Huntington’s disease is a progressive, fatal neurological disorder with no cure. But now researchers at the National Yang-Ming University in Taiwan and Stanford’s School of Medicine have discovered a protein that may one day be a viable therapeutic target for those afflicted with the condition. According to co-senior author Tzu-Hao Cheng, PhD, associate professor at National Yang-Ming University’s Institute of Biochemistry and Molecular Biology:

Huntington’s disease is a devastating disease with no cure available at this time. Targeting the transcription factor identified in our research may one day be able to prevent or delay the formation of the protein aggregates that are the hallmark of this and other neurodegenerative diseases. We are hopeful that our studies will be a major advance in the field.

The research will be published tomorrow in the journal Cell. It was a joint collaboration between Cheng’s laboratory and that of Stanley N. Cohen, MD, professor of genetics here at Stanford. The findings are exciting because they suggest there may be a way to prevent the tangled clumps of huntingtin protein that cause the disorder.

About one in 10,000 people of western European descent have Huntington’s disease, which is particularly heartbreaking because of the slow but inevitable decline in sufferers’ physical and mental capacity. The disorder is characterized by uncontrollable movements, mental deterioration and eventual dementia. It’s genetic, and a child of an affected parent has a 50 percent chance of also developing the condition.

The advent of genetic testing has allowed people to know whether they carry the gene years before symptoms begin (usually in mid-life), but the lack of a cure or any kind of treatment has sparked discussion as to the utility of early diagnosis.

People with the condition have long stretches of repeats of the same three nucleotides in their huntingtin gene. Unaffected people have between eight and twenty-five repeats of the nucleotides cytosine, adenine and guanine, or CAG; the genes of affected people have 36 or more of these genetic stutters. As a result, the mutant protein has an extended region of glutamine, which is sticky and binds to itself and to similar regions in other huntingtin protein molecules to create clumps of useless protein that can severely damage nerve cells and lead to the disease.

In the current study, the researchers identified a molecule in yeast called Spt4 (or Supt4h in mammals) necessary to transcribe the huntingtin gene into protein. Interfering with the function of Supt4h reduces the amount of huntingtin protein in mouse cells that mimic the disease, as well as the number of protein clumps. Although any human trials are far off, there are intriguing glimpses of a pathway to possible therapy. According to the study:

Together these observations argue that agents targeting Supt4h may reduce the transcription of genes containing lengthy trinucleotide repeats while having limited effects on normal mammalian cell function.

Previously: New insights into protein folding could aid in developing therapies for neurodegenerative diseases
Photo by MJ/TR

Anthrax toxin is a deadly poison. But it doesn’t affect all people the same way. Research published today by Stanford geneticists Mikhail Martchenko, PhD; Sophie Candille, PhD; Hua Tang, PhD; and Stanley N. Cohen, MD, has shown that susceptibility is a genetic trait that is passed from parents to children. According to our release:

Among 234 people studied, the cells of three people were virtually insensitive to the toxin, while the cells of some people were hundreds of times more sensitive than those of others. The findings may have important implications for national security, as people known to be more resistant to anthrax exposure could be effective first-line responders in times of crises.

…

In the new study, Cohen and his colleagues found that variation in the level of expression of a gene that produces a cell-surface protein called CMG2 affects the success of the anthrax toxin in gaining entry into human cells. The research suggests that analogous effects may occur in people exposed to anthrax bacteria. The authors suggest that the investigational approach they used may be broadly applicable for learning about individual susceptibility to various pathogens in human populations.

The research is published in the Proceedings of the National Academy of Sciences and was funded by the Defense Threat Reduction Agency of the United States Department of Defense. According to Alan Rudolph, PhD, the director of DTRA’s Chemical and Biological Technologies Directorate:

This paper is an important contribution to our understanding of the mechanisms of host susceptibility to anthrax. We are committed to supporting outstanding science in this field and will seek opportunities to translate key discoveries such as this into useful applications in diagnostics and medical countermeasures for enhanced preparedness for the department of defense and global health security.

