Sound Beam Could One Day Be Invisible Scalpel

Sound Beam Could One Day Be Invisible Scalpel

  4:34:00 PM    Science Lover

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A carbon-nanotube-coated lens that converts light to sound can focus high-pressure sound waves to finer points than ever before. The University of Michigan engineering researchers who developed the new therapeutic ultrasound approach say it could lead to an invisible knife for noninvasive surgery.

With a new technique that uses tightly-focused sound waves for micro-surgery, University of Michigan engineering researchers drilled a 150-micrometer hole in a confetti-sized artificial kidney stone. (Credit: Hyoung Won Baac)

Today's ultrasound technology enables far more than glimpses into the womb. Doctors routinely use focused sound waves to blast apart kidney stones and prostate tumors, for example. The tools work primarily by focusing sound waves tightly enough to generate heat, says Jay Guo, a professor of electrical engineering and computer science, mechanical engineering, and macromolecular science and engineering. Guo is a co-author of a paper on the new technique published in the current issue of Nature's journal Scientific Reports.

The beams that today's technology produces can be unwieldy, says Hyoung Won Baac, a research fellow at Harvard Medical School who worked on this project as a doctoral student in Guo's lab.

"A major drawback of current strongly focused ultrasound technology is a bulky focal spot, which is on the order of several millimeters," Baac said. "A few centimeters is typical. Therefore, it can be difficult to treat tissue objects in a high-precision manner, for targeting delicate vasculature, thin tissue layer and cellular texture. We can enhance the focal accuracy 100-fold."

The team was able to concentrate high-amplitude sound waves to a speck just 75 by 400 micrometers (a micrometer is one-thousandth of a millimeter). Their beam can blast and cut with pressure, rather than heat. Guo speculates that it might be able to operate painlessly because its beam is so finely focused it could avoid nerve fibers. The device hasn't been tested in animals or humans yet, though.

"We believe this could be used as an invisible knife for noninvasive surgery," Guo said. "Nothing pokes into your body, just the ultrasound beam. And it is so tightly focused, you can disrupt individual cells."

To achieve this superfine beam, Guo's team took an optoacoustic approach that converts light from a pulsed laser to high-amplitude sound waves through a specially designed lens. The general technique has been around since Thomas Edison's time. It has advanced over the centuries, but for medical applications today, the process doesn't normally generate a sound signal strong enough to be useful.

The U-M researchers' system is unique because it performs three functions: it converts the light to sound, focuses it to a tiny spot and amplifies the sound waves. To achieve the amplification, the researchers coated their lens with a layer of carbon nanotubes and a layer of a rubbery material called polydimethylsiloxane. The carbon nanotube layer absorbs the light and generates heat from it. Then the rubbery layer, which expands when exposed to heat, drastically boosts the signal by the rapid thermal expansion.

The resulting sound waves are 10,000 times higher frequency than humans can hear. They work in tissues by creating shockwaves and microbubbles that exert pressure toward the target, which Guo envisions could be tiny cancerous tumors, artery-clogging plaques or single cells to deliver drugs. The technique might also have applications in cosmetic surgery.

In experiments, the researchers demonstrated micro ultrasonic surgery, accurately detaching a single ovarian cancer cell and blasting a hole less than 150 micrometers in an artificial kidney stone in less than a minute.

"This is just the beginning," Guo said. "This work opens a way to probe cells or tissues in much smaller scale."

The researchers will present the work at the SPIE Photonics West meeting in San Francisco. The research was funded by the National Science Foundation and the National Institutes of Health.

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Entire Genetic Sequence of Individual Human Sperm Determined

Entire Genetic Sequence of Individual Human Sperm Determined

  11:46:00 AM    Science Lover

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The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete -- the only cells that become a child and through which parents pass on physical traits.

Every sperm cell looks essentially the same, with that characteristic tadpole appearance. But inside, sperm cells carry differences within their genes -- even cells from the same man. Now, researchers provide a detailed picture of how the cell's DNA varies in a new study published in the July 20, 2012 issue of the Cell Press journal Cell. The techniques used could be helpful for understanding male reproductive disorders or, when applied to other areas of research, for characterizing normal and diseased cells in the body. (Credit: iStockphoto/Alexandr Mitiuc)

"This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. "We now have devices that will allow us to routinely amplify and sequence to a high degree of accuracy the entire genomes of single cells, which has far-ranging implications for the study of cancer, infertility and many other disorders."

Quake is the senior author of the research, published July 20 in Cell. Graduate student Jianbin Wang and former graduate student H. Christina Fan, PhD, now a senior scientist at ImmuMetrix, share first authorship of the paper.

