This year has proven to be a veritable cliff-hanger for the world of biomedicine. At the same time that the US government stands poised on the brink of the so-called ‘fiscal cliff’, pharmaceutical companies are stumbling with the industry’s ‘patent cliff’ and academic researchers face the looming ‘funding cliff’. But not everything in 2012 was so dire, with dozens of new drugs to hit worldwide markets and countless discoveries made to enable the next generation of medicines. What follows are a set of ‘Cliff’s notes’ to the year that was for the field.
The recent tragedy in Newtown, Connecticut, perpetrated by 20 year-old Adam Lanza, has intensified the discussion about how mental health is handled and documented in the US. Officials have not provided information about Lanza’s motivation and state of mind, and many are rightfully quick to point out that it is wrong to equate mental illness with the fatal sociopathic actions of a small group of individuals. The conversation about access to mental health care should, however, take into account new data showing an increasing contribution of mental and behavioral disorders to deterioration in the health-related quality of life among teenagers in the US and Canada over the last two decades, and increases elsewhere around the globe.
The estimation of ‘years lived with disabilities’, or YLDs, is used as a collective metric to determine how much a particular disorder deprives the population of healthy years of life during a particular window of time. In 2010 just as in 1990, depression ranked as the number two contributor of YLDs, affecting 4% of the global population, eclipsed only by back pain that affected almost 10% of population worldwide. Among 10 to 14 year olds, the top contributor worldwide is iron deficiency. Asthma had been the largest contributor to YLDs for youths in that age range in the US and Canada in 1990, but the study published in The Lancet on Thursday led by researchers at the Institute of Health Metrics and Evaluation (IHME) at the University of Washington in Seattle showed that depression surpassed asthma to claim the number one spot in this group in 2010. Among this cohort, the collective number of ‘years lost to disability’ grew from about 140,000 in 1990 to almost 180,000 in 2010, a 30% increase. Notably, global figures for the same age group show that the number of years lost to disability from depression grew from 4.9 million in 1990 to 5.5 million in 2010, a 13% increase as shown in the graphs below.
Cell biologists have long thought that cytokinesis, the final step of cell division in which the cytoplasm and its contents are split, is necessary for the proper assortment of chromosomes. Disrupt this process, the prevailing wisdom held, and aneuploidy will result, with cancerous implications. But a team led by Mark Burkard at the University of Wisconsin–Madison has discovered a new type of cell division, dubbed ‘klerokinesis’, that protects cells from failed cytokinesis.
Using live-cell imaging, the researchers watched retinal pigment epithelial cells for five days after they had chemically inhibited cytokinesis. Reporting today at the American Society for Cell Biology’s annual meeting in San Francisco, they showed that many cells managed to split into two during the first growth phase of the nextcell cycle—not during mitosis—allowing each to recover a normal chromosome set. Burkard says that therapeutic strategies that boost this type of nonmitotic cell fission could prevent cancer in people at high risk of developing tumors marked by abnormal chromosomal counts.
Beth Galliart and her horse Austin{credit}Michelle Arani{/credit}
In June 2008, Beth Galliart was diagnosed with chronic myeloid leukemia. At the time, her doctors put her on Gleevec (imatinib), a small-molecule drug available since 2001 that is often touted as the poster child of personalized medicine. Marketed by Switzerland’s Novartis, Gleevec specifically targets the tyrosine kinase enzyme that is overactive in the white blood cells of people with leukemia. For close to nine months, the drug worked wonders for Galliart, and her blood counts returned to normal levels. But she soon started to feel tired again. A blood test confirmed that her cancer had returned.
Galliart’s doctors made a decision in March 2009 to switch her to Sprycel (dasatinib), a comparable tyrosine kinase inhibitor (TKI) from New York’s Bristol-Myers Squibb. She ended up taking that drug for only three days, though: her doctors took her off the drug when they received the results of a genetic test revealing that her cancer cellshad evolved the T315I mutation in the tyrosine kinase BCR-ABL, making it impervious to allapproved TKIs for the disease, including Gleevec and Sprycel. Galliart, an executive assistant at an investment firm in Silicon Valley, California, prepared herself for a risky bone marrow transplant. Her family prepared for the possibility that she might die.
