Cancer sequence: Scientists have identified genetic mutations in the tumor tissue of a breast cancer patient, shown here.  Credit: BC Cancer Agency

The mutations that trigger cancer progression suggest that a shift is needed in drug development.

MIT Technology Review, October 7, 2009, by Emily Singer  —  Scientists have sequenced the genomes of two tumors from the same breast cancer patient–a primary tumor and a metastatic tumor that occurred nine years later–illuminating some of the genetic changes that trigger the progression of cancer. The initial findings suggest that both primary cancers and the process of metastasis–the spread of cancer cells–are more complicated and more variable than expected, which means that successful cancer treatment might ultimately require a combination of drugs targeted to different mutations.

The project is also a testament to how easy it has become to sequence a human genome. The researchers, from the British Columbia Cancer Agency, in Vancouver, now plan to sequence the tumor genomes of more than 250 additional patients over the next year. “We are sequencing dozens of tumors a week now,” says Samuel Aparicio, the scientist who led the study. Oncologists hope eventually to be able to profile every patient’s tumor this way, using the results to tailor treatment. Scientists sequenced a tumor for the first time last year–the current study is the first to compare the sequencing of two types of tumors.

Cancer develops when a number of mutations accumulate in a cell, disrupting the cell’s normal protective mechanisms and causing it to divide uncontrollably. Scientists have identified a number of genes involved in this process, such as BRCA1 and BRCA2, that predispose women to developing breast cancer. Some drugs, such as herceptin, specifically target molecular differences in cancer cells. But a broader understanding of the genetic triggers that enable both cancer development and metastasis would aid the development of new treatments. For example, women with triple-negative breast cancer, an aggressive subtype of cancer that often strikes younger women, tend to be resistant to existing drugs.

Using sequencing technology from San Diego-based Illumina, Aparicio and colleagues sequenced the genome of metastatic tissue from a breast cancer patient 43 times–to make sure that the sequence was accurate and that it covered every part of the genome–allowing them to identify the rare spots where the tumor genome differed from the patient’s normal genome. By comparing the genome sequence in noncancerous and metastatic tissue, scientists found 32 protein-altering mutations unique to the secondary tumor. “This paper is a remarkable tour de force in how thoroughly they examined this tumor,” says Leif Ellisen, a physician and scientist at Massachusetts General Hospital, in Boston, who was not involved in the study. The research was published today in the journal Nature.

The number of mutations in cancerous tissue was greater than some scientists had expected, making it challenging to determine which mutations enhance a cancer’s ability to spread, and which are the so-called “carrier mutations” that have no effect. “Many metastatic mutations occur in the patient as the tumor evolves into a more aggressive form,” says Arul Chinnaiyan, director of the Michigan Center for Translational Pathology, in Ann Arbor, who was not involved in the study. “In order to find mutations that trigger the formation of cancer from a benign cell, it will be important to focus on the sequence of early forms of the tumor rather than metastatic tumors.”

One of the major questions in cancer metastasis is whether tumors start out with the ability to spread, or they evolve that capacity over time. So the researchers looked for mutations found in both the metastatic tissue and in the primary tumor, to try to understand what made it eventually spread. Nineteen of the metastatic mutations were completely absent from the primary tumor, suggesting that they arose after the cancer spread. And six mutations appeared to be present in only a subset of the cells in the primary tumor, suggesting that the cells carrying these mutations may have been selected for as the cancer progressed, eclipsing other cells.

That suggests that even low-grade and medium-grade tumors can be genetically heterogeneous, which could be problematic for molecularly targeted drugs. “We think this points to the need to shift the way we develop and apply cancer treatments–we need to think about multiple mutations from the outset,” says Aparicio. “We are going to end up with recurrence of cancers unless we address the fact that there are cells that do not respond to the drug.”

Some diseases, such as malaria and HIV, have already been shown to require this strategy. “You need to use a cocktail of three different drugs, which target different bits of the pathology,” says Aparicio. “If you only have one or two, eventually you end up with resistance to the drugs. This may be going on in cancer as well, so we have to adapt our strategies accordingly.”

In the primary tumor, the researchers identified some proteins thought to play a role in cancer, such as PALB2, which is known to interact with the breast cancer risk factor BRCA2, as well as new mutations such as HAUS3, which plays a role in cell division.

