Mutations in numerous pathways need to accumulate for cancer to progress. Given the ability of transposons to cause mutation and the role of mutation in cancer, it seemed likely that transposons would play a role in cancer. A few years ago, Iskow and colleagues showed that transposons jump in some lung tumors, suggesting a link to cancer progression. They also showed that methylation levels are often lower in lung cancers. Methylation is important for transposons silencing, so they hypothesized that lowered methylation in cancer could lead to more transposon jumps. This would “destabilize” the genome, allowing more mutations to accumulate, and accelerating cancer progression.

However, very little evidence of this connection existed until recently. With the advent of high-throughput sequencing, it is becoming possible to examine changes in the genomes of cancer cells. Lee and colleagues report on one such study. They decided to look at the effect of retrotransposons by comparing the location of these jumping genes in normal and cancer cells. Retrotransposons copy their sequence from one location to another by going through an RNA intermediate that is read “backwards” from RNA to DNA.

In their study, they had to overcome a problem: because transposons are found throughout the genome and are mostly the same in different individuals, it is hard to figure out exactly where new transposons are located. To sort this out, they developed a bioinformatics tool that could align sequence to a reference genome and identify new transposon sequence associated with this sequence. They then used normal tissue and cancer tissue from the same individual to identify transposition events in cancer cells.

Interestingly, different cancer types had different numbers of transposon jumps. Brain and blood cancers did not have many transposon-induced mutations, while epithelial cancers had frequent insertions. These jumping-gene insertions are probably important for cancer, as many of the insertions occur within genes known to affect cancer biology.

If these jumping genes cause mutations and promote cancer, why are they there? It’s still an area of contention, but all that jumping around helps provide diversity in our genomes. Sometimes that will prove to be bad, but it also allows natural selection to act on the diversity, allowing new, helpful innovations in our DNA power evolution.

Iskow el al, 2010. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 141(7):1253-61.

Lee et. al, 2012. Landscape of Somatic Retrotransposition in Human Cancers. Science. 337(6097): 967-971.

How often do you moisturize your skin? Every day? Once a month? Well researchers at Northwestern University in Chicago have given a moisturizer the ability to perform RNA interference and regulate genes.

Topical treatments are common for skin cancers like melanoma, as they can be applied directly to the affected cells. But our skin is very effective at blocking toxins getting into our bodies so the challenge was how to cross that barrier.

Again, enter the realm of nanotechnology, a topic I post about regularly.

This time, the scientists paired gold nanoparticles with small interfering RNA (siRNA) molecules to form a siRNA “sphere.” These miniscule balls were able to penetrate skin cells, and then the specifically-designed siRNA was able to effectively switch off the EGFR gene that codes for the epidermal growth factor receptor protein. EGFR is one of the crucial proteins in pathways to cancer, and can cause cancer cells to go into overdrive and proliferate.

The key factor was the sphere shape, concentrating the nucleic acid in the RNA. Linear nucleic acids can’t get into cells, but spherical ones can.

So what miraculous moisturizer did they use? La Mer? Clinique? Something mixed up in a special laboratory? Nope. They used a cheap, readily available moisturizer.

This type of breakthrough is yet another example of the brilliant strides science can make when one discipline talks to another. In this case, dermatology, cancer and chemistry came together under the remit of the Skin Disease Cancer Research Center at the Feinberg School of Medicine at Northwestern.

I recently blogged about harnessing the power of bioinformatics for cancer research. An interested reader, Linda Zabriske, commented that the blogosphere (and government organizations such as the Bureau of Labor Statistics) has been gradually filling with talk about cancer research and its role in our future. Linda’s tool, the Online Graduate Programs, collates some of these articles and ideas and she’s co-written this month’s post with me, reflecting on Online Graduate Education in Biotechnology.

In past decades, the field of biological science and engineering were considered separate and distinct. Biology dealt with the complexities and wonders of humans, animals and plants, while the engineering (and technology) revolved around mechanics, electronics, and other systems for developing new devices. Recently, however, scientists are creating ways to allow these schools of thought to interact with one another in new and exciting ways through biotechnology.

These breakthroughs have generated a slew of breakthroughs in health, medicine, technology, ecology, computing, telecommunications, the list goes on, with new fields constantly emerging. Case in point: bioinformatics, which was the topic of another DNALC blog post recently. In response, there are several new virtual masters degree programs.