Previously: Human immune system has developed elegant self-defense against anthrax infection, Report questions whether U.S. is adequately prepared for future public health threats and Show explores scientific questions surrounding 2001 anthrax attacks
Photo of Martchenko by Steve Fisch

California stem-cell research aficionados are of course familiar with the California Institute for Regenerative Medicine, or CIRM. The state stem-cell agency has handed out over a billion dollars of funding to build new facilities, recruit promising faculty members and otherwise encourage and support stem cell research in California (Stanford has received the lion’s share of grants, to the tune of nearly 200 million dollars). But, as noted in today’s Nature News:

Halfway through its initial ten-year mandate, the California Institute for Regenerative Medicine (CIRM) in San Francisco is confronting a topic familiar to anyone at middle age: its own mortality.

The publicly funded institute, one of the world’s largest supporters of stem-cell research, was born from a state referendum in 2004. Endorsements from celebrities such as then-state governor Arnold Schwarzenegger and the late actor Christopher Reeve, who had been paralysed by a spinal injury, helped to garner voter support for a public bond to underwrite the institute. But with half of the US$3 billion that it received from the state now spent and the rest expected to run out by 2021, CIRM is now actively planning for a future that may not include any further state support.

The article quotes Stanford dermatologist and stem cell researcher Howard Chang, MD, PhD:

“It would be a very different landscape if CIRM were not around,” says Howard Chang, a dermatologist and genome scientist at Stanford University in California. Chang has a CIRM grant to examine epigenetics in human embryonic stem cells, and is part of another CIRM-funded team that is preparing a developmental regulatory protein for use as a regenerative therapy. Both projects would be difficult to continue without the agency, he says. Federal funding for research using human embryonic stem cells remains controversial, and could dry up altogether after the next presidential election (see Nature 481, 421–423; 2012). And neither of Chang’s other funders — the US National Institutes of Health (NIH) and the Howard Hughes Medical Institute in Chevy Chase, Maryland — supports his interdisciplinary translational work.

You can read more about Chang’s research here and here. The news article is brief, but it’s interesting to hear directly from researchers how CIRM grants have affected their work, and what it might be like if the agency is unable to find new sources of funding.

Previously New job description for RNA, oldest professional biomolecule and Stanford researcher finds new marker to identify severe breast cancer cases.

I was excited last week to learn about the recent work of stem cell scientist Marius Wernig, MD, published today (direct link to come) in the Proceedings of the National Academy of Sciences. Wernig directly converted mouse skin cells to neural precursor cells – an extension of previous work in which he created functional neurons from the same types of cells. Although functional neurons might sound more exciting, neural precursor cells promise to be research workhorses. That’s because these cells can become any of three main components of the nervous system: neurons, oligodendrocytes and astrocytes. They can also be grown to large numbers in the laboratory – a critical factor when carrying out drug screening or considering future transplantation into animals or perhaps even one day even into humans. As Wernig explained in our release:

We are thrilled about the prospects for potential medical use of these cells. We’ve shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons. This is important because the mouse model we used mimics that of a human genetic brain disease. However, more work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy.

The release also advances what, for some researchers, may be an even more intriguing idea:

The multiple successes of the direct conversion method could refute the idea that pluripotency (a term that describes the ability of stem cells to become nearly any cell in the body) is necessary for a cell to transform from one cell type to another. Together, the results raise the possibility that embryonic stem cell research and another technique called “induced pluripotency” could be supplanted by a more direct way of generating specific types of cells for therapy or research.

As always, however, more research is needed to determine how cell types generated by the various techniques differ or resemble one another at a molecular level. Right now, there’s no clear winner and it appears there are still several horses in the race.

Previously: Human neurons from skin cells without pluripotency?

