In Memoriam: Dottie Thomas, a story of scientific love

About a month ago, Dottie Thomas died at her home in Seattle, Washington. She was 92. You probably aren't familiar with Dottie Thomas or her life, but you may be familiar with her work! Along with her husband (and Nobel laureate Don), she was an integral part of the team that proved that bone marrow transplantation could cure leukemia and a host of other blood related disorders. I couldn't possibly detail her life history as well as this summary by Diane Mapes, but here is a summary of a life of love and science.

Figure 1: Cells of the blood, which come from stem cells in the bone marrow

Imagine it. The University of Texas at Austin, 1940. A rare snowstorm finds its way to the Lonestar state and shuts down campus for the day. A young Dottie Martin, a freshman journalism major, takes part in a campus snowball fight and nails a senior chemistry student in the face. That man was Don Thomas, who she would fall in love with and marry in 1942. They were married for 70 years until his death in 2012.

Throughout her life, she relented tirelessly with her husband Don at the University of Washington to show that bone marrow transplantation could be a highly effective treatment. She served as the chief administrator for the Clinical Research Division at the Fred Hutchinson Cancer Research Center for 15 years and was a devoted scientist, editor, and mother. Their research has saved thousands of people around the world, and her husband went on to win the Nobel prize in Physiology or Medicine in 1990.

"They were incredible workaholics - working 80 and 90 hour weeks -- but they were also incredibly good parents. Mom always had time for us no matter how busy she was. She went to the PTA meetings. She did the macaroni art." -Dr. Elaine Thomas, Dottie's daughter

The procedure mentioned above removes bone marrow from a healthy donor and gives it to someone without healthy bone marrow. Bone marrow is very important, as it contains very important cells known as hematopoeitic stem cells. These are the cells that will eventually transform into the cells in your blood. Having healthy stem cells is the key to having healthy blood cells! The treatment can be used in patients with leukemia, lymphoma, and other disorders of the bone marrow.

For the full story on the life of Dottie Thomas, click on the hyperlink above. In the meantime, I encourage you all to enter yourselves into the national bone marrow donation registry at http://bethematch.org/. 360 people a day are diagnosed with cancers of the blood - will you be someone's cure?

Detecting cancer, one CTC at a time

In honor of breast cancer awareness month, I've been scouring science headlines around the internet to find really interesting, clever, and unique approaches to fighting all sorts of cancer. I stumbled on some fantastic research this morning that really piqued my interest; I hope it does the same for you! The early diagnosis of cancer makes a dramatic difference in the prognosis of patients. Take, for example, breast cancer. Below is a chart showing 5 year survival rates of breast cancer patients relative to the stage at which the cancer was diagnosed:

Figure 1: The 5-year relative survival rates among breast cancer patients

The contrast between Stage I and IV survival is pretty stark, as you can see! The cause of this jump is a phenomenon known as metastasis, which is cancer's ability to spread its tumors from the primary site to remote organs. In fact, the majority of breast cancer fatalities occur due to these remote tumors (in the bone, liver, etc) rather than solely cancer in the breast. This is a defining feature of Stage IV cancers.

Detecting these metastatic tumors has been a challenge, but recent advances have allowed scientists and clinicians to detect circulating tumor cells (CTCs) in the blood. This allows us to study and monitor cancer in a noninvasive manner, which is critical in ensuring that the cancer treatment process is as painless as possible. Aceto et al. published a paper in Cell describing a very interesting discovery in the nature of these cells. As it turns out, the cells that are the most successful in establishing remote tumors travel in clusters, rather than in isolation.

Figure 2: A schematic showing CTC mediated tumor establishment. Credit: Aceto et al. 2014

These cells express a protein called plakoglobin, a cell adhesion protein which presumably allows the cells to remain in contact with one another until they reach their destination. Traveling in this way seems to provide a protective advantage, as the scientists also noted that solitary tumor cells suffered much higher rates of cell death. Patients with high levels of this protein in their cancer cells had a much shorter metastasis-free survival time.

Researchers hope that with this new knowledge, our monitoring of cancer patients will become much more effective. For example, if a clinician notices that levels of plakoglobin and/or clustered CTCs are rising in his/her patient, that may call for a more aggressive treatment regimen. It may also warrant a closer examination of the genetics of these clusters, as metastatic tumors are notorious for having different genetics than their parent tumors, which may partially explain why some chemotherapies eventually stop working.