Distant cousins from Kansas came to visit and say their final goodbyes. They and Galliart were picking strawberries one day in May 2009 when her phone rang. It was a clinical study coordinator from the University of California–San Francisco (UCSF) on the line. A managing partner from Galliart’s firm knew a UCSF doctor who was running a phase 1 clinical trial with an experimental agent called ponatinib. On the basis of preclinicalwork, this drug was thought to inhibit the mutated forms of the BCR-ABL protein that are responsible for people’s resistance to most TKIs—including the T315I mutation.
Galliart quickly enrolled in the study. A month later, she received her first dose of the drug.
Although she did suffer intense bone pain for three days after first receiving ponatinib—“It was sort of like a bomb was going off in my whole body,” recalls Galliart, 47—her cancerous blood cells have not come back since. She is now training for a half-marathon and regularly rides and jumps horses.
Fortunately, Galliart’s positive experience with ponatinib is not unique. In a phase 2 trial of 449 people with CML or the similar acute lymphoblastic leukemia (ALL) who were intolerant to other TKIs or who had a confirmed T315I mutation, around half responded favorably to the drug. The results were presented earlier this month at the American Society for Hematology meeting in Atlanta. Phase 1 trial results involving 81 participants, including Galliart, were published in late November in the New England Journal of Medicine (367, 2075–2088, 2012). Ponatinib was approved by the US Food and Drug Administration (FDA) today. It will be marketed by Ariad Pharmaceuticals of Cambridge, Massachusetts, as Iclusig.
“This drug has the potential to be a best-in-class agent that may be completely invulnerable to single-kinase-domain mutations,” says Neil Shah, the UCSF hematologist who treated Galliart. “I’m hopeful that it really will remove single-kinase-mutation–mediated resistance out of the picture.”
Over the past decade, neglected diseases have attracted increased attention and larger investments in research. Even often overlooked tropical diseases such as sleeping sickness and leishmaniasis have received more funding. “These Cinderella diseases, long ignored and underappreciated, are a rags-to-riches story,” said Margaret Chan, director-general of the World Health Organization, in an address in May. But these newfound ‘riches’ have given rise to just a few dozen newly approved therapies and only a handful of truly novel drugs. A new analysis by Médecins Sans Frontières (MSF) and the Drugs for Neglected Diseases Initiative (DNDi) finds that the rate of approvals for new compounds over the past decade is roughly the same as it was during the previous two-and-a-half decades, when the diseases received little attention.
“It is still a very depressing picture,” says Manica Balasegaram, head of MSF’s Access Campaign in Geneva. “This is a little bit disheartening considering the huge amount of activity that’s been happening in the global health world.”
The new analysis, presented today at a symposium in New York, shows that of the 850 new therapies and vaccines approved by the US Food and Drug Administration, the European Medicines Agency and other agencies between 2000 and 2011, 37 focused on neglected diseases, and just four of those were new chemical entities. The work builds on a pioneering paper published in 2002 by members of the Drugs for Neglected Diseases Working Group, which counted 1,393 new drug approvals—16 of which focused on neglected diseases—between 1975 and 1999 (Lancet 359, 2188–2194, 2002). According to DNDi, 11 of those 16 drugs could be considered new chemical entities. The numbers suggest that although the rate of approvals for drugs for neglected diseases has gone up, the rate of approvals for new chemical entities seems to have remained relatively flat.
Direct comparisons, however, are difficult, as the new analysis is more comprehensive than the previous one, and tallying drug approvals can prove challenging. Joshua Cohen, a health economist with the Tufts Center for the Study of Drug Development in Boston, reanalyzed the working group’s data a few years ago and came up with a different count—32 new drugs approved for neglected diseases, including 13 new chemical entities (PLoS ONE 5, e10610, 2010).