What is Biotechnology?
As part of my role as Evaluation Manager at the DNALC, I’m currently asking biotechnology teachers at community college across America to help me define the term ‘biotechnology.’ (The teachers are participating in an NSF-funded training program, Genomic Approaches to Biosciences). According to the Biotechnology Institute, a nonprofit group that promotes biotechnology education and initiatives, biotechnology is “the use of living organisms by humans.” While most observers associate biotechnology with scientists in white lab coats, its origins stem back to ancient times. Farmers would employ biotechnology techniques to crossbreed plants to withstand adverse weather conditions or to produce more food (see, for example, the chapter on domestication of corn in Weed to Wonder, available as a website, iPad app, or PDF). Livestock owners would selectively breed their animals to provide more meat, carry more weight or run faster in a race.
Importance of Biotechnology
Biotechnology is applying the familiar scientific disciplines of biology and biochemistry, along with the fields of physics, engineering, and computer science, to produce new developments that carry extraordinary potential for the future of mankind. Advances in genetic engineering, nanotechnology, and microbiology have expanded human understanding of some of the most basic and vital processes of life.

Applications of Biotechnology
While many of these research efforts involve medical applications, biotechnology is not limited strictly to prolonging and improving the human body. Agricultural applications, such as genetic engineering of plants and animals (e.g for biofortification), can do the work of several generations of crossbreeding in a much shorter time frame. Other efforts involve the development of biofuels, including biodiesel for use in automobiles, which can reduce the worldwide dependency on fossil fuels and other pollutants.

Careers in Biotechnology
With so many different applications for biotechnology, the opportunities for new careers have been growing at a staggering pace. The DNALC teacher training program mentioned above specifically aims to train graduates for careers in biotechnology, partnering with Bio-Link, the Next Generation National Advanced Technological Education (ATE) Center of Excellence for Biotechnology and Life Sciences. Some students will use their biotechnology degrees in cutting-edge laboratories around the world, while others apply their knowledge as physicians, public health officials, and policy makers. Students also explore the legal, ethical and business applications of biotechnology to understand and resolve the inherent conflicts in
these fields, and become informed citizens.

Degrees in Biotechnology

Two of the top-flight medical schools in the US are endeavoring to give students the online education they need to pursue a career in biotechnology. Harvard University’s Graduate Program in Biotechnology allows students to pursue advanced degrees online. Fields of study include Life Sciences, Management Principles, Bioengineering/Nanotechnology, and Bioinformatics, which is the application of computer technology to solving biotechnology issues. For nearly a century, Johns Hopkins University in Baltimore, Maryland, has been one of the leading medical schools in the country. Today, the school offers students four online degree programs in biotechnology. The programs cover topics ranging from entrepreneurship and federal regulations of the biotechnology industry, to the development of complex computer programs that analyze data from biotechnology experiments.

Just as communications technologies brought in thousands of new jobs in previous decades, biotechnology is revolutionizing the workplace in the 21^st century. As the wave of advancing technology carries this field to new levels, the access to online classes in biotechnology has never been better.

And who knows, maybe one of the new grads may someone harness the power of bioinformatics to find a new treatment for cancer! Watch this space…

Tumor cells are a mosaic of different cell types

For the last decade or so, progressive cancer treatments involved taking samples of tumors, testing the cells to determine the genetic makeup, and then prescribing medicines targeted to specific mutations. There are many benefits to this approach, but it doesn’t always work.

It turns out that tumors aren’t uniform; they are mosaics of cells that can be genetically very different. A recent paper in the New England Journal of Medicine showed that a cell in one area may not be the same as a call in another area (a phenomenon called “intratumor heterogeneity”). So a treatment based on a sample from one area may not work for the whole tumor. Some tumor cells may be resistant to the drug so the cancer persists, or even grows.

In this British pilot study, cells from 9 different locations within a primary kidney tumor, and several metastatic tumors, were analyzed using next generation DNA sequencing. Only 34% of the 118 mutations identified were present in all the samples, and several of the major cancer genes were mutated in different ways in different locations. This turned traditional ideas about cancer cells being “clones” of a single, mutated cell on its head.

Previously, it was thought that a tumor develops when a single cell accumulates sufficient mutations over time that eventually lead to it dividing uncontrollably. Therefore if you could find the original mutation, and target treatment to that, then every cell would react to the treatment. But if the tumor is made up of a mosaic of cells, then they could all react differently to the drug. The researchers then created a phylogenetic “tree,” identifying which cells were more persistent, being in the trunk of the tree. They proposed that if those cells were receptive to a targeted medicine, the treatment might be more effective; if not, less so.

Although this study only involved four patients, the results provide a new way of thinking for researchers and clinicians. If we remove the presumption that all tumor cells are identical, we open the way for more creative thinking about how to tackle the problem.

