Immunologist Awarded Nobel Prize

Ralph Steinman's discovery and continuing investigation of a "missing link" in the human immune system have changed the field, colleagues say. This year, his work also has earned him the Nobel Prize. 
"He discovered this important cell type, dendritic cells," says Max Cooper at the University of Alabama at Birmingham, a fellow immunologist who has known Steinman and his work for more than 30 years. "Back at a time when no one really believed him, he pushed the idea very hard and backed it up by isolating this very small fraction of cells to show that they were important in activating our T‑ and B‑cells in immune responses. "His digging them out, isolating them, characterizing them in a painstaking way really did change the way we view how microbes enter the body and get recognized and responded to. And that changed our view of the way we understand how immunity is kicked off." Steinman, the director of the Chris Browne Center for Immunology and Immune Diseases at The Rockefeller University, is practiced at describing the cells he studies. "The dendritic cell is, so to speak, a missing link in the immune system," he says. "The immune system has a number of different cells that provide resistance to infection and are involved in other disease conditions like cancer, allergy, transplantation and autoimmunity. Immune cells are like musicians in a symphony, each very talented and specialized, but they need a conductor and composer, and that's what dendritic cells are." "The cells sit up at surfaces of our body, along airways and along our intestine and in our skin, ready to pick up infections that enter the body. If they find one, they pick it up to display to the immune system. The cells migrate in the body, and when they get to the immune organs—lymphoid tissues—they find the musicians, so to speak, and then orchestrate the immune response. They tell the immune cells to grow and to develop into functioning protective cells." In the 1970s, when Steinman started his research career, researchers knew about the "musician" cells and they knew about infections. But in their laboratories, they could not seem to energize the immune cells to react to the infections. A link was missing, some cell in the immune-system soup that flipped the immune system cells on, and on in the right direction. They called the cells they were looking for "accessory cells." Steinman was working in the lab of the late Zanvil Cohn at Rockefeller University, an expert in the physiology of macrophages, which were considered to be a leading candidate for the missing accessory cells. "We looked at the populations [of cells] that were the source of the accessory cells," Steinman says. Using spleen tissue from mice.,"we found unusual cells that had never been seen before; they were tree-like in shape. Hence the name we gave them, dendritic, from the Greek word for tree." Exacting work Michel Nussenzweig was the first student to work with Steinman on dendritic cells, in 1977, shortly after the purification method for dendritic cells had been developed. He, Steinman and Cohn found that dendritic cells were very potent immune stimulators. Still, almost nobody believed dendritic cells were that special or significant, he says. For the next nearly 15 years, a good deal of the research published on dendritic cells came from Steinman and his colleagues. The cells are rare, making up less than one percent of white blood cells, and separating them out was an onerous process until Steinman and his colleagues devised a new method in the 1990s. "Once it became easy to work on the cells, then the field exploded, and there are now thousands of labs who study dendritic cells," Nussenzweig says. Steinman wasn’t afraid to argue that something so rare could be so important, says Antony Rosen, who worked in the Cohn lab with Steinman in the late 1980s and now is at Johns Hopkins University. "He was confident enough that it didn't matter to him that nobody had ever seen it before. It didn't matter to him that everybody rejected what he said. And he stayed at it and he knew he was right, and he proved that he was right." Vast potential Researchers are studying the properties of dendritic cells and how to control their activities for many potential uses. Helping dendritic cells to dampen immune response could ease symptoms of autoimmune disorders and allergies. Helping dendritic cells to boost immune response could help fight infections like AIDS and cancers. Steinman is currently concentrating his work on investigating and designing vaccines. "I just feel the vaccines we already have are medical miracles, but the scope and potential of new vaccines that target dendritic cells is just enormous," he says. "I also find that when I try to think about making a vaccine against HIV or against cancer, that I start asking some interesting scientific questions about how our immune systems operate." He also continues to call for research that aims to study science in people, to help people and to extend scientific understanding. "We need to build a new kind of research network, one that develops and supports researchers who can study the immune system in patients," he says. "I think the natural deductive instinct of most scientists is to keep figuring out how the cells work in simpler systems like mice, learn more about mechanism, and that's obviously going to be very productive. "But what I'd like to see is that we set our standards on the medical conditions that involve the immune system. I think that's where the biggest scientific challenges are, and if we don't direct ourselves to these conditions, we won't have the standards high enough for what we need to know." Part of that work is his role as a consultant for the Dana Foundation's immunology grants program, which targets patient-oriented research. Steinman has been a vociferous spokesman for such research, says Cooper at the University of Alabama. "He's just been unwavering in his insistence on trying to translate basic findings about how the immune system functions in a very basic way to see that that information gets translated into something that has relevance to people and their diseases." Of all the systems in the body, the immune system is the one "you can really teach, really make better," said Steinman during a forum at the Dana Center in 2006. But, he added, we don't yet know all the rules. Curiosity and collaboration The discovery of dendritic cells was a co-discovery, shared with Zanvil Cohn and other colleagues, Steinman says. He continues to collaborate, with colleagues at Rockefeller University and across the world. "He has been a mentor to a lot of people," says Madhav Dhodapkar, who worked in his lab a decade ago and now runs his own lab at Rockefeller. "People who haven't necessarily trained in his lab, I know, have benefited from interacting with him." Professionally, if one looks at how often his papers have been cited, thousands of times, it's easy to see how influential he is, says Rosen of Johns Hopkins. Most citations are for his work with dendritic cells, of course, but also for work on endocytosis and on basic cell biological progresses. "And some of those were classics in their time as well," he says. "He has this great knowledge of science, and it's like he's a child discovering something for the first time every time he reads it," Rosen says. "He's just got a hunger for it. That's why I think he made a big discovery." "He would come into the lab with a journal or with a paper that he thought you would be interested in, and he told you about it as if it were the coolest thing that he could ever have come across." It's a reciprocal pleasure, Steinman says. "I think young people, especially in a complex, intricate science like immunology, need support and discussion time. It's just too intricate to do everything yourself. They certainly reciprocate, and you know, the young, energetic mind has the best ideas." The two Lasker prizes for medical research, nicknamed "America's Nobels," are given each year. Steinman received the Lasker award for basic medical research. This year's award for clinical medical research was shared by Alain Carpentier and Albert Starr, who developed replacement heart valves.

Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden

Objective To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months.
Design Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period.
Setting Stockholm county, Sweden.
Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1 024 019 were vaccinated against H1N1 and 921 005 remained unvaccinated.
Main outcome measures Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell’s palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status.
Results Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell’s palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0.94, 0.91 to 0.98), whereas those vaccinated in the late phase had an overall reduced mortality (0.68, 0.64 to 0.71). These associations could be real or explained, partly or entirely, by residual confounding.
Conclusions Results for the safety of Pandemrix over 8-10 months of follow-up were reassuring —notably, no change in the risk for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Relative risks were significantly increased for Bell’s palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the vaccination campaign. Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions. 

Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease


Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease.

Methodology/Principal Findings

(A) Time-dependent morphological changes of cells reseeded in a 24-well plate. Neuronal and glial cells were stained by anti-Tuj1 (left; red), anti-synapsin I (left; green), anti-MAP2 (right; red), and anti-GFAP (right; green) antibodies and DAPI (right; blue) at 38, 45, and 52 days. Scale bar, left; 20 µm, right; 50 µm. Expression levels of Tuj1 (B), synapsin I (C), MAP2 (D), and GFAP (E) at days 0, 24, 38, 45, and 52 were measured by qPCR and normalized by that of GAPDH. “Fold expression” is the ratio of expression at each day compared to day 0. Each point represents mean ± SD of 3 assays. *p<0.05, **p<0.01, ***p<0.001, significantly different from day 0 by Dunnett's test. (F–H) Neurotransmitter phenotypes at day 52. PAG (red)- and GAD (green)-positive (F), vGlut1 (green)- and Tuj1 (red)-positive (G), and GABA (green)- and Tuj1 (red)-positive cells (H). Blue, DAPI. Scale bar, 50 µm.
We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production.


These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.