Exciting news! Researchers at UCLA and Advanced Cell Technology have published the first report (.pdf) of the use of human embryonic stem cell therapy for blindness caused by a condition called macular degeneration. The preliminary report indicates that the cells are well-tolerated and appear safe. Although the two trials were not designed to test whether the cells can improve vision, the investigators were encouraged by the fact that the two trial participants did not show any further vision loss during the first four months of the trial and the vision of one participant seemed to improve. In an article published in The Lancet today, the authors wrote:

We noted clear functional visual improvement in the study eye of the patient with Stargardt’s macular dystrophy corresponding subjectively to the transplanted region of the posterior pole. At baseline the central vision was hand motions. By week 2, best corrected visual acuity was improved to counting fingers (one ETDRS letter). We recorded continued improvement during the study period (five ETDRS letters [best corrected visual acuity 20/800] at 1, 2, and 3 months; table). The patient is very reliable and worked for years as a graphic artist. She reports subjectively improved colour vision and improved contrast and dark adaptation from the operated eye.

Before implantation, the stem cells were coaxed to become cells that form the retinal pigment epithelium – the tissue that is compromised in both dry age-related macular degeneration and Stargardt’s macular dystrophy. The newly derived epithelial cells were then transplanted into two patients, where they integrated and survived over time. They appeared to grow normally after transplantation.

Much more work needs to be done, of course, before any conclusions can be made about the potential usefulness of these cells as therapy. But I imagine that proponents of human embryonic stem cell research are breathing a cautious sigh of relief this morning. After Geron abruptly dropped their hESC trial for spinal cord injury last November, researchers and media people alike wondered aloud whether the move would set the field back irreversibly. This news, however preliminary, must be welcome indeed.

(If you’d like to learn more about Advanced Cell Technology and their chief scientific officer, Robert Lanza, MD, check out this fascinating history of the company published in Nature earlier this month.)

Previously: Two new human embryonic stem cell trials launched

Exercise physiologist Peter Janiszewski, PhD, wrote yesterday for the PLoS blog Obesity Panacea about a fantastic video that my colleague posted here last month. The video comes from the University of Toronto’s Mike Evans, MD, an associate professor of family medicine and public health at the university and a staff physician at St. Michael’s Hospital in Toronto. According to Evans’ bio:

My interests are in evaluating sustainable interventions that make for more informed health decisions. My target has traditionally been the primary care provider, but now has developed more into targeting the patient in the clinic or at “the kitchen table”. Specifically, what is the best way to bring together academic evidence-based information with the common media that people use (TV, news, print, social networks, Dr. Google, email, etc.). I also have a significant interest in shinny hockey, but am still working on a research angle.

I’d say this kitchen-table approach is working: The video has been viewed over a million times and has garnered 13,000 ‘likes’ on YouTube, and its popularity was featured on CBC last week. As for me, I just got around to watching the entire 10 minutes and am now planning to sneak out to the gym – that is, after I start following “Dr. Mike” on Twitter (@docmikeevans).

Previously: Fitness research: A year in review, What you can do in thirty minutes per day and How sedentary behavior affects your health

Tumor suppressors are potent cancer fighters. These molecules are primed to note a cell’s behavior and to stop its division, or even trigger a suicide program, if it violates certain predetermined cellular rules. Many powerful tumor suppressors were first identified because they were missing or mutated in cancerous cells, but some have continued to fly under the radar. Now Stanford researchers have identified a protein complex that appears to function as a tumor suppressor in pancreatic cancer. From our release:

A well-known protein complex responsible for controlling how DNA is expressed plays a previously unsuspected role in preventing pancreatic cancer, according to researchers at the Stanford University School of Medicine.

Technological advances in the way researchers can compare normal and tumor DNA showed that the gene for at least one subunit of the multi-subunit SWI/SNF protein complex was either deleted, mutated or rearranged in about a third of the 70 human pancreatic cancers that the Stanford team examined. Additionally, the researchers found that restoring the expression of one of the missing genes slowed the growth of pancreatic cancer cells in the laboratory and caused them to enter an arresting state called senescence. [...]