Sequencing sperm cells is particularly interesting because of a natural process called recombination that ensures that a baby is a blend of DNA from all four of his or her grandparents. Until now, scientists had to rely on genetic studies of populations to estimate how frequently recombination had occurred in individual sperm and egg cells, and how much genetic mixing that entailed.

"Single-sperm sequencing will allow us to chart and understand how recombination differs between individuals at the finest scales. This is an important proof of principle that will allow us to study both fundamental dynamics of recombination in humans and whether it is involved in issues relating to male infertility," said Gilean McVean, PhD, professor of statistical genetics at the Wellcome Trust Centre for Human Genetics. McVean was not involved in the research.

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," said study co-author Barry Behr, PhD, HCLD, professor of obstetrics and gynecology and director of Stanford's in vitro fertilization laboratory. "Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems."

Most cells in the human body have two copies of each of 23 chromosomes, and are known as "diploid" cells. Recombination occurs during a process called meiosis, which partitions a single copy of each chromosome into a sperm (in a man) or egg (in a woman) cell. When a sperm and an egg join, the resulting fertilized egg again has a full complement of DNA.

To ensure an orderly distribution during recombination, pairs of chromosomes are lined up in tight formation along the midsection of the cell. During this snug embrace, portions of matching chromosomes are sometimes randomly swapped. The process generates much more genetic variation in a potential offspring than would be possible if only intact chromosomes were segregated into the reproductive cells.

"The exact sites, frequency and degree of this genetic mixing process is unique for each sperm and egg cell," said Quake, "and we've never before been able to see it with this level of detail. It's very interesting that what happens in one person's body mirrors the population average."

Major problems with the recombination process can generate sperm missing portions or even whole chromosomes, making them incapable of or unlikely to fertilize an egg. But it can be difficult for fertility researchers to identify potential problems.

"Most of the techniques we currently use to assess sperm viability are fairly crude," said Quake.

To conduct the research, Wang, Quake and Behr first isolated and sequenced nearly 100 sperm cells from the study subject, a 40-year-old man. The man has healthy offspring, and the semen sample appeared normal. His whole-genome sequence (obtained from diploid cells) has been previously sequenced to a high level of accuracy.

They then compared the sequence of the sperm with that of the study subject's diploid genome. They could see, by comparing the sequences of the chromosomes in the diploid cells with those in the haploid sperm cells, where each recombination event took place. The researchers also identified 25 to 36 new single nucleotide mutations in each sperm cell that were not present in the subject's diploid genome. Such random mutations are another way to generate genetic variation, but if they occur at particular points in the genome they can have deleterious effects.

It's important to note that individual sperm cells are destroyed by the sequencing process, meaning that they couldn't go on to be used for fertilization. However, the single-cell sequencing described in the paper could potentially be used to diagnose male reproductive disorders and help infertile couples assess their options. It could also be used to learn more about how male fertility and sperm quality change with increasing age.

"This could serve as a new kind of early detection system for men who may have reproductive problems," said Behr, who also co-directs Stanford's reproductive endocrinology and infertility program. "It's also possible that we could one day use other, correlating features to harmlessly identify healthy sperm for use in IVF. In the end, the DNA is the raw material that ultimately defines a sperm's potential. If we can learn more about this process, we can better understand human fertility."

The research was supported by the National Institute of Health, the Chinese Scholarship Council and the Siebel Foundation.

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Stem Cells: Nearing Goal of Using Patient's Own Cells to Make Stem Cells to Replace Lost or Diseased Tissue

Stem Cells: Nearing Goal of Using Patient's Own Cells to Make Stem Cells to Replace Lost or Diseased Tissue

  1:27:00 AM    Science Lover

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Scientists at the Salk Institute for Biological Studies have developed an improved technique for generating large numbers of blood cells from a patient's own cells. The new technique will be immediately useful in further stem cell studies, and when perfected, could be used in stem cell therapies for a wide variety of conditions including cancers and immune ailments.

Round hematopoietic (blood) cells emerge from 
differentiating human pluripotent stem cells. 
(Credit: Courtesy of Aaron Parker, Salk Institute 
for Biological Studies)

"There are further improvements that we need to make, but this takes us a significant step closer to the ultimate goal, which is to be able to take ordinary cells from a patient, induce them to become stem cells, and then use those stem cells to rebuild lost or diseased tissues, for example the patient's bone marrow," says Inder M. Verma, PhD, Irwin and Joan Jacobs Chair in Exemplary Life Science and American Cancer Society Professor of Molecular Biology at the Salk Institute Laboratory of Genetics. Verma is senior author of the report, which is published in the July edition of the journal Stem Cells.

