Biomedicine

Mapping the genome of a fetus from its mother’s blood could mean less risky screening for prenatal diseases.

MIT Technology Review, December 20, 2010, by Emily Singer  —  A way of mapping the genome of an unborn child using DNA from the mother’s blood shows potential for broad genetic testing without risk to the fetus. While the technique is too expensive to be put into practice now, the research is important because it shows that the fetus’s entire genome is present in the mother’s blood.

“I think this paper is a major landmark to eventually offering noninvasive testing to all pregnant women,” says Arthur Beaudet, chairman of the department of molecular and human genetics at Baylor College of Medicine in Texas. Beaudet, who was not involved in the study, is pursuing similar research, to develop a method of isolating fetal cells from maternal blood.

The two most accurate prenatal tests for genetic abnormalities, such as Down syndrome, in use today are amniocentesis and chorionic villus sampling. Because these procedures are invasive and therefore carry a small risk of miscarriage, they are typically recommended only for women with known risk factors.

The discovery more than a decade ago of small amounts of free-floating fetal DNA circulating in maternal blood opened the possibility for noninvasive testing. A limited number of practical applications of this discovery are already in use. When a fetus is at risk for sex-linked diseases, some clinical labs analyze the free-floating DNA to determine the baby’s sex. It is also used to screen for Rh incompatibility syndrome, in which a blood-type mismatch between mother and fetus can trigger a dangerous immune reaction against the baby.

These two tests require analysis of only a single genetic factor. The broader analysis of the fetal DNA in maternal blood presents several challenges. For one thing, the DNA fragments are quite small—about 150 letters of DNA—making them difficult to piece together into a genome. For another, the fetal DNA accounts for only about 10 percent of the DNA fragments in blood, the remainder being the mother’s. That means scientists have to sequence the DNA about 60 times to sequence the fetal DNA six times. (It’s necessary to analyze the same stretch of DNA repeatedly in order to generate an accurate sequence.) The fact that the fetus shares half its DNA with its mother makes it especially difficult to determine which fragments are fetal and which are maternal.

“It’s like trying to assemble a jigsaw puzzle with millions of pieces, where 90 percent of the pieces are from another puzzle,” says Dennis Lo, a professor of chemical pathology at the Chinese University of Hong Kong, who first discovered fetal DNA in blood and is the lead author of the current study.

An old drug gets new use as an immune boost for the elderly.

MIT Technology Review, December 20, 2010, by Jennifer Chu  —  For many, flu season is simply a nuisance. But for the elderly, it can be like navigating a minefield. With just one exposure, the virus can break through an aging immune system and make the person very sick for a long time. Now researchers at the University of California, San Francisco, have found a drug that may boost immune systems in the elderly, bringing them back to “youthful levels.”

The drug, lenalidomide, is a cousin of thalidomide, the notorious sedative that was found to cause birth defects in the 1950s. Both drugs have been used recently to treat multiple myeloma, a cancer of plasma cells in bone marrow. At much lower doses, scientists recently discovered, lenalidomide can stimulate immune responses in the elderly. The results of their study will be published in the January issue of Clinical Immunology.

“We’re looking at increasing health span versus lifespan,” says Edward Goetzl, director of allergy and immunology research at UCSF. “People have found that somewhere in their fifties, things start trickling down, and we want to keep them up.”

As we age, our immune defenses slowly become less vigilant and slower to respond to attack. A gland called the thymus shrinks, releasing fewer protective T-cells with each passing year. Researchers have found that not only do older people have fewer T-cells, but the T-cells they do have are less active, unable to migrate and patrol the body as effectively as those of young adults. Older people’s T-cells produce fewer cytokines, proteins that help the cells differentiate and proliferate through the body.

Goetzl and his colleagues hypothesized that stimulating production of cytokines could increase the proliferation of T-cells and boost aging immune systems. The team looked through libraries of existing drugs and found five that, at low doses, stimulate the immune system. After more detailed analyses, Goetzl found that only one of the five, lenalidomide, was able both to stimulate cytokine production and increase T-cell proliferation.

The team tested the drug on healthy seniors and healthy young adults. The researchers isolated T-cells from blood samples, and exposed the cells to lenalidomide. They found that the drug boosted the levels of two kinds of cytokines—IL-2, and IFN-gamma—both of which are known to stimulate T-cell production. The team found that the increased levels in seniors matched normal cytokine levels in young adults. They also observed improvements in T-cell migration in the blood samples from seniors.

It will be important to learn what kind of T-cells are producing the additional cytokines, says Janko Nikolich-Zugich, chairman of the immunobiology department at the University of Arizona and codirector of the Arizona Center on Aging. There are many subtypes of T-cells, and certain types decrease in number as we age, while the level of others remains nearly constant. “The compound could be just stimulating something that’s always been there,” says Nikolich-Zugich. “It doesn’t mean this compound might not be something useful down the line—they just have to identify what exactly it might be working on.”