The tumor-suppressing role of the SWI/SNF complex had not been previously discovered because the disabling changes were spread among five of the complex’s protein subunits. In other words, one person’s pancreatic cancer might have a mutation or deletion in one protein subunit, while another’s could have a change in a different subunit. Considered individually, each variation occurs relatively infrequently.

The research, conducted by graduate student Hunter Shain and pathologist Jonathan Pollack path, MD, PhD, was published today in the Proceedings of the National Academy of Sciences. They are hopeful that the identification of SWI/SNF’s tumor suppressing function may contribute to new ways to fight the deadly disease.

Validation is always a good thing, whether in our personal or professional lives. It shows we’re on the right track. Even research studies need ways to compare their findings with studies that use similar methods and to confirm their conclusions. But that can be difficult to do when the technology or concepts are very new. Stanford researcher John Ioannidis, MD, DSc, chief of the Stanford Prevention Research Center talks about the problem, and offers some possible solutions, in a perspective (registration required) in today’s Science magazine:

The exponential growth of the “omics” fields (genomics, transcriptomics, proteomics, metabolomics, and others) fuels expectations for a new era of personalized medicine. However, clinically meaningful discoveries are hidden within millions of analyses. Given this immense biological complexity, separating true signals from red herrings is challenging, and validation of proposed discoveries is essential

Ioannidis co-authored the piece, which appears in a special issue of the magazine on data replication and reproducibility, with researcher Miun Khoury, MD, PhD, from the CDC’s Office of Public Health Genomics. The two researchers suggest applying a multi-step way to validate large studies, including assessing the analytic validity, repeatability, replication, external validation, clinical validity and clinical utility of the studies. The authors conclude:

One may argue that this is not easy because of technical and cost considerations. However, similar arguments were made for fields such as human genome epidemiology, which then saw the cost of DNA sequencing decrease over a billionfold over the past 20 years and the amount of information increase proportionally. Costs could decrease for other technologies as technologies attract the attention of many investigators, especially in large consortia, thereby driving data reproducibility in a field. Funding incentives, reproducibility rewards and/or nonreproducibility penalties, and targeted requirements for repeatability checks may enhance the public availability of useful data and valid analyses.

As a former graduate student, I found this round-up of advice for graduate students really interesting. Says Travis Saunders, who co-hosts the smart and topical PLOS blog Obesity Panacea:

Grad school is not always an easy ride. In fact, it can sometimes be a soul-sucking experience. But it can also be an incredibly fulfilling experience that leaves you waking up excited to head to the lab every morning (seriously!)

Saunders, who is himself a graduate student, goes on to talk about his involvement in the blog roundtable organized by fellow blogger Atif Kukaswadia. Topics include how to choose an adviser, what to do if you’re falling behind or losing interest in your research project, and what it takes to be a successful graduate student. The series of posts is over, but Kukaswadia is encouraging current and former graduate students, as well as faculty members who serve as mentors to maintain the discussion in the posts’ comment threads. Says Saunders:

If you have even a passing interest in grad school, then take a few minutes and read through the posts that sound most relevant to you. The posts are broken down into easily-digestible chunks, so you can get through them all rather quickly. And if you’ve already played the grad school game or have gone on to *gasp* supervise grad students, then please add your own two cents in the comments section.

At the risk of being overly depressing, we’re all getting older. And there’s more to bemoan than just the gray hairs and wrinkles that might be popping up. Every cell in our body is aging, including the hematopoietic stem cells that generate our blood cells and immune system. According to our release:

Specifically, the researchers found that hematopoietic stem cells from healthy people over age 65 make fewer lymphocytes — cells responsible for mounting an immune response to viruses and bacteria — than stem cells from healthy people between ages 20 and 35. (The cells were isolated from bone marrow samples.) Instead, elderly hematopoietic stem cells, or HSCs, have a tendency to be biased in their production of another type of white blood cell called a myeloid cell. This bias may explain why older people are more likely than younger people to develop myeloid malignancies.