The method is more effective than just using light. When light passes through tissue, it is scattered, and the scattering blurs images from light reflected off tissue. The effect is dramatic, because sound waves pass through tissue with about 10,000 times less scattering, so the sound waves coming from tissues are much less blurry. This means that tissues can be imaged with good detail up to 10 centimeters deep -rather than a few millimeters using just light.
Photoacoustic tomography is very flexible, as almost all molecules absorb light at some wavelengths. By changing the wavelength of light used to excite the tissue, different molecules can be heated and detected. For instance, DNA and RNA absorb specific wavelengths of ultraviolet light, so by shining UV light on tissue, they can be imaged. This can be used to identify nuclei with abnormal chromosomes, a common defect seen in cancer cells. Hemoglobin is also easy to image, which can identify blood vessel formation around tumors. In fact, the flow of blood can be imaged. Likewise, the level of oxygen can be measured, which can indicate regions with hypoxia which are found at the center of tumors and regions with heightened metabolism, such a quickly growing tumors. Tissues that are hard to image can also be imaged by introducing a dye that changes the light absorption. For instance, nanoparticles designed to stick to cancer cells can increase the contrast of the cells and make them easier to detect.

The technique is now being used to image skin cancer, detect breast and prostate cancer, and to follow the response of tumors to treatments. As the technology gets better, hearing the “echoes” off of tumors may become one of the best ways to find and monitor them!

Reference:
Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs. Lihong V. Wang and Song Hu Science 23 March 2012: 1458-1462

Recently three high school students took out top honors in science fairs for their projects involving cancer research:

• Angela Zhang from California developed nanotechnology to destroy cancer stem cells and win the 2011 Siemens Competition in Math, Science & Technology;
• Shree Bose from Texas discovered a protein that could help prevent resistance to chemotherapy to take out first prize in the first International Google Science Fair; and
• Michigan native Nithin Tumma won the 2012 Intel Science Talent Search with his investigation of molecular pathways to compare breast cancer treatments.

The budding researchers walked away with a combined $250,000 in prize money for their efforts!

Angela used nanotechnology in a three-pronged approach to eradicating cancer stem cells, similar to my recent post on using DNA nano-robots to deliver cancer drugs to tumor cells. Not only did Angela design a nanoparticle to find the stem cells, and deliver the drug straight to the cells, but she used gold and iron molecules in the nanoparticle to allow non-invasive imaging via MRI and photoacoustic methods. Any one of these discoveries was worthy of an advanced level science fair project, let alone combining all three. As she told ABC News, “I created a nanoparticle that’s kind of like the Swiss Army knife of cancer treatment in that it can detect cancer cells, eradicate the cancer cells and then monitor the treatment response. So the major aim of the project was to personalize cancer medicine.”

Shree investigated how cancer cells become resistant to chemotherapy. Using ovarian cancer cell cultures, she found that the protein adenosine monophosphate-activated protein kinase (AMPK) modulated resistance to the drug cisplatin at different times during treatment. If AMPK was combined with cisplatin early in treatment, it reduced the drug’s effectiveness, but if added later during treatment, it helped maintain effectiveness; in effect, reducing resistance. Shree realized the importance of her work, commenting, “That opens up a lot of new avenues for research.”

Nithin’s project looked at the protein cytokine TGF-A involved in cell signaling, one of the key concepts in the Pathways to Cancer. As I wrote in a past post, we can use the analogy of a car to think about cancer cell growth: tumor cell overgrowth is like pressing down on the accelerator; apoptosis is like applying the brakes. Nithin used computational biology techniques (bioinformatics) to research how to inhibit TGF-A to slow cancer cell growth and decrease malignancy.

Science fairs have been running almost as long as we’ve been teaching science, and giving aspiring scientists an opportunity to shine. Alumni of the Intel competition alone have gone on to win seven Nobel Prizes, two Fields Medals, three National Medals of Science and 11 MacArthur Foundation Fellowships!

So what’s your next science fair project going to be about?

You can find out more about cancer treatments and cell signalling pathways at www.insidecancer.org.

I have often wondered what impact the diesel fumes from yellow school buses might have on students. I know that I don’t like driving behind those buses because the fumes don’t smell good, so it seemed to me that there might be some health consequences. Others have wondered, too, and there is evidence that exhaust levels in buses can have health effects. However, it is hard to study this sort of thing, because finding people that are exposed to high levels of diesel in a controlled environment over long enough periods to measure the effects is challenging. Now, a study from the National Cancer Institute in Maryland looking at people working with another type of big yellow vehicle- the diesel trucks used in mines- has shown that heavy exposure to their fumes can increase the risk of death from lung cancer.
In the study, underground mines with no high levels of other known cancer causing agents were used. The study looked at the rate of lung cancer in workers and measured the levels of exposure to diesel fumes. As would be expected, the higher the level of exposure, the higher the increase in risk of getting cancer. In mines with the highest levels of exhaust the risk of lung cancer was three times the risk in mines with little exhaust, and even in these mines, the risk of lung cancer was increased over levels seen in the population.
Clearly, this suggests that miners should be aware of the levels of exhaust, and that increasing air quality in mines would be to their benefit. However, the results also suggest that people working in other places with high levels of diesel fumes may also be at risk, and this includes millions of workers at warehouses and bus depots. Likewise, people living in cities are exposed to diesel fumes.
Luckily, there is a solution to this problem: reduce emissions from diesel vehicles. In fact, modern diesel engines produce much lower levels emissions than older models, with some diesel cars producing nearly no emissions.
I can’t help thinking back to the kids in the buses. It is hard to tell what the effect might be, but sitting in a bus every day that has diesel fumes coming out the tailpipe might not be very good for all those schoolchildren, and if a child grows up taking buses every day, the exposure will add up. Hopefully, the effects are minimal. Then again, it may be worth investing in buses and other diesels that are cleaner!
Reference: The Diesel Exhaust in Miners Study: A Nested Case–Control Study of Lung Cancer and Diesel Exhaust
J Natl Cancer Inst 2012;104:1–14