For more information, check out the full paper in the first hyperlink above. The more you know!

Breast Cancer Awareness Month - The State of the Research

Happy Breast Cancer Awareness Month! In the United States, October has been designated as a month to increase awareness and to raise funds to help accelerate biomedical research in the valiant search for a cure (The actual origins of NBCAM are a little shady, but I won't get into that here).

Figure 1: A pink ribbon, go find and wear one today!

All across the country, charities are organizing walks, concerts, and various other events to get people to donate to the cause and to start meaningful conversations about breast cancer. Every year, 1 in 8 women in the United States are diagnosed with breast cancer and it is estimated that we lose 40,000 women a year to this terrible disease. While these statistics are painful to look at, modern medicine has increased survival rates to levels never thought possible. I am continually encouraged and inspired by the strong women who continue to beat breast cancer every year and it is extremely important that we keep fighting for this cause. Below is a brief summary of what breast cancer is and what is the latest research in the field.

What is breast cancer?

Breast cancer is a disease in which cells in the breast (typically the cells that line the milk ducts) become cancerous. The mechanisms by which cells develop into cancer are complicated and varied and the risk factors that play into your likelihood of developing cancer are equally varied. Many of you have heard of BRCA1 and BRCA2, so called "breast cancer genes", which caused Angelina Jolie to receive a double mastectomy in 2013. This terminology, however, is a little misleading!

Having BRCA1 and BRCA2 is actually normal, as these genes are responsible for repairing damage to DNA (which is one way in which cells can turn into cancer cells). It's when these genes are mutated that cancer can arise. It's estimated that about 5-10% of breast cancers are related to this mutation, which leaves a significant portion of breast cancer cases open to a slew of other causes. Obesity, smoking, environmental conditions; it's all been implicated in potentially causing breast cancer. *Note* The research linking breastfeeding (or not breastfeeding) to an increased risk for breast cancer remains inconclusive.

Figure 2: BRCA1

As I mentioned, survival rates for breast cancer have reached all time highs. Nevertheless, breast cancer is still a significant killer of women (and men!) every year.  It accounts for 25% of all cancers in women and resulted in half a million deaths worldwide in 2012. Recommended screenings for breast cancer are recommended for women over the age of 50, but it never hurts to start performing self exam today!

What is currently being done to treat breast cancer?

Currently, the conventional approaches to treating breast cancer are a combination of therapies used in other cancers, including radiation and chemotherapies. With respect to BRCA1/2, a new class of drugs known as PARP inhibitors are currently in clinical trials that are being in used in patients with the above mutations. PARP1 (poly ADP ribose polymerase) is a protein that repairs DNA damage. Removing this beneficial protein results in the death of cancer cells, which divide so quickly that they rapidly succumb to a lack of significant DNA repair. Your normal cells divide more slowly and have other mechanisms for fixing this damage, so (for the most part). your normal cells remain unharmed via PARP1 inhibition.

There are also a few anti-angiogenesis drugs currently being tested in the clinic. As you can imagine, tumors require significant amounts of energy and nutrients to grow. One way it accomplishes this is through angiogensis, which is a process that leads to the creation of new blood vessels that lead to the tumor itself. If you can block this, you can effectively "starve" the tumor!

Lastly, there are some drugs known as HER2 inhibitors being tested in the clinic as well. HER2 (human epidermal growth factor receptor 2) is a receptor that sits on the surface of cells. When this receptor is in overabundance, it tends to lead towards certain types of aggressive cancers, so drugs currently developed are trying to destroy these receptors.

All of these treatments are very promising and are creative attacks on cancer mechanisms. This is a very brief summary of the sort of therapies that are being developed around the world; there are many other interesting treatments that are constantly being investigated, both in the clinic and in the laboratory! While we will always have to live with cancer as a part of our lives, I am confident that with continued research we will be able to reduce cancer from a high-level threat to a minor inconvenience.

Using stem cells to treat cancer?

Cancer is a very interesting disease. As I mentioned in a previous blog post, its ability to mutate into countless different forms means that generating effective ways to combat it is no small task. Researchers and physicians usually have to be pretty creative with how they approach treatment- no one drug will help every patient! A very interesting review coming out of Nature talks about a very interesting new way in which scientists are approaching this problem. As was reported by several laboratories, it turns out that stem cells have the natural tendency to migrate towards tumors. Using this principle, biologists are beginning to hijack these stem cells to deliver a wide variety of different things. Here is a brief summary of some of the therapies discussed (for the full story, check out the paper that I linked above!