It could also be why elderly people find it hard to shake off colds, flu and other viruses, say graduate student Wendy Pang, MD and stem cell biologist Irving Weissman, MD, who co-authored the study in today’s Proceedings of the National Academy of Sciences.

“In both mice and humans, the puzzle has been how the system ages,” said Weissman, who is also the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and a member of Stanford’s Cancer Institute. “Because HSCs in old mice and humans are derived from the HSCs they had in their youth, there are two possibilities to describe how these differences occur. Either individual, young HSCs change their gene expression patterns as they age, undergoing heritable adaptations that favor the myeloid lineage, or each young HSC already has a specific lineage bias and is battling for precious niches through the natural selection of aging, which favors those biased toward myeloid cells.” Understanding which possibility is true could help clinicians of the future encourage the survival of HSCs with more-appropriate properties in patients with age-related diseases, Weissman believes.

Previously Freshen up those stem cells with young blood

Anyone interested in the trials and tribulations of bringing a new cancer therapy to market, and keeping it there, is likely already aware of the fate of Genentech’s Avastin. Last Friday, the FDA revoked its approval of the use of the drug to treat metastatic breast cancer, to the dismay of many patients and their advocates. The revocation was based on studies showing that the drug, which can have serious side effects, failed to help patients live longer.

FDA Commissioner Margaret Hamburg, MD, issued a 69-page document explaining her decision. Today David Kroll, author of the PLoS Blog Take as Directed, called my attention to the fact that the lengthy document includes a good Q&A about the issue to help patients and their physicians understand what the new ruling means to them. Topics include whether physicians can continue to prescribe the drug for metastatic breast cancer, how the FDA ensured that Avastin got a fair hearing, and whether it’s possible that Avastin could again be approved at some point in the future for use in breast cancer patients.

You can read the full Q&A on Kroll’s blog post, or find it in the opening pages of the FDA document

The National Academy of Sciences has released a report recommending the development of a new tool linking diseases with molecular and genetic data to help clinicians and researchers. The concept has been termed “precision medicine” and it calls for a revamping of the 100-year-old diagnostic practice of simply matching up symptoms with diseases. As explained in ScienceInsider:

Precision medicine is already emerging in cancer diagnosis and treatment, the report says: some patients now receive drugs matched to a specific molecular marker in their tumor, and relatives can be tested for certain cancer risks. By contrast, a middle-aged man diagnosed with type II diabetes typically receives a 50-year-old drug that may or may not help him. And no type II diabetes risk tests are available for family members.

What’s needed, the report says, is for patient’s health records to be combined with layers of genomic and other molecular measurements, such as blood proteins and the microbes in a patient’s gut. Like the GPS data used to make Google maps, these data could be plumbed in detail by researchers and used more superficially by others, such as doctors to treat patients, the report says. Separate databases would be combined to form a single network.

The data bank would also be a boon to researchers seeking to identify shared molecular threads that link different conditions. However, the effort is likely to take decades and may require new, more permissive attitudes about patient privacy, notes Nature News today. Stanford’s Stephen Galli, MD, who chairs the department of pathology, was a member of the committee that wrote the report. Galli also co-directs the Stanford’s Center for Genomics and Personalized Medicine.

Previously: New Stanford genomics center to bring personalized medicine to patients

The beta cells of the pancreas are the only cells in your body that can produce insulin. While beta cells proliferate robustly in newborn and very young animals, they stop growing in adults. Developmental biologist Seung Kim, MD, PhD, describes why in a paper (subscription required) published today in Nature. From our release:

The researchers found that, in mice and humans, the pathway is governed by the expression of a molecule called platelet-derived growth factor receptor. PDGF-receptor expression declines over time in mice and humans in a pattern that parallels the decrease in the proliferation of pancreatic beta cells, which produce insulin to control blood sugar levels.