In a brilliant example of multidisciplinary research, Harvard Medical School’s Shawn Douglas, Ido Bachelet, and George Church combined forces to build nanostructures that would mimic the body’s immune system to recognize cancer cells and trick them into self-destructing. Their research is published today in Science but the discovery didn’t just happen overnight. It’s the culmination of several key discoveries going back several years, by researchers around the globe.

In 2006, Paul Rothemund at the California Institute of Technology, discovered  “DNA origami,” where the Watson-Crick base-pairing rules are exploited to create molecules from viral DNA in specific 3-dimensional shapes. The molecules use small, “staple” strands to bind longer strands and hold them in place. In 2009, chemists and nano-technologists at the Danish National Research Foundation’s Center for DNA Nanotechnology then used DNA origami to create a nano-cube that self-assembled, using staple strands to open a lid.

The Harvard group wondered if there was a way to deliver a nano-cube “robot” to cancer cells and kill them. This is where the immunology expertise paid off: antibodies patrol the bloodstream, honing in on specific cells, binding to them, and signalling them to self-destruct. So how can a DNA nano-robot deliver antibodies to the surface of cancer cells? Remember the cube’s lid?

“We could actually make an open-ended container and then all it would need to do is just turn itself inside out,” Douglas said.

A visual rendering of the DNA "nano-robot." Image courtesy of the Wyss Institute.

They created a “nano-clam” with antibodies waiting inside, ready to launch their attack. The nano-clam springs open when one of the staple strands is broken, just like turning a key in a lock.

And the really clever thing? The lock can be designed so that the key is in the shape of certain cancer cells. So when the cube encounters a cancer cell, such as lymphoma or leukemia cells, it springs open, exposing antibody fragments to the surface of the cell in a “surgical strike.” Unlike chemotherapy, which doesn’t discriminate between cell types, these DNA nano-robots only strike down cancer cells, leaving good cells alone.

The beauty of this discovery is that the underlying mechanism can be adapted for different diseases, by using different combinations of locks and antibodies. As the Danish chemist Kurt Gothelf commented, “People have been talking a lot about robots that enter your body, and go to a place where something is wrong and fix it. This is the first example that this might come true one day.”

The next step is to work out scalability. The current research was in Petri dishes in the lab, with 100 billion copies of the robot, but trillions are required for animals and humans. And the robot needs to become more robust to travel through the bloodstream, rather than through a pipette. Our body is very adept at getting rid of foreign bodies so they have to figure out a way for the nano-clams to swim “under the radar.”

Watch this space…

Researchers have known for a while that not only are glioblastoma multiforme cells highly resistant to chemotherapy, but they can also deftly migrate away from sites of radiation or surgery, setting up camp and regrowing in other parts of the brain. This means that brain cancer is notoriously difficult to treat and the prognosis is almost always grim.

Last year the New York Times described Hanahan and Weinberg’s Hallmarks of Cancer as follows:

“Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline. With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.”

This is a nice analogy, relating overgrowth of cells paired with lack of cell death (apoptosis) as the accelerator and brakes of a car.

However Amy Keating and colleagues at the University of Colorado Cancer Center focused on the car’s GPS system. They published data in Nature: Oncogene showing that when a receptor tyrosine kinase involved in cancer cell growth, Mer, is switched off, significantly less cancer cells migrate to neighboring tissue in cultured laboratory cells. Keating found that not only does Mer interfere with the molecular signaling pathway, but also the cytoskeletal organization (the structure of the cell).

In other words, the Mer switch interferes with the electrics of the GPS system as well as the steering wheel of the car.

This added to their previous finding that Mer could increase some brain cancer cells’ sensitivity to chemotherapy.

So Mer inhibition could be a “double whammy” approach to treating brain cancer: kill as many cancer cells as possible and stop those remaining from migrating.