Goetzl is planning a pilot study in which he will administer very low doses of the drug to patients with certain types of leukemia—ones that result in a weakened immune response similar to that seen in the elderly. He plans to monitor their immune performance and their tolerance for the drug to determine an optimal dosage. “We’re thinking of this as a pharmacological probe,” says Goetzl. “If it doesn’t end up being a drug, at least we know we can get cytokine levels up, and we know what to look for in developing new drugs.”

Biomedicine

Bone fixer: A liquid that solidifies into a bone-like material is injected into a

model bone defect through a syringe.   Credit: Thomas Webster

An artificial bone-like material could speed up recovery from injury

MIT Technology Review, December 20, 2010, by Karen Weintraub  —  Today, a broken hip usually means surgery and extensive rehab. But what if all you needed was an injection and a shorter recovery period? That’s the vision that inspires Thomas Webster, an associate professor of engineering at Brown University.

Webster has developed a nanomaterial that quickly solidifies at body temperature into a bone-like substance. This week, Brown announced a deal with medical device maker Audax Medical of Littleton, Massachusetts, to further develop the material and launch trials in animals.

The material contains the same nucleic acids as DNA, Webster says. Each molecule has two covalent bonds and links with other molecules to form a tube. Hence it’s called a “twin-base linker.” (Audax will develop it under the name Arxis.)

“It self-assembles into a nano structure, emulates natural tissue, solidifies quickly at body temperature, and can be made to match the mechanical properties of the tissue you inject it into,” Webster says.

That sounds great, says tissue engineer Kevin Shakesheff, of the University of Nottingham in the United Kingdom, but it will also need to sustain weight like bone can.

He and his colleagues have developed a different material for the same purpose. “If you press down on our material, it’s as strong as bone, but if you try and snap it, it’s nowhere near as strong,” he says.

Webster says he’s confident that his material, which has so far only been tested in a laboratory, will be able to bear weight like bone.

“It will have that strength after solidifying in the body—after a couple of minutes,” he says.

Ali Khademhosseini, an assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston says Webster’s material sounds interesting, and there’s plenty of room for innovation in the area of bone-like materials.

Today, metal plates are often inserted to provide strength and support while bones, such as the hip joint, slowly heal. But the metal degrades over time, and particularly in younger patients, it may eventually have to be replaced. Khademhosseini says tissue engineers are looking for materials that will better integrate with the body and last longer. If Webster succeeds in developing such a material to replace metal entirely, that would transform the field, he says.

Audax will begin testing Arxis in the hip and knee, according to company president and CEO Mark Johanson. Johanson hopes to have the first product ready for market in 2013. The company recently raised $1 million and plans to raise more capital soon, Johanson says. If Arxis is injectable on an outpatient basis, the sales volume will be high and the price relatively low, Johanson predicts. An injection is likely to run $1,000 to $1,500.

“The material can be processed and manufactured relatively inexpensively, which positions it well for the higher-volume-procedural market,” Johanson says.

Bone Breakthrough

MIT researchers created this nanoscale map of the stiffness of bone.   Credit: Beryl Simon

Nanoscale research explains bones’ resilience

MIT Technology Review, by Gandra Gwanson  —  By taking bone analysis to a new level of precision, researchers at MIT have revealed an engineering marvel under our skin. Their work may help improve the resilience of man-made materials and enable earlier diagnosis of bone diseases.

Researchers led by Christine Ortiz, associate professor of materials science and engineering, examined the mechani­cal properties of collagen molecules–bone’s building blocks–at a scale of less than 50 nanometers. (To put that in perspective, a human hair has a diameter of about 80,000 nanometers.) Their close inspection showed that the heterogeneous composition of bone at the nanoscale makes it tougher overall.

The researchers used a molecular force probe to poke one-square-­millimeter samples of bovine shin bone hundreds of times in a grid pattern. “It basically tells you where bone is stiff and where it’s not,” says Ortiz. Using the probe’s measurements, they produced maps of the samples’ stiffness and found a dramatically varied terrain. “We weren’t expecting the structure to be so complex,” she says.

Materials science researchers have long known that bone’s structure is heterogeneous at the nanoscale because of variation in the size, shape, and spacing of its primary components, collagen molecules and mineral particles. But they disagreed on one important point, says Subra Suresh, dean of the School of Engineering at MIT and coauthor of the team’s research paper (published in May in Nature Materials).

“If you have a material that’s perfectly ordered and periodic, is that better than a material that has the same average properties, but has high values in some places and low values in others?” says Suresh. “There was no consensus on whether nonuniformity was better or worse.” He believes the MIT team’s research settled that debate. Using the bovine-bone data, the team created a computer model that can virtually bend the bone and predict its behavior. The simulations compared bone with other tough but more uniform materials and showed that it takes more energy to deform a highly heterogeneous material than a uniform one.

These results offer a promising blueprint for stronger composite materials in load-bearing structures. Imitating nature, engineers could enhance a material’s resilience by boosting its nanoscale variability. The project, funded by the MIT Institute for Soldier Nanotechnolo­gies, may help improve body armor and other combat equipment.

The research could also lead to earlier detection of osteoporosis and other bone diseases. “Now that we can measure bone at the nanoscale,” says Suresh, “it might be possible someday to remove a tiny biopsy and to tell if there’s an abnormality in that bone fragment.”