Figuring out a way to artificially activate the PDGF receptor pathway in adults could possibly lead to new treatments for diabetes, the researchers say:

“We’re hopeful that soon we might be able to manipulate this pathway in a therapeutic way in humans,” said professor of developmental biology Seung Kim, MD, PhD, “perhaps by rekindling its expression and then activating it through a drug we could give in an injection or through some other route. This could be a kind of one-two punch against diabetes.”

Photo by Seung Kim and Hainan Chen showing an increase in beta cell mass and number after PRGF receptor stimulation

Happy International Stem Cell Awareness Day! Researchers from the New York Stem Cell Foundation are celebrating by publishing (subscription required) the first reports of human stem cell lines created through a technique called somatic cell nuclear transfer, or SCNT. Although the technique is similar to that used to clone Dolly the sheep in 1996, the resulting human embryonic stem cell lines have three copies of each gene, rather than the normal two. As a result, they can not be used for therapies. But the research is an important proof of principle that will set the stage for future work, said study co-author Scott Noggle, PhD, in a press briefing yesterday:

The goal of this research was to create patient-specific embryonic stem cells. We have shown for the first time that the human oocyte has the capacity to reprogram somatic nuclei to a pluripotent state.

To conduct the research, Noggle and Dieter Egli, PhD, used donated human eggs. They first tried removing the eggs’ own haploid genomes (as reproductive cells, eggs and sperm each have one half the normal complement of genetic material) and replacing it with the nuclei of a somatic, or specialized adult, cell. They found that the resulting cell underwent only a few cell divisions before halting. When they simply added the somatic nuclei to the eggs, they had much better luck: the cell went on to form a multi-cellular structure called a blastocyst, from which Noggle and Egli successfully prepared human embryonic stem cell lines with three, rather than two, copies of each gene. Says Egli:

We are now trying a number of approaches to remove the egg genome. Although the long-term goal is to generate cells for use in therapies, we can use these cells now for several important studies, including comparing them to human iPS cells.

iPS cells are pluripotent cells created from somatic cells by using viruses or other genetic manipulation. While they, like cells derived from SCNT, can be generated from the patient they are meant to treat (and thus should not generate an immune response), researchers agree that they are not genetically identical to true embryonic stem cells and more research is needed to determine their therapeutic usefulness.

The full study requires a subscription to access. But you can read a nice review of the work in today’s Nature News.

Brendan Maher has a fantastic story out this morning in Nature News about using whole genome sequencing in the clinic. The article reviews some of the technique’s successes (mostly in finding the causes of rare, inherited diseases or cancers) while pointing out hurdles that still need to be overcome:

…unlike the results of most medical tests, a genome sequence provides a vast amount of difficult-to-interpret data, not all of which will be necessary for diagnosing or treating the patient’s condition and which could provide unwanted clues to future health risks. The few success stories published so far also suggest that wringing information from the human genome and counselling patients and their families adequately may be too big a burden for medical systems that are already stretched to their limits. “You can’t immediately jump from those few profound but limited stories and think that you can reduce this to practice for clinical care,” says Eric Green, director of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland.

There are also regulatory issues that need to be ironed out:

Moving whole-genome sequencing from research to clinic is beset with challenges. Unlike in research, DNA sequencing that is intended to inform a diagnosis must be done in accredited laboratories, such as those used by Illumina. The institutional review boards that oversee research in humans have not reached a consensus on whether approval is needed for clinical genome sequencing; and the US Food and Drug Administration is yet to work out how to regulate the coming wave of clinical sequencing.

Previously: Researchers analyze family’s whole genome sequences, predict members’ inherited health risks, Economic impact of human genome sequencing, Stanford researchers work on ‘molecular autopsies’ and Whole genome sequencing data vaults into clinic