Sergey Brin, the co-founder of Google, has an increased risk of developing Parkinson’s disease because he harbors a mutation in a protein called Leucine-rich repeat kinase 2, or LRRK2. The protein is viewed as a promising drug target to treat Parkinson’s, a progressive neurological disorder, but it’s not possible to track LRRK2 activity in the brain, making the search for targeted therapies against the disease challenging. In a new study, researchers now provide evidence for a way to measure LRRK2 activity—and a new compound that can block the damaging effects of the protein in rodent neurons.
“This study is important because the authors showed that specific mutations in LRRK2 activate it and cause damage to nerve cells. This finding can now provide opportunities to monitor the effects of LRRK2 inhibitors in cells and animals,” says Howard Federoff, executive deanof Georgetown University’s School of Medicine in Washington, DC, who was not involved in the study.
Parkinson’s disease affects approximately 10 million people worldwide by impairing motor functioning caused by the death of dopamine-secreting neurons in the brain. Mutations in LRRK2 are the most common cause of familial Parkinson’s disease, accounting for about 2% of all patients with Parkinson’s. Specific mutations in LRRK2 increase its enzyme activity. A 2006 study in Nature Neuroscience revealed that mutations affecting LRRK2 activity can damage mouse nerve cells grown in culture. A 2010 study published inNature Medicineshowed that inhibiting LRRK2 can prevent some of the symptoms of Parkinson’s disease in a mouse model. However, an understanding of how LRRK2 causes neuronal damage remained elusive.
Today, reporting in Science Translational Medicine, a collaborative team led by neurologist Haitao Zhu and chemist Don Kirkpatrick at biotech powerhouse Genentech, based in South San Francisco, California, identified several abnormalities in mutated LRRK2 at a site of the protein known as serine 1292 that make it more active—and thereby more toxic to neurons. The identification of serine 1292 allowed the researchers to develop an antibody that could bind to the protein, allowing them to build an assay that measured the amount and activity of LRRK2.
Subsequently, the researchers found that the amount of LRRK2 with this serine 1292 modification—specifically, the addition of a molecule known as a phosphate group—was ten times higher in cells taken from the brains of mice genetically engineered to carry mutated LRRK2 compared to that seen in normal mice.
The scientists also developed a molecular screening approach to test hundreds of potential LRRK2 inhibitors. In the end, they identified one such compound, G1023, which completely removed the bound phosphate group in mutated LRRK2. G1023 protected embryonic neurons taken from mice with the LRRK2 mutation, returning the growth rate of these cells to the same level as that seen in cells taken from healthy mice.
“The serine 1292 site is highly conserved through evolution from worms to humans, suggesting that it is very important for the function of LRRK2 and can be used as a starting point in drug discovery to prioritize compounds that are selective, potent, and brain-penetrable,” says Zhu.
“We still don’t know if this inhibitor molecule will be protective in an animal, but now they are well prepared to do these studies,” says Federoff. Zhu and Kirkpatrick agree that the next step, now that they have an inhibitor, is to test its efficacy in an animal model, as a necessary first step to evaluate whether to ultimately go forward with a human clinical trial.
Here’s a look back at where the search was in 2010 when the Nature Medicine story came out:
Testing fetal DNA for fine-scale copy number variations can reveal more genetic defects than standard karyotyping methods that look for genetic abnormalities in developing fetuses on a whole-chromosome level, according to the largest clinical trial of its kind.
“These findings will undoubtedly cause many clinical and laboratory geneticists to consider whether chromosomal microarrays should be recommended as a first-tiered prenatal diagnostic test,” says Cynthia Morton, director of cytogenetics at the Brigham and Women’s Hospital in Boston, who was not involved in the trial.
