Liquid Biopsy Predicts Colon Cancer Recurrence

One of the most exciting applications of precision medicine is the minimally to noninvasive technique of isolating tumor DNA from biofluids for diagnostic purposes—the aptly named liquid biopsy. This screening tool incorporates the power and speed of next-generation sequencing (NGS) to either diagnose disease or track the progression of a disease throughout a patient’s life or treatment course.

Now, investigators at Johns Hopkins Kimmel Cancer Center and the University of Melbourne have utilized liquid biopsy screening to predict the likelihood of recurrence in some—but not all—of a small group of patients with early-stage colon cancer. If confirmed by further research, this new test could eventually help clinicians decide which patients need additional treatment at the time of their initial cancer diagnosis of stage II cancer. Stage II tumors, in general, have invaded nearby tissues but have not spread to other organs, and uncertainty has long surrounded the question of whether chemotherapy prescribed after surgical treatment is beneficial.

"Prior studies, including ones from our group, have shown that this technique is sensitive enough to detect tumor DNA fragments in patients with advanced cancer," explained co-senior study author Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins. "But this new study gets us one major step closer to the real goal because it suggests that it can detect residual disease in early-stage patients well before conventional clinical or radiologic criteria can."

"Most patients with stage 2 colon cancers will be cured of the disease after surgery alone," Dr. Vogelstein added. "However, some of these cancers will recur, and we need to improve our diagnostic approaches to detect recurrence earlier than it can be found with current, conventional methods."

In the current study, the researchers followed 230 stage 2 colon cancer patients in 13 Australian hospitals for 4 years, beginning in 2011, collecting more than 1000 blood samples from them. After scanning the genetic sequences of tissue taken from the patients' tumors during surgery, the scientists identified at least one colon cancer-related gene mutation in the patients' original tumor.

The research team tracked each patient's cancer-related mutation in their blood samples using NGS. Samples were taken between 4 and 10 weeks after surgery and every 3 months afterward for up to 2 years. Patients also underwent a computed tomography (CT) scan of their entire body every 6 months after surgery for 2 years.

"The routine procedure is to give 6 months of chemotherapy, but we don't have any way of knowing if the treatment is effective," noted lead study author Jeanne Tie, M.D., a Ludwig investigator at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Victoria, Australia. "We have to be able to pick out a single tumor DNA among 10,000 normal DNA fragments. That's the level of sensitivity that we needed to get down to, and that wasn't possible until now."

The findings from this study were published recently in Science Translational Medicine in an article entitled “Circulating Tumor DNA Analysis Detects Minimal Residual Disease and Predicts Recurrence in Patients with Stage II Colon Cancer.”

Among the 230 patients, 20 had cancer-linked DNA fragments in their blood, including 14 who did not to receive additional chemotherapy and six who did. Of the 14, 11 developed a recurrence, found on a CT scan, during the study. Of the six who received additional chemotherapy, three experienced a recurrence of their cancers during the study period. An additional 14 patients experienced cancer recurrences, but their blood tests showed no cancer-linked DNA.

"Although this and other DNA-based blood tests are not perfect, this study shows that when we find tumor DNA circulating in the blood of cancer patients, recurrence is very likely," stated co-author Nickolas Papadopoulos, Ph.D., professor of oncology at the Johns Hopkins University School of Medicine and member of its Kimmel Cancer Center.

"When such a generic test is developed, it could still catch more than 90% of colorectal cancers, and it would eliminate the need to retrieve and test individual tumor samples, thus saving time, effort, and money," added Peter Gibbs, M.D., a Ludwig investigator at WEHI who co-led the study.

The researchers surmised that better methods to predict the risk of recurrence, such as the liquid biopsy described in the current study, could identify a very-high-risk subset of patients who can form the basis of rigorous study of the benefit of additional treatment. The new findings affirm how research on cancer diagnostics goes hand in hand with research on new therapies.

"There is mounting evidence that ctDNA [circulating tumor DNA] is a viable approach for earlier detection of cancer recurrence, and more research is underway to refine the technology, improve its sensitivity and determine the best testing intervals," concluded co-author Kenneth Kinzler, Ph.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center.

Massive Lake Discovered 

Under Antarctica 

May Harbor Ancient, 

Extreme Life

Antarctic scientists have revealed a potential new lake hidden beneath the continent’s ancient ice sheet; it may prove to be an important new proving ground for technology designed to probe subsurface bodies of water in the outer Solar System.

A series of aerial radar images, obtained this past Christmas by U.S. and Chinese researchers, has revealed a new addition to Antarctica’s sizable complement of subglacial lakes.