Stem cell researchers have been racing towards this goal since 2006, when techniques for turning ordinary skin cells into induced pluripotential stem cells (iPSCs) were first reported. In principle, iPSCs mimic the embryonic stem cells (ESCs) from which organisms develop. Researchers now want to find the precise mixes and sequences of chemical compounds needed to coax iPSCs to mature into the tissue-specific stem cells of their choice. The latter are self-renewing, and can be transplanted into the body to produce the 'progenitor' cells that multiply locally and produce mature tissue cells.

However, researchers don't know yet how to induce iPSCs to become tissue-specific stem cells or mature tissue cells with high efficiency. "We've been producing these cells in quantities that are too low to enable them to be studied easily, much less used for therapies," says Aaron Parker, PhD, a former graduate student and now a postdoctoral researcher in Verma's lab. Parker is a co-lead-author of the paper, with Niels-Bjarne Woods, PhD, who was a postdoctoral researcher in the Verma lab at the outset of the project, and is now an assistant professor at Lund University in Sweden.

Like many other stem cell research laboratories, the Verma lab has been trying to find more efficient ways to turn iPSCs into blood-forming 'hematopoietic' stem cells (HSCs). These may be more valuable medically than any other tissue-specific stem cell, because they can supply not only oxygen-carrying red blood cells but also all the white blood cells of the immune system. "There would be an almost unlimited number of usages for true HSCs," says Verma.

For the present study, the research team sought to do a better job of mimicking the changing conditions that naturally direct ESCs to become HSCs in the womb. "We took seven lines of human ESCs and iPSCs, and experimented with different combinations and sequences of growth factors and other chemical compounds that are known to be present as ESCs move to the HSC state in a developing human," says Parker.



Applying cocktails of these factors, Parker and Woods and their colleagues induced the iPSCs and ESCs to form colonies of cells that bore the distinctive molecular markers of blood cells. With their best such cocktail they were able to detect blood-specific markers on 84% of their cells after three weeks. "That's a big jump in efficiency from what we saw in the field just a few years ago," says Parker.

The technique still has room for improvement. The researchers detected progenitor cells and mature cells from only one category or lineage: myeloid cells, which include red blood cells and primitive immune cells such as macrophages. "We didn't see any cells from the lymphoid lineage, meaning T-cells and B-cells," Parker says.

Another drawback was that the blood cell population they produced from ESCs and iPSCs contained short-lived progenitors and mature blood cells but no indefinitely renewing, transplantable HSCs. Their cocktail, they believed, either pushed the cells past the HSC state to the progenitor state too quickly, or made the maturing cells skip the HSC state entirely.

From this and other labs' results, the team hypothesized the existence of an intermediate, pre-hematopoietic type of stem cell, produced by ESCs and iPSCs and in turn producing HSCs. "We know that HSCs appear in a particular region of mammals during embryonic development, and our idea is that these pre-hematopoietic stem cells are there and are somehow made to mature into HSCs," says Parker. "So our lab is now going to focus on finding the precise maturation signals provided by that embryonic region to produce these true, transplantable HSCs."

Once that is done, researchers will need to make a number of further refinements to improve the safety of HSCs intended for human patients. "But we're now tantalizingly close to our ultimate goal," says Verma.

The other authors who contributed to the work were Roksana Moraghebi, of Lund University's Stem Cell Center; Margaret K. Lutz, Amy L. Firth, Kristen J. Brennand, W. Travis Berggren and Fred H. Gage of the Salk Institute Laboratory for Genetics; Juan Carlos Izpisúa Belmonte of the Salk Institute Gene Expression Laboratory; and Angel Raya of the Center of Regenerative Medicine in Barcelona, Spain.

Funding for this research was provided by the National Institutes for Health, the California Institute for Regenerative Medicine, the Leducq Foundation, the Merieux Foundation, the Ellison Medical Foundation, Ipsen/Biomeasure, Sanofi Aventis, the Prostate Cancer Foundation, the H.N. and Frances C. Berger Foundation, The Royal Physiographic Society of Sweden, the Lund University Medical Faculty, and the Lars Hierta Memorial Foundation, and the H.A. and Mary K. Chapman Charitable Trust.