Karyotypic staining analyzes the composition and structure of chromosomes to reveal abnormal changes in chromosome number and shape that are commonly implicated in disease. This technique is currently the gold standard for detecting prenatal genetic defects, but is far from perfect. Karyotyping routinely misses small genetic aberrations and the method only works on cultured cells. To overcome these limitations, researchers have recently turned to a method known as ‘array-comparative genomic hybridization’, which relies on a small chip embedded with millions of molecular probes that recognize particular genomic DNA regions and pinpoint genetic abnormalities too small to be detected by current methods. And as an added bonus, it works on any tissue, living or dead.
Such ‘chromosomal microarrays’ have historically only been used in small scale studies for prenatal diagnostics. But now, a team led by Ronald Wapner, director of Maternal Fetal Medicine at the Columbia University Medical Center (CUMC) in New York, has tested fetal DNA from more than 4,400 expectant mothers at 29 centers across the US using both standard karyotyping and chromosomal microarrays. Microarray analysis, the researchers found, detected chromosomal deletions or duplications in 6% of cases in a group that was flagged as structurally abnormal by ultrasound but scored normal by karyotyping and also revealed genetic abnormalities in about 2% cases missed by karyotyping in another group with advanced maternal age.
“The advantage of microarrays is their high resolution and sensitivity, which allows detection of events at the level of genes, as opposed to the level of chromosomes for karyotyping,” says Wapner, who published the results today in the New England Journal of Medicine (NEJM).
Also today in NEJM, a team led by Uma Reddy, an obstetrician-gynecologistat the US National Institute of Child Health and Human Development in Bethesda, Maryland, compared the ability of microarrays and karyotyping to diagnose the cause of more than 500 stillbirths. Because of the challenges associated with culturing tissue from a dead fetus, karyotyping failed to give results in 30% of cases, whereas microarrays, which don’t require live cells, yielded a genetic culprit in 87% of stillbirth cases. “With microarrays, you are more likely to obtain a result, which is important for families waiting for answers,” says Reddy.
In the 1920s, the German physiologist Otto Warburg proposed that cancer cells generate energy in ways that are distinct from normal cells. Healthy cells mainly metabolize sugar via respiration in the mitochondria, switching only to glycolysis in the cytoplasm when oxygen levels are low. In contrast, cancer cells rely on glycolysis all the time, even under oxygen-rich scenarios. This shift in how energy is produced—the so-called ‘Warburg effect’, as the observation came to be known—is now recognized as a primary driver of tumor formation, but a mechanistic explanation for the phenomenon has remained elusive.
Now, researchers have implicated a chromatin regulator known as SIRT6 as a key mediator of the switch to glycolysis in cancer cells, a finding that could lead to new therapeutic modalities. “This work is very significant for the cancer field,” says Andrei Seluanov, a cancer biologist at the University of Rochester in New York State who studies SIRT6 but was not involved in the latest study. “It establishes the role of SIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”
SIRT6 encodes one of seven mammalian proteins called sirtuins, a group of histone deacetylases that play a role in regulating metabolism, lifespan and aging. SIRT1—which is activated by resveratrol, a molecule found in the skin of red grapes—is perhaps the best known sirtuin, but several of the others are now the focus of active investigation as therapeutic targets for a range of conditions, from metabolic syndrome to cancer. Just last month, for example, a paper in Nature Medicine demonstrated that SIRT6 plays an important role in heart disease.
Six years ago, a team led by Raul Mostoslavsky, a molecular biologist at the Massachusetts General Hospital Cancer Center in Boston, first showed that SIRT6 protects mice from DNA damage and had anti-aging properties. In 2010, the same team establishedSIRT6 as a critical regulator of glycolysis. Now, reporting today in Cell, Mostoslavsky and his colleagues have shown that SIRT6 function is lost in cancer cells—thus, definitively establishing SIRT6 as a potent tumor suppressor.
US regulators are teaming up with medical device companies and non-profit organizations in an effort to advance better and safer tools for evaluating the safety, quality and efficacy of medical technologies.