It’s quite large, about 12,000 sq/km (7,400 sq/mi). For comparison, New York state is 87,800 sq/km (54,500 square mi) . And the lake has likely been entombed within the unfathomably ancient Antarctic ice cap for millions of years. Scientists are uncertain whether the feature is actually a subglacial lake—akin to the more famous lakes Vostok and Ellsworth—or a semi-frozen slurry of sediment.

The feature, located in the remote Princess Elizabeth Land of East Antarctica, must await a future expedition during the coming southern summer to elucidate more of its hidden mysteries.

An image showing Princess Elizabeth Land in East Antarctica, with the profuse canyon systems and the potential new subglacial lake highlighted. Credit: The Grantham Institute, Imperial College – London, England

If the feature really is a sediment slurry, it will furnish climate scientists with a window onto the past climatic regimes that have shaped the present state of the Antarctic continent—and thus, by extension, provide more information about the Earth’s changing weather patterns.

If it’s a lake, then it means another pristine, uncontaminated environment that has been wholly free of external biological and evolutionary influences for uncounted millions of years. It means an important terrestrial analogue to those subsurface aqueous environments astronomers suspect may be lurking in the outer Solar System—beneath the surface of Europa andEnceladus, for instance.

New drug-delivery capsule may replace injections

Pill coated with tiny needles can deliver drugs 

directly into the lining of the digestive tract.

Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.

To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” says Giovanni Traverso, a research fellow at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which appears in the Journal of Pharmaceutical Sciences.

Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn’s disease. This class of drugs, known as “biologics,” also includes vaccines, recombinant DNA, and RNA.

“The large size of these biologic drugs makes them nonabsorbable. And before they even would be absorbed, they’re degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive,” says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.

Safe and effective delivery

Scientists have tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.

Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimeters long and 1 centimeter in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimeters long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of insulin was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Traverso says. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

“This is a very interesting approach,” says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. “Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe.”

Further optimization

This approach could also be used to administer vaccines that normally have to be injected, the researchers say.

The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Avi Schroeder, a former Koch Institute postdoc, is also a lead author of the paper. The senior authors are Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, the Institute for Medical Engineering and Science (IMES), and the Department of Chemical Engineering; Daniel Blankschtein, the Herman P. Meissner Professor of Chemical Engineering; and Daniel Anderson, the Samuel A. Goldblith Associate Professor of Chemical Engineering and a member of the Koch Institute and IMES.

The research was funded by the National Institutes of Health.

Engineers develop a pill for long-term drug release

New tablet attaches to the lining of the GI tract, resists being pulled away.

Anne Trafton | MIT News Office 

Researchers from MIT and Brigham and Women’s Hospital have designed a new type of pill that, once swallowed, can attach to the lining of the gastrointestinal tract and slowly release its contents. The tablet is engineered so that one side adheres to tissue, while the other repels food and liquids that would otherwise pull it away from the attachment site.

Such extended-release pills could be used to reduce the dosage frequency of some drugs, the researchers say. For example, antibiotics that normally have to be taken two or three times a day could be given just once, making it easier for patients to stick to their dosing schedule.

“This could be adapted to many drugs. Any drug that is dosed frequently could be amenable to this kind of system,” says Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist at Brigham and Women’s Hospital, and one of the senior authors of a paper describing the device in the April 6 issue of the journalAdvanced Healthcare Materials.

Robert Langer, the David H. Koch Institute Professor and a member of the Koch Institute, is also a senior author of the paper. The paper’s lead author is Young-Ah Lucy Lee, a technical assistant at the Koch Institute.

Two faces

Over the past several decades, Langer’s lab has developed many types of materials that can be implanted in the body or attached to the skin for long-term drug release. To achieve similar, long-term drug release in the gastrointestinal tract, the researchers focused on a type of material known as mucoadhesives, which can stick to the mucosal linings of organs such as the stomach.

Scientists have previously explored using this kind of material for drug delivery to the GI tract, but it has proven difficult because food and liquid in the stomach become stuck to the tablet, pulling it away from the tissue before it can deliver its entire drug payload.

“The challenge with mucoadhesives is that the GI tract is a very rough and abrasive environment,” says Lee, a 2014 Wellesley College graduate who began this project as her senior thesis.

To overcome this challenge, the researchers decided to create a dual-sided device, also called a Janus device after the two-faced Roman god. One side sticks to mucosal surfaces, while the other is omniphobic, meaning that it repels everything it encounters.