Figure 1: A colony of stem cells!

Strategy 1: Delivering Therapeutic Proteins

There are many proteins out there that can be used to cause the spontaneous death of cells. One of these proteins is called TRAIL; it binds to a protein called death receptor 4 (ominous, I know!) and causes apoptosis, which is the cells way of destroying itself. By navigating directly to the tumor, stem cells are able to deliver these noxious proteins directly to the cells they wish to kill while sparing the surrounding tissue!

Strategy 2: Stem Cell Mediated Suicide Therapy

In this treatment, stem cells migrate to the tumors of interest and convert a previously harmless drug into one that is pretty nasty! By doing, this the stem cell sacrifices itself while simultaneously preventing the risk of it going on to divide into different things. This also means that dangerous drugs will only appear at the tumor site - if the drug manages to escape and go somewhere else, it won't be toxic because it hasn't been converted any stem cells!

Strategy 3: Nanoparticle delivery

One of the biggest difficulties in getting drugs to their targets is the body's own immune system. Your innate defense system is pretty potent (which is a very good thing!), but it also means that drugs are recognized as foreign entities and are quickly destroyed. To get around this, scientist have begun to surround drugs in nanoparticles, which your body doesn't identify as being a bad thing. This "Trojan horse" method allows your therapeutic of choice to sail past the defenders and make it to the end zone. Touchdown!

Figure 2: What your stem cell friends look like delivering nanoparticles. Close enough, right?

Strategy 4: Oncolytic Virus delivery

Oncolytic viruses are viruses that selectively destroy the rapidly dividing cells characteristic of cancerous tumors. However, the delivery of such viruses is difficult due to the same hiccup described in strategy 3: avoiding host immune defenses. The ability to "hide" within a stem cell allows the virus to remain inconspicuous until the moment is right!

Figure 3: A schematic of the therapies discussed above. Pretty snazzy! Picture courtesy of Nature Reviews Cancer.

But as you may note from the the title of the review, Stem cell-based therapies for cancer treatment: separating hope from hype, not everything is as simple as it seems! The field of stem cell research is still relatively young; thus, there are still a myriad of problems with using stem cells in humans. These issues are too long to list here (contact me if you wish to discuss!), but always take any new revolutionary treatment with a grain of salt. I, however, remain incredibly optimistic that we will circumvent these challenges and that stem cell therapies will soon become routinely used in the clinic!

Will we ever cure cancer?

One of the most common complaints that I receive at my kitchen table (and at numerous family gatherings) is why we haven't come up for a cure for cancer. If we can put a man on the moon, surely we can fight a disease that has been around for centuries, right? Well, as you might imagine, it's not that easy!

A very interesting study published in Nature Communications that recently came out of Kiel University is making quite a stir. In short, the study established that evidence of cancer can be found in organisms that are extraordinarily high in the evolutionary chain, suggesting that cancer has been around since the dawn of time and that it may ALWAYS be a part of life.

So is curing cancer even possible?

Figure 1. Cancer cells from a human prostate

I think that its important to rethink what we mean when we say "cancer" and critically look at the nature of the beast. The word "cancer" is an enormous umbrella term, encompassing over 200 different types of cancer. Each of these different types of cancer could have multiple unique pathways that contribute to their manifestation, and that these cancers can invade every organ in your body. Eradicating cancer as a global health problem would mean finding  treatments to combat hundreds of molecular pathways. That's a lot of chemotherapeutics!

It's also important to note that when one thinks of cancer, they usually think of it running in someone's family. As it turns out, only 5-10% of cancers are related to inherited genetic mutations; the remaining are due to environmental factors. And when I say environmental factors, I mean everything. Stress. Diet. Viruses. Pollution. Solar radiation. Smoking. The list goes on and on!

There are 7  billion humans on this planet. Curing cancer would involve having treatments for every mechanism of cancer, for every type of cancer, and that are compatible with each person's unique genetic make up. So will we ever live in a world without cancer?

Probably not. However, we will one day live in a world where cancer becomes so easily treatable that it will be effectively eradicated, which is still a very promising vision of the future!

I have come across some very interesting new research on cancer therapies that I will be publishing within the next week. There are thousands of scientists around the world who work tirelessly to find a cure, and I remain INCREDIBLY optimistic that we will one day beat cancer. Every single time.