We look back on some of the key insights into biomedicine published this year.
Metabolism: Bile thumper
Bile acids are known to ward off fatty liver disease and maintain stable blood sugar levels. Thus, researchers have been on the lookout for ways to boost the production of these liver secretions. The liver receptor homolog-1 (LRH-1) protein is crucial for maintaining normal levels of bile acids, so a team led by scientists at the Baylor College of Medicine in Houston screened for small-molecule agonists of LRH-1. They found that a natural compound known as dilauroyl phosphatidylcholine (DLPC)—a trace component of lecithin, a common food ingredient derived from plant and animal sources—is a potent activator of both the mouse and human forms of the protein (Nature 474, 506–510, 2011).
In two different mouse models of obesity, the researchers showed that DLPC mildly increased bile acid levels in the blood, reduced fat generation by the liver and increased the rate at which the mice burned fat. These effects reduced the incidence of fatty liver disease and improved glucose tolerance and insulin sensitivity in the mice. The group's collaborators are now running a pilot clinical trial testing DLPC in prediabetic individuals.—RL
Cardiovascular disease: A gut reaction
The way to a man's heart is through his stomach, the old adage goes. And new research suggests that the way to heart disease could be through the gut, too.
Scientists from the Cleveland Clinic in Ohio and the University of California–Los Angeles screened small-molecule metabolites circulating in people's blood plasma and found that the presence of byproducts made after gut bacteria break down phospatidylcoline—a fatty substance found commonly in certain types of food—predicted who would later suffer from heart disease. Experiments in mice then showed that intestinal microbes have a central role in setting off a metabolic chain reaction that leads to this dietary lipid getting converted into a molecule called trimethylamine N-oxide (TMAO), which boosts the formation of artery-clogging plaques that can lead to cardiovascular problems (Nature 472, 57–63, 2011).
These findings add to a growing body of evidence showing that commensal bacteria can cause or worsen certain conditions, including obesity and immune disorders. The work also suggests that drugs might be able to target TMAO to prevent atherosclerosis and heart disease. —CP
Development: Three's company
Ever since Dolly the sheep was cloned, researchers have sought to derive patient-specific human stem cells by transferring the nucleus of an adult cell into a hollowed-out egg—with little success. In part, this failure to get so-called 'somatic cell nuclear transfer' to work in human cells can be chalked up to the paucity of human oocytes for research purposes. But a study published in October suggests there might be intrinsic biological barriers, too.
A team led by scientists at the New York Stem Cell Foundation paid 16 women for a total of 270 eggs. They tried removing the egg's nucleus and then inserting the donor adult nucleus—the standard cloning protocol—but this approach led to embryo arrest after just six to ten cells. However, adding the adult nucleus to an egg that still had its nucleus intact overcame this developmental hurdle, allowing the researchers to isolate stem cells that showed the hallmarks of pluripotency from the resulting early-stage embryos (Nature 478, 70–75, 2011).
Although the authors demonstrate the feasibility of human therapeutic cloning, the resulting stem cells contain three sets of chromosomes—two from the adult cell and one from the oocyte—and so would not be suitable for clinical applications.—MS
Infectious disease: Lost in transmission
Stopping HIV/AIDS requires a multifactorial approach, and a number of new strategies are proving effective at reducing infection rates. The latest success story came in July when members of the HIV Prevention Trials Network published a paper showing that initiating antiretroviral therapy soon after infection lowered the risk of HIV-positive individuals transmitting the virus to their uninfected sexual partners by 96% (N. Engl. J. Med. 365, 493–505, 2011).
The trial randomly assigned 1,763 couples in which one partner was HIV positive to receive treatment either immediately upon enrollment or only when his or her CD4+ T cell counts declined to a previously specified point. After a median follow-up period of close to two years, 28 infections occurred that could be linked to the infected partner, but only one happened in the early-treatment group. The findings support administering antiretroviral therapy at earlier stages of the disease to slow the spread of HIV. —AF
Regenerative medicine: Direct conversion
Patient-specific stem cells derived by reprogramming adult cells to an embryonic-like state are ideal candidates for regenerative therapy because they can form any cell type in the body. But a major problem inherent to these so-called 'induced pluripotent stem cells' is that a subset of them may not mature into the cell type of choice following transplantation, and lingering stem cells can, unfortunately, trigger tumors. Now, two independent groups have figured out how to turn skin cells taken from people suffering from debilitating neurodegenerative diseases directly into functional neurons, thereby bypassing the need for a stem cell stage in between and, thus, possibly reducing the risk of cancer formation.