For the mucoadhesive side, the researchers used a commercially available polymer known as Carbopol, which is often used industrially as a stabilizing or thickening agent. The omniphobic side consists of cellulose acetate that the researchers textured so that its surface would mimic that of a lotus leaf, which has micro and nanoscale protrusions that make it extremely hydrophobic. They then fluorinated and lubricated the surface, making it repel nearly any material.

The researchers used a pill presser to combine the polymers into two-sided tablets, which can be formed in many shape and sizes. Drugs can be either embedded within the cellulose acetate layer or placed between the two layers.

Long-term attachment

Using intestinal tissue from pigs, the researchers tested three versions of the tablet — a dual-sided mucoadhesive tablet, a dual-sided omniphobic tablet, and the Janus version, with one mucoadhesive side and one omniphobic side.

To simulate the tumultuous environment of the GI tract, the researchers flowed a mix of food including liquids and small pieces of bread and rice along the tissue and then added the tablets. The dual-sided omniphobic tablet took less than 1 second to travel along the tissue, and the dual-sided mucoadhesive stuck to the tissue for only 7 seconds before being pulled off. The Janus version stayed attached for the length of the experiment, about 10 minutes.

Tejal Desai, a professor of bioengineering and therapeutic sciences at the University of California at San Francisco, says this approach could make it possible to deliver larger quantities of drugs through the GI tract.

“The ability to precisely engineer the adhesiveness of a particle opens up possibilities of designing particles to selectively adhere to specific regions of the GI tract, which in turn can increase the local or systemic concentrations of a particular drug,” says Desai, who was not involved in the work.  

The researchers now plan to do further tests in animals to help them tune how long the tablets can stay attached, the rate at which drugs are released from the material, and the ability to target the material to specific sections of the GI tract.

In addition to delivering antibiotics, the two-sided material may help to simplify drug regimens for malaria or tuberculosis, among other diseases, Traverso says. The researchers may also further pursue the development of tablets with omniphobic coatings on both sides, which they believe could help patients who have trouble swallowing pills.

“There are certain medications that are known to get stuck, particularly in the esophagus. It causes this massive amount of inflammation because it gets stuck and it causes irritation,” Traverso says. “Texturing the surfaces really opens up a new way of thinking about controlling and tuning how these drug formulations travel.”

The research was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health, and the Alexander von Humboldt Foundation.

We’ve Figured Out How to

 Program Living Cells

Researchers at MIT have developed an easy-to-use “biological programming language” that allows genetic engineers (or just about anyone) to design biological circuits and “hack” the genomes of living cells.

LIFE-SHAPING

The evolution of human technology has proceeded in lockstep with the biological evolution of our species. For millions of years we were content with our primitive Oldowan choppers and Acheulean bifaces; in the Neolithic, we started playing with more sophisticated tools, and the Bronze and Iron ages followed in quick succession.

Now, researchers at MIT have developed a programming language that will allow the toolmakers of the future to “program” living cells—outfitting them with DNA-encoded circuitsthat confer a host of new functions on the “hacked” organism.

Christopher Voigt, professor of biological engineering at MIT, explains: “It is literally a programming language for bacteria. You use a text-based language, just like you’re programming a computer. Then you take that text and you compile it and it turns it into a DNA sequence that you put into the cell, and the circuit runs inside the cell.”

Essentially, you start with the ability you want to program into the bacterium—say, detecting the presence of certain harmful chemicals. You write up a program describing it, and a DNA sequence is created that will achieve the desired function.

And just like that, you’ve got a toxin-sniffing germ.

IT’S EASY TO USE

The new language, which was described in the April 1 issue of Science, has already been used to create biological circuits that can respond to up to three inputs in different ways. And its implications for medical technology, agriculture, and even biological computing are simply staggering.

But the really revolutionary aspect of the new programming language is that it can be used by literally anyone—you needn’t have any training in genetic or biological engineering. Hell, you don’t even need to know what a gene is.

It’s genetic engineering for the masses. The designers even plan to make the language’s user interface universally available on the Internet.

“You could be a student in high school and go onto the Web-based server and type out the program you want, and it spits back the DNA sequence,” says Voigt.

The designers based their language on Verilog, a popular coding language for programming computer chips. The key to making the whole thing work was tailoring the language to the complex conditions within cells; they had to make computing elements like logic gates that could be slipped into a bacterial genome.

Furthermore, the language is easily customizable. Right now, the genetic elements are specialized for the E. coli genome; but the researchers are working on a means for allowing designers to write a single code, which could then be translated to fit the genomes of other organisms.

And the speed of the new method means that DNA circuits that would normally take years to design and build now require the mere touch of a button.