The new Medical Device Innovation Consortium (MDIC)—a public-private partnership established jointly by the US Food and Drug Adminsitration (FDA) and LifeScience Alley, a Minnesota-based trade association, and other industry representatives—will “create a safe haven for pre-competitive collaborative research between academia and industry focusing on medical devices,” FDA commissioner Margaret Hamburg said at a press conference earlier today to unveil the initiative.
The path to developing new medical devices for clinical use in the US is a lengthy one. Unlike in Europe, where companies only have to show that a device is safe, in the US they must also demonstrate a device’s clinical effectiveness in treating a disease or medical condition. This has led to an approval lag in which devices typically reach US patients only after they have been on the market in the EU for several years.
To shorten that time lag, the FDA is now looking to industry for ideas—which is where the consortium comes in. By sharing resources between MDIC members, for example, the FDA hopes to create effective, efficient and standardized ways to validate and review devices and to prioritize funding and regulatory science decisions. “For the first time, we can determine priorities, bring together collaborative minds and analyze post-market values to determine safety and efficacy,” Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said at the press conference.
Dale Nordenberg, executive director of the Medical Device Innovation, Safety and Security Consortium (MDISS), a nonprofit professional organization not associated with MDIC, praised the FDA for bringing together stakeholders through the private-public partnership. “However, the success depends on robust governance by FDA to ensure effective representation across stakeholder groups for public health needs,” he told Nature Medicine.
Worldwide, one in about 1,000 newborns is diagnosed with Down syndrome, a genetic disorder predominantly caused by an extra copy of chromosome 21—also known as trisomy 21—and in countries such as the US the number of children affected by the condition appears to be increasing. No medicines can currently treat the memory and learning impairments seen in Down syndrome; a new study published today in the Journal of Clinical Investigation could offer insight into the cellular pathways to target to improve cognitive function.
In the study, Italian researchers report that a one-month lithium treatment promotes the growth of new neurons in the hippocampus and improves cognitive functions in an animal model of Down syndrome. The team, led by neuroscientistLaura Gasparini at the Italian Institute of Technology in Genoa, took advantage of the fact that mice with an extra copy of chromosome 16 demonstrate cognitive impairment and neuronal dysfunction similar to that seen in trisomy 21. “We hypothesized that stimulating the growth of new neurons in this mouse model will benefit cognitive function in Down syndrome,” Gasparini says.
The scientists gave the genetically engineered mice lithium—a drug already used to treat mood disorders in people. Previous studies, including one in 2010 in these mice, have shown that lithium increases the production of new brain cells in a region know as the hippocampus, which has a key role in memory. In their experiment, Gasparini and her colleagues measured the expression of a marker, doublecortin (DCX), which is present on the surface of newly formed neurons.
At the end of the one month treatment, the ‘Down syndrome’ mice who received lithium had approximately 3,500 cells in the hippocampus expressing DCX, about the same number as that seen in healthy mice without the condition. By comparison, those mice with the trisomy mutation that received saline solution only had about 1,500 cells expressing DCX, indicating that they had about 40% fewer newly formed neurons. Additionally, trisomic mice that received lithium treatment performed much better than their untreated counterparts on the behavioral assessments designed to test their contextual learning by fear conditioning, spatial memory and object discrimination.
Brain gain: The US Department of Health and Human Services published a draft framework on 9 January laying out a national plan for fighting Alzheimer’s disease. The document, which was finalized in May 2012, calls for effectively preventing and treating the disorder by 2025. A month later, the EU’s Joint Programme in Neurodegenerative Disease Research launched a strategy to improve coordination between research and funding efforts on such diseases.
Over the past decade, neglected diseases have attracted increased attention and larger investments in research. Even often overlooked tropical diseases such as 
but it’s not possible to track LRRK2 activity in the brain, making the search for targeted therapies against the disease challenging. In a new study, researchers now provide evidence for a way to measure LRRK2 activity—and a new compound that can block the damaging effects of the protein in rodent neurons.