The study also suggests that the mutations underlying different women’s cancers appear to be highly variable. Genetically screening other breast tumor tissue samples revealed that none shared the exact mutations identified in the original patient, although some samples contained mutations in the same gene. “A number of mutations were present in less than 1 percent frequency, so we need to look quite hard to find them,” says Aparicio.

The researchers are now sequencing tumors from women with triple-negative breast cancers in hope of identifying mutations that would suggest new drug targets for these cancers. They are also sequencing tumors of women in a clinical trial for an experimental cancer drug, in order to identify genetic markers that predict who will respond best to the drug.


This is Dr. Charles “Chuck” Murry, University of Washington (UW) professor of pathology working in a UW Institute of Stem Cell and Regenerative Medicine laboratory where studies are conducted to engineer heart repair patches from stem cells. (Credit: Clare McClean) 


ScienceDaily (Oct. 7, 2009) – University of Washington (UW) researchers have succeeded in engineering human tissue patches free of some problems that have stymied stem-cell repair for damaged hearts.

The disk-shaped patches can be fabricated in sizes ranging from less than a millimeter to a half-inch in diameter. Until now, engineering tissue for heart repair has been hampered by cells dying at the transplant core, because nutrients and oxygen reached the edges of the patch but not the center. To make matters worse, the scaffolding materials to position the cells often proved to be harmful.

Heart tissue patches composed only of heart muscle cells couldn’t grow big enough or survive long enough to take hold after they were implanted in rodents, the researchers noted in their article, published last month in the Proceedings of the National Academy of Sciences. The researchers decided to look at the possibility of building new tissue with supply lines for the oxygen and nutrients that living cells require.

The scientists testing this idea are from the UW Center for Cardiovascular Biology and the UW Institute for Stem Cell and Regenerative Medicine, under the guidance of senior author Dr. Charles “Chuck” Murry, professor of pathology and bioengineering. The lead author is Dr. Kelly R. Stevens, a UW doctoral student in bioengineering who came up with solutions to the problems observed in previous grafts. The study is part of a collaborative tissue engineering effort called BEAT (Biological Engineering of Allogeneic Tissue).

Stevens and her fellow researchers added two other types of cells to the heart muscle cell mixture. These were cells similar to those that line the inside of blood vessels and cells that provide the vessel’s muscular support. All of the heart muscle cells were derived from embryonic stem cells, while the vascular cells were derived from embryonic stem cells or a variety of more mature sources such as the umbilical cord. The resulting cell mixture began forming a tissue containing tiny blood vessels.

“These were rudimentary blood vessel networks like those seen early in embryonic development,” Murry said.

In contrast to the heart muscle cell-only tissue, which failed to survive transplantation and which remained apart from the rat’s heart circulatory system, the pre-formed vessels in the mixed-cell tissue joined with the rat’s heart circulatory system and delivered rat blood to the transplanted graft.

“The viability of the transplanted graft was remarkably improved,” Murry observed. “We think the gain in viability is due to the ability for the tissue to form blood vessels.”

Equally as exciting, the scientists observed that the patches of engineered tissue actively contracted. Moreover, these contractions could be electronically paced, up to what would translate to 120 beats per minute. Beyond that point, the tissue patch didn’t relax fully and the contractions weakened. However, the average resting adult heart pulses about 70 beats per minute. This suggests that the engineered tissue could, within limits, theoretically keep pace with typical adult heart muscle, according to the study authors.

Another physical quality that made the mixed-cell tissue patches superior to heart muscle-cell patches was their mechanical stiffness, which more closely resembled human heart muscle. This was probably due to the addition of supporting cells, which created connective tissues. Passive stiffness allows the heart to fill properly with blood before it contracts.

When the researchers implanted these mixed celled, pre-vascularized tissue patches into rodents, the patches grew into cell grafts that were ten times larger than the too-small results from tissue composed of heart muscle cells only. The rodents were bred without an immune system that rejects tissue transplants.

Murry noted that these results have significance beyond their contribution to the ongoing search for ways to treat heart attack damage by regenerating heart tissue with stem cells.

The study findings, he observed, suggest that researchers consider including blood vessel-generating and vascular-supporting elements when designing human tissues for certain other types of regenerative therapies unrelated to heart disease.

One of the major obstacles still to be overcome is the likelihood that people’s immune systems would reject the stem transplant unless they take medications for the rest of their lives to suppress this reaction. Murry hopes someday that scientists would be able to create new tissues from a person’s own cells.