LOOKING AHEAD

The appearance of this new biological programming language represents something of a game-changer. Along with other techniques, like CRISPR, it removes evolution—human or otherwise—from the uncertain realm of chance and blind happenstance, and it compresses its timescale from the geologic to the merely day-to-day.

It means we can start to have a say in our biological destiny, and that we can likewise control the destinies of the living things with which we share the planet. Whether that’s too much power and responsibility for any one species to wield—especially a species prone to some pretty whopping lapses in judgment—is a discussion for another time.

In the meantime, the researchers are looking to design practical applications for the technology—including ingestible bacteria that can aid in lactose processing, bacteria that can colonize plant roots and generate toxins to ward off insect attacks, and self-regulating yeast strains that automatically “shut off” when producing harmful byproducts in fermentation reactions.

Welcome to the newest technological revolution: The age of living technology.

Astronomers Find the Purest

 Oxygen Atmosphere Ever

 Discovered—

On a White Dwarf

Astronomers have discovered a never-before-seen type of white dwarf star, one that has a pure oxygen atmosphere. In a paper published in Science, the researchers detail the discovery of what is the only star of its kind known.

A PECULIAR WHITE DWARF

White dwarfs are like the doddering seniors of the stellar world: They’re in the last stage of their development, they come just after the most active and expansive phase of a star’s life, and they’re white with age.

These curious objects are the leftovers of a star after it has exhausted its nuclear fuel. Super-dense and super-hot, these white dwarfs have only the lightest elements on their surface, typically hydrogen and helium.

But then again, not all of them.

Astronomers have discovered a white dwarf that has a pure oxygen atmosphere. In a paperpublished in Science, the researchers detail the discovery of what is the only star of its kind ever to be found.

The team of Brazilian astronomers were combing the data of the Apache Point Observatory for a project called the Sloan Digital Sky Survey when they found the star, over 1200 light years distant, which seemingly had an atmosphere of 99.9 % oxygen.

They nicknamed the star “Dox” (Dee-Awks).

STRIPPING A STAR

The question on everybody’s mind is: what happened to it? White dwarfs typically have hydrogen and helium in their atmospheres, and heavier elements like oxygen, neon, and magnesium are found in a pool of these light elements.

Also, stars that have these heavy elements are typically large. For a white dwarf to have any oxygen, it must have been at least twice as big as Dox.

Quite simply, Dox defies most of our knowledge in stellar evolution and white dwarf formation. But this is not to say that there are no theories.

The most popular theory is that the star is a product of a binary evolution; there was another star in the same system, somewhat like the setups in the nearby Sirius and Procyon systems. The other star stripped Dox of its surface, exposing the heavy materials underneath. This explains why such a seemingly small white dwarf harbors such heavy elements: it used to be bigger.

“This star, a possible oxygen-neon white dwarf, will provide a rare observational test of the evolutionary paths toward white dwarfs,” says Dr. Kepler de Souza Oliveira, team leader of the astronomers.

With such a pure oxygen atmosphere, we could probably breathe it—while simultaneously being fried by the white dwarf’s intense radiation and crushed to single-atom thickness by its colossal gravity.

Samsung just patented smart contact lenses with a built-in camera

Welcome to the future.

Samsung just took another step into science fiction. South Korea has just granted the tech giant a patent for contact lenses with a display that can project images straight into the user's eye. The news comes from a Samsung-centric blog SamMobile.

The lenses are equipped with a built-in camera and sensors that can be controlled simply by blinking. Content is sent to your smartphone through embedded antennas. This is where the data is processed.

It seems that Samsung is developing the smart contact lenses as an alternative to creating improved augmented reality experiences over the current crop of wearables, reports SamMobile.

With contact lenses instead of glasses, users will be able to enjoy augmented reality content more discreetly.

A glimpse at the future

Blinking to control an ocular interface may lead to a lot of awkward situations and accidental input, but it's not entirely unrealistic. Thankfully, there's always the option of controlling the interface through your smartphone, like you would everything else.

With this development, Samsung joins Google in the arena, which also owns two patents for smart contact lenses. Google's contact lenses are mainly intended for medical use, with sensors and flexible electronics to read tear fluid chemicals to determine blood sugar levels.

Google and Samsung both filed their smart contact lens patents in their respective countries in 2014; however, it's possible that both companies are currently just at the concept stage, rather than actively developing smart contact lens prototypes.

Indeed, tech companies file (and are granted) all kinds of patents all the time, and it doesn't indicate that a corresponding commercial release is bound to follow suit.

And since so many technologies are constantly being developed and patented by companies large and small, the news is no reason to get too excited, but it is a reason to be hopeful.