In August, researchers from two institutions in New York achieved this feat in people with both spontaneous and familial forms of Alzheimer's disease using a cocktail of five neural transcription factors (Cell 146, 359–371, 2011). A month earlier, an Italian team used just three transcription factors to convert skin cells from two women with genetic forms of Parkinson's disease into dopamine-producing neurons (Nature 476, 224–227, 2011). —EC
Immunology: A helping hand
During an inflammatory reaction, the body often responds to low levels of oxygen by turning on a key transcription factor called hypoxia inducible factor-1α (HIF-1α). This protein has long been known to help with cellular metabolism under anaerobic conditions. But now, new evidence shows that HIF-1α also influences the very immune cells driving the inflammatory response itself.
Researchers from the Johns Hopkins University School of Medicine in Baltimore showed that HIF-1α promotes the proliferation of T helper 17 (TH17) cells by activating RORγt, a transcription factor crucial for TH17 differentiation. At the same time, HIF-1α also inhibits the development of regulatory T cells by mediating the degradation of another transcription factor called Foxp3 (Cell 146, 772–784, 2011).
The findings could have important therapeutic implications. Ablating HIF-1α in a mouse model of multiple sclerosis protected the animals from the development of TH17-mediated disease, the researchers found, suggesting that targeting HIF-1α could prove beneficial in a number of inflammatory contexts. —KDS
Gene therapy: In vivo improvement
In conference presentations this year, Sangamo BioSciences of Richmond, California announced clinical evidence showing that targeted genome editing technology can be used to make the human immune system resistant to HIV. This feat was achieved by modifying trial participants' T cells in the laboratory with designer enzymes called zinc finger nucleases. But, according to a preclinical study published in June, genome editing might be possible without having to remove cells from the body.
In the first successful demonstration of this technology in living animals, researchers from the University of Pennsylvania Perelman School of Medicine in Philadelphia, in collaboration with Sangamo scientists, corrected the genetic defect in a mouse model of hemophilia. They injected mice with a virus encoding a zinc-finger nuclease together with a virus modified to carry a normal version of the blood-clotting–associated gene F9. After treatment, the normal F9 gene was present and correctly positioned in the genomic DNA of liver cells, and the animals' blood clotted faster with no signs of liver toxicity (Nature 475, 217–221, 2011). —MB
Cancer biology: BET-ting on chromatin
Tumor development often involves genomic changes that affect protein expression, so chromatin alterations have received a lot of attention as possible therapeutic targets. A handful of recent studies support this idea by identifying a role for the bromodomain and extraterminal (BET) family of transcriptional regulators, which bind and recognize histone acetylation, in several human hematological malignancies.
Four independent groups—from Boston's Dana-Farber Cancer Institute, New York state's Cold Spring Harbor Laboratory, the UK's Cambridge University and Massachusetts's Constellation Pharmaceuticals—started from different points and used different models, but they all converged on the finding that interfering with the function of BET proteins reduces the transcription of key oncogenes such as Myc, arrests cell-cycle progression and leads to apoptosis (Cell 146, 904–917, 2011; Nature 478, 524–528 & 529–533, 2011; Proc. Natl. Acad. Sci. USA 108, 16669–16674, 2011).
Crucially, the four studies highlighted the clinical implications of this finding by showing that small-molecule inhibitors of BET family members had therapeutic effects in mouse models of leukemia, lymphoma and myeloma, as well as in primary cells isolated from people with cancer. —JCL
Written by Michael Basson, Eva Chmielnicki, Kevin Da Silva, Alison Farrell, Randy Levinson, Juan Carlos López, Carolina Pola and Meera Swami