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First Evidence Of Virus In Malignant Prostate Cells: XMRV Retrovirus Linked To More Aggressive Tumors

First Evidence Of Virus In Malignant Prostate Cells: XMRV Retrovirus Linked To More Aggressive Tumors

  9:53:00 PM    Science Lover

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In a finding with potentially major implications for identifying a viral cause of prostate cancer, researchers at the University of Utah and Columbia University medical schools have reported that a type of virus known to cause leukemia and sarcomas in animals has been found for the first time in malignant human prostate cancer cells.

Histopathology of adenocarcinoma of the prostate. (Credit: CDC/Dr. Edwin P. Ewing, Jr.)

If further investigation proves the virus, XMRV (Xenotropic murine leukemia virus-related virus), causes prostate cancer in people, it would open opportunities for developing diagnostic tests, vaccines, and therapies for treating the cancer, according to the study published Sept. 7 online in the Proceedings of the National Academy of Sciences. Prostate cancer is expected to strike nearly 200,000 U.S. males this year, making it the second most common form of cancer, outside of skin cancers, among men.


"We found that XMRV was present in 27 percent of prostate cancers we examined and that it was associated with more aggressive tumors," said Ila R. Singh, M.D., Ph.D., associate professor of pathology at University of Utah and the study's senior author. "We still don't know that this virus causes cancer in people, but that is an important question we're going to investigate."


Singh, also a member of the U of U's Huntsman Cancer Institute and associate medical director at ARUP Laboratories, moved to Utah from Columbia University Medical Center in 2008, where she began this research. She remains an adjunct faculty member at Columbia.


Along with providing the first proof that XMRV is present in malignant cells, the study also confirmed that XMRV is a gammaretrovirus, a simple retrovirus first isolated from prostate cancers in 2006 by researchers at the University of California, San Francisco (UCSF), and the Cleveland Clinic. Gammaretroviruses are known to cause cancer in animals, but have not been shown to do so in humans. The UCSF study did not examine benign (non-malignant) prostate tissues, so could not link XMRV to prostate cancer. They also did not find the virus in malignant cells.


Singh and her fellow researchers examined more than 200 human prostate cancers, and compared them to more than 100 non-cancerous prostate tissues. They found 27 percent of the cancers contained XMRV, compared to only 6 percent of the benign tissues. The viral proteins were found almost exclusively in malignant prostatic cells, suggesting that XMRV infection may be directly linked to the formation of tumors.


Retroviruses insert a DNA copy of their genome into the chromosomes of the cells they infect. Such an insertion sometimes occurs adjacent to a gene that regulates cell growth, disrupting normal cell growth, resulting in more rapid proliferation of such a cell, which eventually develops into a cancer. This mechanism of carcinogenesis is followed by gammaretroviruses in general. Singh is currently examining if a similar mechanism might be involved with XMRV and prostate cancer.


In another important finding of the study, Singh and her colleagues also showed that susceptibility to XMRV infection is not enhanced by a genetic mutation, as was previously reported. If XMRV were caused by the mutation, only the 10 percent of the population who carry the mutated gene would be at risk for infection with virus. But Singh found no connection between XMRV and the mutation, meaning the risk for infection may extend to the population at large.


While the study answers important questions about XMRV, it also raises a number of other questions, such as whether the virus infects women, is sexually transmitted, how prevalent it is in the general population, and whether it causes cancers in tissues other than the prostate.


"We have many questions right now," Singh said, "and we believe this merits further investigation."


Viruses have been shown to cause cancer of the cervix, connective tissues (sarcomas), immune system (lymphoma), and other organs. If the retrovirus is shown to cause prostate cancer, this could have important implications for preventing viral transmission and for developing vaccines to prevent XMRV infection in people.


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Synthetic Red Blood Cells Developed: Red-Blood-Cell-Like Particles Carry Oxygen, Drugs, and More

Synthetic Red Blood Cells Developed: Red-Blood-Cell-Like Particles Carry Oxygen, Drugs, and More

  12:54:00 AM    Science Lover

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Scientists at UC Santa Barbara, in collaboration with scientists at University of Michigan, have developed synthetic particles that closely mimic the characteristics and key functions of natural red blood cells, including softness, flexibility, and the ability to carry oxygen.

Biocompatible synthetic red blood cells (sRBCs) synthesized by the UCSB team, 

where the shell is composed of alternate layers of hemoglobin and BSA. 

(Scale bar, 5 microns). (Credit: Image courtesy of)

The primary function of natural red blood cells is to carry oxygen, and the synthetic red blood cells (sRBCs) do that very well, retaining 90% of their oxygen-binding capacity after a week. The sRBCs also, however, have been shown to deliver therapeutic drugs effectively and with controlled release, and to carry well-distributed contrast agents for enhanced resolution in diagnostic imaging.

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