“Researchers can currently turn human skin cells back to stem cells, and then move them forward again into other types of cells, such as heart muscle and blood vessel cells,” Murry said. “We hope this will allow us to build tissues that the body will recognize as ‘self.'”

While the clinical application of tissues engineered from stem cells in treating hearts damaged from heart attacks or birth defects is still in the future, the researchers believe progress has been made. This study showed that researchers could create the first entirely human heart tissue patch from human embryonic cell-derived heart muscle cells, blood vessel lining cells and fiber-producing cells, and successfully engraft the tissue into an animal.

Future studies will try to move heart cell regeneration closer toward clinical usefulness, according to Murry and his research team. They forecast that such research would include testing other sources of human cells and developing techniques to create bigger patches for treating larger animals through surgical transplantation or through catheter delivered injections.

Lastly, they concluded, researchers would need to test whether tissue patches actually improve physical functioning after implantation in damaged hearts.

In addition to Stevens and Murry, the other researchers on this study, entitled Physiological Function and Transplantation of Scaffold-Free and Vascularized Human Cardiac Muscle Tissue, were Kareen L. Kreutziger, senior fellow in pathology; Sarah K. Dupras, research scientist in pathology; F. Steven Korte, senior fellow in bioengineering: Michael Regnier, associate professor of bioengineering; Veronica Muskheli, research scientist in pathology; Marilyn B. Nourse, postdoctoral scientist, Geron Corp.; Kira Bendixen, research technologist; and Hans Reinecke, research assistant professor of pathology.

The research was supported by grants from the National Institutes of Health, a Bioengineering Cardiovascular Training Grant, and a Pathology of Cardiovascular Disease Training Grant.

Adapted from materials provided by University of Washington

Combining nanotech and microchips, IBM says it’s aiming for cheaper, faster DNA sequencing

October 7, 2009, by Sharon Gaudin  —   (Computerworld) Scientists at IBM are using a combination of nanotechnology and microchips to map out personal genetic code — a development that could significantly improve the process of diagnosing and treating diseases.

Merging biology with computer technology, researchers at IBM are working on a project that aims to make it easier to decode human DNA, and thus help scientists discover and test new medicines and medical techniques. And, IBM says, a faster and less expensive way to obtain genetic information would help doctors better understand their patients’ predisposition to diseases.

The ultimate goal of IBM’s project is to create process that could read, or sequence, a person’s genome at a cost of $100 to $1,000. In comparison, the first sequencing ever done by the Human Genome Project cost $3 billion, according to IBM.

“The technologies that make reading DNA fast, cheap and widely available have the potential to revolutionize bio-medical research and herald an era of personalized medicine,” said IBM research scientist Gustavo Stolovitzky, in a statement today. “Ultimately, it could improve the quality of medical care by identifying patients who will gain the greatest benefit from a particular medicine and those who are most at risk of adverse reaction.”

IBM reported today that its researchers have drilled nano-sized holes, or nanopores, into microchips. When DNA strands are passed through the holes, the chips can sequence the genes.

Researchers said one of their challenges has been to figure out how to control the speed of the DNA strand’s movement through the tiny nanopore. It needs to move slowly through the hole in order for sensors in the chip to be able to read the sequencing.

IBM reported that its scientists used a multi-layer nanostructure to surround the nanopore. The structure creates an electrical field inside the nanopore, which traps the DNA strand and should allow scientists to have minute control over the speed at which the strand moves through the hole.

Combining DNA with nanotechnology is an idea that’s been getting some traction.

Just two months ago, IBM announced that it was using a combination of DNA molecules and nanotechnology to create tiny circuits that could form the basis of smaller, more powerful and energy-efficient computer chips that also are easier and cheaper to manufacture.

The DNA molecules would serve as scaffolding on which carbon nanotubes could assemble themselves into precise patterns. IBM said the process could help chip manufacturers move from 45-nanometer processor technology to 22nm or smaller.

And last winter, researchers at MIT found a way to use a combination of nanotechnology and DNA to fight cancerous tumors. The university announced that a group of scientists there had developed sensors made out of carbon nanotubes that were wrapped in DNA. The sensors then were placed inside living cells to determine whether chemotherapy drugs were reaching their targets or attacking healthy cells.


Valley Stream, NY
October 5, 2009
Photo Credit: teach50