesn’t exist. This loops us back to the Tasmanian Devils.

Due to the massive population downsizing and isolation of a small population of the devils, they have a very limited variety of these MHC molecules. This observation is one of the major reasons why DFTD is so rampant. As I mentioned before, MHC molecules are self markers. The variety that we see in these molecules allows for a greater system of defining what “self” is compared to nonself. For example, if you have a signal of two letters for variety, there’s only 262 (676) options. So out of the 7.1 billion people on earth, your body will see 10.5 MILLION people’s cells are your cells. If you have a signal for ten letters of variety, there’s 2610 (140,000,000,000,000), so your body will only recognize your body’s cells are your cells.

When rejection occurs after an organ transplant, this is due to the acceptor’s body recognizing the MHC on the donor’s organ, thereby seeing it as nonself and attacking it. Although this isn’t good for a transplant, this keeps a lot of problems at bay. Unfortunately, due to their lack of variety of MHC genes, Tasmanian Devils do not have this ability. The cancer cells of the DFTD can be found on teeth and on lesions on infected devils’ faces. When they bite another devil, these cells are transferred into the wounds of the uninfected devil. If there were enough variety in the MHC genes of the devils, the newly infected devil would recognize the cancerous cells as nonself and would eliminate them, preventing the development of a facial tumor. However, because there is so little variety in the devil’s genes, the newly infected organisms do not recognize the cancerous cells as nonself, and instead see them as self. Self cells are not attacked by the system normally, so the cancerous cells stay, and develop into tumors. This perpetuates the cycle, leading to the cancer spreading throughout the population.

There are currently two other known transmissible cancers. One is a venereal tumor that affects dogs that has been spreading around the world for the past 11,000 years. The second was recently confirmed as a transmissible cancer—it is a soft-shell clam leukemia that has spread throughout the east coast of North America.

The extinction of the Tasmanian Devil is being driven by this transmissible cancer that the devils are unable to eliminate. However, without the initial downsizing of their population due to human predation, its highly probable that the population would have enough diversity of their MHC genes that this cancer would not have been able to even come about.

Did someone really prove that eating red meat causes cancer?

By: Ross Federman

One frustration facing many scientists today is the manner in which primary research articles are interpreted by other writers and subsequently reported to the general public.  Often, important subtleties and details regarding the experimental design are disregarded, and while researchers are careful to qualify their conclusions based on this, other writers may not be. The past few weeks has provided a clear example of this.  This research article provides some implications, and promises to guide future research to gain more insight into the question at hand. However, many articles covering the research, such as this one from The Telegraph, are stating these implications as a concept that the article “proved,” in this case, that eating red meat will cause cancer.

First off, it should be noted that there is long standing epidemiological data to show that those who consume meat in their diets, on average, have a higher risk of developing cancer than those who abstain from meat consumption.  It’s also a widely held opinion that this is likely due to increased chronic inflammation that is present in meat eaters.  To date, there was very little mechanistic evidence or insight into why meat eaters suffer from more inflammation and thus higher risk of cancer.  An article published at the end of last year in The Proceedings of the National Academy of Sciences, a very reputable and highly respected journal, provided some a possible mechanism to account for this.  They showed that there is a specific sialic acid molecule (N-Glycolylneuraminic acid or Neu5Gc for short) present in almost all meat consumed by humans, and that this molecule becomes incorporated into the human body after consumption.  The molecule is of course also present in any animal that the meat came from.  To these animals, Neu5Gc is considered “self.” That is, their immune systems are trained to ignore it.  Humans however, do not produce this molecule on their own, so their immune systems likely see it as foreign.  This in theory could lead to an antibody response whereby antibodies specific for the molecule are created, and induce inflammatory conditions wherever it is present. In a meat consumer, this would be all over the place.  The resultant chronic inflammation would thus increase an individual’s risk of cancer.

So what did these researchers actually do?  They used a mouse model in which they deleted the gene in mice that produces Neu5Gc. This deletion essentially made the mice more like humans in the sense that they would now see Neu5Gc as foreign.  They artificially introduced antibodies directed at the molecule, found that these antibodies did indeed promote chronic inflammation, and that mice treated with the antibodies had significantly higher incidence of cancer.  This provides a mechanism whereby a mammal that does not produce Neu5Gc inherently may be able to produce antibodies against it that promote inflammation.

What did they not show?  First off, none of this work was done in humans, and while mice provide a great experimental model, they are different animals, and not all conclusions drawn from mouse work can simply be transferred to our understanding of humans.  But more importantly, the antibodies that mediate this mechanism were artificially introduced into the mice, and without them, there was no response to the foreign meat residue whatsoever, or at least not enough to significantly impact tumor development.  The authors justify this by stating that antibody responses to this molecule have been shown in the past, but that they are quite complex and not easily controlled in an experimental system.  That’s not a major problem in terms of the research itself.  This still provides a model mechanism to explain the increased inflammation caused by meat consumption.  However, this does become problematic in others’ interpretations of the work because it is a subtle distinction that any immunologist would look and therefore take some of these implications with a grain of salt.  Those covering this research for broader scope publications however may have either not picked up on this, or simply chosen to ignore it. 

Thus, while this research is well executed and appropriately interpreted by the authors, the interpretation by some of the writers that have covered this article are really not supported by the work.  The interpretation that this work has “proven that meat eating causes cancer” is far too great of an over-simplification, and not a correct conclusion to draw from this particular study.  Again, the mice and human differences cannot be overlooked.  Hopefully, because of this study, researchers may begin to look at human antibody responses to this particular molecule, but until that is examined, the relevance to human health is merely an implication, certainly not a conclusion.  The other elephant in the room here is that the gene deletion was not enough to induce this mechanism without the artificial addition of antibodies specific for the residue.  This implies that the true mechanism at work in a physiological context is likely far too complex to be easily explained by this particular study.  So while this is great science, and certainly contributes to the story of “cancer from carnivore,” it is not sufficient to prove much other than the fact that this particular mechanism is possible given all the right conditions that may or may not be present in human meat eaters, but they could be, potentially, and that is really the heart of the paper. 

In all reality, very few individual research papers “prove” major concepts such as these.  Rather, each paper contributes in a way that creates a larger and larger foundation for future studies, fills in knowledge gaps in the field, or both.  This paper does both.  It sheds light on the knowledge gap between meat consumption, and cancer promoting chronic inflammation, while guiding efforts to begin to examine the human antibody response to the molecule in question.

At the end of the day, this shouldn’t really change what the average person thinks about meat consumption.  It was already known that this diet habit is linked to higher rates of cancer.  There are many similar associations of this nature.  Pilots and other flight crewmembers have significantly higher risk of developing acute myeloid leukemia likely due to the increased UV radiation exposure that occurs at flying altitudes over accumulated flight hours for example. This has not stopped us from taking full advantage of flight as a convenience of the modern age, and for many to pursue careers as pilots. Most people would be amazed to see the list of materials or conditions that cause cancer. It’s astounding. And based on how long mankind has been consuming meat, it is likely that the impact meat consumption has on cancer development is fairly minimal. The long history of meat consumption (as far as our records can tell) would imply that if meat consumption significantly impacted human cancer development to such a great extent that it impacted our fitness, we likely would have evolved to be strictly herbivores.  The bigger concern should always be for those highly potent carcinogens, materials like asbestos, benzenes, or even gamma radiation, all of which are not nearly as enjoyable as eating a nice delicious steak. If you’re not going to eat meat, do it because you don’t like it, or you care too much about animals, not because you think this particular research article proved that doing so causes cancer.